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‘Dramatic’ inroads against aggressive brain cancer

Cutting-edge therapy shrinks tumors in early glioblastoma trial

Haley Bridger

Mass General Communications

A collaborative project to bring the promise of cell therapy to patients with a deadly form of brain cancer has shown dramatic results among the first patients to receive the novel treatment.

In a paper published Wednesday in The New England Journal of Medicine, researchers from Mass General Cancer Center shared the results for the first three patient cases from a Phase 1 clinical trial evaluating a new approach to CAR-T therapy for glioblastoma.

Just days after a single treatment, patients experienced dramatic reductions in their tumors, with one patient achieving near-complete tumor regression. In time, the researchers observed tumor progression in these patients, but given the strategy’s promising preliminary results, the team will pursue strategies to extend the durability of response.

Left: MRI in Participant 3 before infusion. Right: After infusion on day five.

Image courtesy of The New England Journal of Medicine

“This is a story of bench-to-bedside therapy, with a novel cell therapy designed in the laboratories of Massachusetts General Hospital and translated for patient use within five years, to meet an urgent need,” said co-author Bryan Choi , a neurosurgeon at Harvard-affiliated Mass General and an assistant professor at Harvard Medical School. “The CAR-T platform has revolutionized how we think about treating patients with cancer, but solid tumors like glioblastoma have remained challenging to treat because not all cancer cells are exactly alike and cells within the tumor vary. Our approach combines two forms of therapy, allowing us to treat glioblastoma in a broader, potentially more effective way.”

The new approach is a result of years of collaboration and innovation springing from the lab of Marcela Maus , director of the Cellular Immunotherapy Program and an associate professor at the Medical School. Maus’ lab has set up a team of collaborating scientists and expert personnel to rapidly bring next-generation genetically modified T cells from the bench to clinical trials in patients with cancer.

“We’ve made an investment in developing the team to enable translation of our innovations in immunotherapy from our lab to the clinic, to transform care for patients with cancer,” said Maus. “These results are exciting, but they are also just the beginning — they tell us that we are on the right track in pursuing a therapy that has the potential to change the outlook for this intractable disease. We haven’t cured patients yet, but that is our audacious goal.”

CAR-T (chimeric antigen receptor T-cell) therapy works by using a patient’s own cells to fight cancer — it is known as the most personalized way to treat the disease. A patient’s cells are extracted, modified to produce proteins on their surface called chimeric antigen receptors, and then injected back into the body to target the tumor directly. Cells used in this study were manufactured by the Connell and O’Reilly Families Cell Manipulation Core Facility of the Dana-Farber/Harvard Cancer Center.

CAR-T therapies have been approved for the treatment of blood cancers, but the therapy’s use for solid tumors is limited. Solid tumors contain mixed populations of cells, allowing some malignant cells to continue to evade the immune system’s detection even after treatment with CAR-T. Maus’ team is working to overcome this challenge by combining two previously separate strategies: CAR-T and bispecific antibodies, known as T-cell engaging antibody molecules. The version of CAR-TEAM for glioblastoma is designed to be directly injected into a patient’s brain.

In the new study, the three patients’ T cells were collected and transformed into the new version of CAR-TEAM cells, which were then infused back into each patient. Patients were monitored for toxicity throughout the duration of the study. All patients had been treated with standard-of-care radiation and temozolomide chemotherapy and were enrolled in the trial after disease recurrence.

A 74-year-old man had his tumor regress rapidly but transiently after a single infusion of the new CAR-TEAM cells.
A 72-year-old man was treated with a single infusion of CAR-TEAM cells. Two days after receiving the cells, an MRI showed a decrease in the tumor’s size by 18 percent. By day 69, the tumor had decreased by 60 percent, and the response was sustained for more than six months.
A 57-year-old woman was treated with CAR-TEAM cells. An MRI five days after the infusion showed near-complete tumor regression.

The authors note that despite the remarkable responses among the first three patients, they observed eventual tumor progression in all the cases, though in one case, there was no progression for over six months. Progression corresponded in part with the limited persistence of the CAR-TEAM cells over the weeks following infusion. As a next step, the team is considering serial infusions or preconditioning with chemotherapy to prolong the response.

“We report a dramatic and rapid response in these three patients. Our work to date shows signs that we are making progress, but there is more to do,” said co-author Elizabeth Gerstner, a Mass General neuro-oncologist.

In addition to Choi, Maus, and Gerstner, other authors are Matthew J. Frigault, Mark B. Leick. Christopher W. Mount, Leonora Balaj, Sarah Nikiforow, Bob S. Carter, William T. Curry, and Kathleen Gallagher.

The study was supported in part by the National Gene Vector Biorepository at Indiana University, which is funded under a National Cancer Institute contract.

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Press Release Mar | 13 | 2024

Preliminary Clinical Trial Results Show ‘Dramatic and Rapid’ Regression of Glioblastoma after Next Generation CAR-T Therapy

Members of the Mass General Cancer Center INCIPIENT team (from left to right): Elizabeth Gerstner, MD, William Curry, MD, Marcela Maus, MD, PhD, Bryan Choi, MD, PhD, Kathleen Gallagher, PhD and Matthew Frigault, MD.

Mass General Cancer Center researchers took a new approach to CAR-T, engineering CAR-TEAM cells to treat mixed cell populations within tumors
Working in collaboration with Mass General neurosurgeons, the team tested the approach in a phase 1 clinical trial of patients with recurrent glioblastoma
First three patients in the trial showed dramatic responses within days

A collaborative project to bring the promise of cell therapy to patients with a deadly form of brain cancer has shown dramatic results among the first patients to receive the novel treatment. In a paper published today in The New England Journal of Medicine , researchers from the Mass General Cancer Center, a member of the Mass General Brigham healthcare system, shared the results for the first three patient cases from a phase 1 clinical trial evaluating a new approach to CAR-T therapy for glioblastoma (GBM). The trial, known as INCIPIENT, is designed to evaluate the safety of CARv3-TEAM-E T cells in patients with recurrent GBM. Just days after a single treatment, patients experienced dramatic reductions in their tumors, with one patient achieving near-complete tumor regression. In time, the researchers observed tumor progression in these patients, but given the strategy’s promising preliminary results, the team will pursue strategies to extend the durability of response.

Mass General Cancer Center INCIPIENT team

“This is a story of bench-to-bedside therapy, with a novel cell therapy designed in the laboratories of Massachusetts General Hospital and translated for patient use within five years, to meet an urgent need,” said Bryan Choi, MD, PhD , neurosurgeon and associate director of the Center for Brain Tumor Immunology and Immunotherapy, Cellular Immunotherapy Program, Mass General Cancer Center and Department of Neurosurgery. “The CAR-T platform has revolutionized how we think about treating patients with cancer, but solid tumors like glioblastoma have remained challenging to treat because not all cancer cells are exactly alike and cells within the tumor vary. Our approach combines two forms of therapy, allowing us to treat glioblastoma in a broader, potentially more effective way.”

The new approach is a result of years of collaboration and innovation springing from the lab of Marcela Maus, MD, PhD , director of the Cellular Immunotherapy Program at the Mass General Cancer Center, Paula J. O'Keeffe chair in Oncology, and faculty of the Krantz Family Center for Cancer Research. Maus’ lab has set up a team of collaborating scientists and expert personnel to rapidly bring next generation genetically modified T cells from the bench to clinical trials in patients with cancer.

“We’ve made an investment in developing the team to enable translation of our innovations in immunotherapy from our lab to the clinic, to transform care for patients with cancer,” said Maus. “These results are exciting, but they are also just the beginning—they tell us that we are on the right track in pursuing a therapy that has the potential to change the outlook for this intractable disease. We haven’t cured patients yet, but that is our audacious goal.”

Studies like this one show the promise of cell therapy for treating incurable conditions. Mass General Brigham’s Gene and Cell Therapy Institute, where Maus is Associate Head & Head of Cell Therapies , is helping to translate scientific discoveries made by researchers into first-in-human clinical trials and, ultimately, life-changing treatments for patients. The Institute’s multidisciplinary approach sets it apart from others in the space, helping researchers to rapidly advance new therapies and push the technological and clinical boundaries of this new frontier.

CAR-T therapy works by using a patient's own cells to fight cancer—it is known as the most personalized way to treat cancer. A patient's cells are extracted, modified to produce proteins on their surface called chimeric antigen receptors, and then injected back into the body to target the tumor directly. Cells used in this study were manufactured by the Connell and O’Reilly Families Cell Manipulation Core Facility of the Dana-Farber/Harvard Cancer Center.

CAR-T therapies have been approved for the treatment of blood cancers but the therapy’s use for solid tumors is limited. Solid tumors contain mixed populations of cells, allowing some cancer cells to continue to evade the immune system’s detection, even after treatment with CAR-T. Maus’s team is working to overcome this challenge of tumor heterogeneity with an innovative strategy that combines two previously separate strategies: CAR-T and bispecific antibodies, known as T-cell engaging antibody molecules (TEAMs). The version of CAR-TEAM for glioblastoma is designed to be directly injected into a patient’s brain.

Maus and colleagues previously developed CAR-T cells to target a common cancer mutation known as EGFRvIII, but when that alone had limited effects, her team engineered these CAR-T cells to deliver TEAMs against wild-type EGFR, which is not detected in normal brain tissue but is expressed in more than 80 percent of cases of GBM.

The combination approach showed promise in preclinical models of glioblastoma , encouraging the research team to pursue clinical translation. In collaboration with Mass General neurosurgeons and neuro-oncologists, including Elizabeth Gerstner, MD, and William Curry, MD, as well as specialists in cell therapy delivery, Matthew Frigault, MD, and immunotherapy monitoring, Kathleen Gallagher, PhD, the team launched INCIPIENT (ClinicalTrials.gov number, NCT05660369), a non-randomized, open label, single-site Phase 1 study.

Three patients were enrolled in the study between March 2023 and July 2023. Patients’ T cells were collected and transformed into the new version of CAR-TEAM cells, which were then infused back into each patient. Patients were monitored for toxicity throughout the duration of the study.

All patients had been treated with standard-of-care radiation and temozolomide chemotherapy and were enrolled in the trial after disease recurrence:

A 74-year-old man had his tumor regress rapidly, but transiently after a single infusion of the new CAR-TEAM cells. Blood and cerebrospinal fluid from the patient showed a decrease in EGFRvIII and EGFR copy numbers, eventually becoming undetectable.
A 72-year-old man was treated with a single infusion of CAR-TEAM cells. Two days after receiving CAR-TEAM cells, an MRI showed a decrease in the tumor’s size by 18.5 percent. By day 69, the tumor had decreased by 60.7 percent, and the response was sustained for over 6 months.
A 57-year-old woman was treated with CAR-TEAM cells. An MRI five days after a single infusion of CAR-TEAM cells showed near-complete tumor regression.

The patients tolerated the infusions well, though nearly all had fevers and altered mental status soon after infusion, as was expected from an active CAR-T therapy administered into the fluid around the brain. All patients were observed in the hospital before discharge.

To learn more, visit mauslab.com .

If you are interested in learning more about the INCIPIENT clinical trial, please call 617-724-6226 or email [email protected] . A member of our clinical team will contact you within 48 business hours.

Authorship: In addition to Choi, Maus and Gerstner, other authors include Matthew J. Frigault (MGH), Mark B. Leick (MGH), Christopher W. Mount (MGH), Leonora Balaj (MGH), Sarah Nikiforow (DFHCC), Bob S. Carter (MGH), William T. Curry (MGH), Kathleen Gallagher (MGH).

Disclosures: Disclosure forms provided by the authors is available with the full text of this article at NEJM.org.

Funding: This study was supported by a grant to MVM from Gateway for Cancer Research, the Mass General Cancer Center, Mass General Brigham, and philanthropic gifts. Support was also provided by the National Gene Vector Biorepository at Indiana University which is funded under National Cancer Institute contract HSN261201500003I Task Order No. HHSN26100077.

Paper cited: Choi BD et al. “Rapid Regression of Recurrent Glioblastoma with CARv3-TEAM-E T Cells.” New England Journal of Medicine DOI: 10.1056/NEJMoa2314390

About Mass General Brigham

Mass General Brigham is an integrated academic health care system, uniting great minds to solve the hardest problems in medicine for our communities and the world. Mass General Brigham connects a full continuum of care across a system of academic medical centers, community and specialty hospitals, a health insurance plan, physician networks, community health centers, home care, and long-term care services. Mass General Brigham is a nonprofit organization committed to patient care, research, teaching, and service to the community. In addition, Mass General Brigham is one of the nation’s leading biomedical research organizations with several Harvard Medical School teaching hospitals. For more information, please visit massgeneralbrigham.org .

Video: New CAR-T Therapy Shows Promise for Glioblastoma

A collaborative project to bring the promise of cell therapy to patients with a deadly form of brain cancer has shown dramatic results among the first patients to receive the novel treatment.

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New CAR-T Therapy Shows Promise for Glioblastoma: Why Is This Study Important?

Learn more about the findings and importance of a study led by a research and clinical team from the Mass General Cancer Center who is developing new cell therapy for patients with recurrent glioblastoma.

If you are interested in learning more about the INCIPIENT clinical trial, please call or email us. A member of our clinical team will contact you within 48 business hours.

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New treatment merges two technologies to fight brain cancer.

Bioadhesive nanoparticles within human glioma tumor cells.

A new treatment developed by Yale researchers uses bioadhesive nanoparticles that adhere to the site of the tumor and then slowly release the synthesized peptide nucleic acids that they’re carrying. In this image, the nanoparticles (red) are visible within human glioma tumor cells (green with blue nuclei).

A team of researchers from Yale and the University of Connecticut (UConn) has developed a nanoparticle-based treatment that targets multiple culprits in glioblastoma, a particularly aggressive and deadly form of brain cancer.

The results are published Feb. 8 in Science Advances.

The new treatment uses bioadhesive nanoparticles that adhere to the site of the tumor and then slowly release the synthesized peptide nucleic acids that they’re carrying. These peptide nucleic acids target certain microRNAs — that is, short strands of RNA that play a role in gene expression. Specifically, they’re directed at a type of overexpressed microRNA known as “oncomiRs” that lead to the proliferation of cancer cells and growth of the tumor. When the peptide nucleic acids attach to the oncomiRs, they stop the tumor-promoting activity.

The laboratories of professors Mark Saltzman of Yale and Raman Bahal of the University of Connecticut collaborated on the treatment system. Unlike similar efforts that target only one oncomiR at a time, this treatment targets two, making its effect on cancer cells stronger, the researchers say. The test mice who received the treatment lived for a significantly longer time than the control mice.

“ The treatment can knock down both targets at the same time, which turns out to have a remarkably more powerful result, as we saw with the increased survival results,” said Saltzman, the Goizueta Foundation Professor of Biomedical Engineering, Chemical & Environmental Engineering & Physiology and member of Yale Cancer Center. “These results are the best I've ever seen in this sort of aggressive brain tumor.”

One challenge in developing the treatment was designing the anti-cancer agents, known as antimiRs, so that two different ones could fit in a single nanoparticle.

“ We synthesized all these compounds and came up with the idea that you don't have to target one oncomiR at a time,” said Bahal, associate professor of pharmaceutics at UConn. “Now we can think about multiple oncomiR targets.”

For this work, the researchers targeted the oncomiRs known as miR-10b and miR-21, which are both very common in glioblastoma. Future treatments, though, can be easily tailored for specific patients. For instance, if a biopsy of a patient’s tumor produces a profile showing the proliferation of different oncomiRs, the treatment could be appropriately altered.

Saltzman calls the treatment “a marriage of two technologies.”

“ One is the bioadhesive nanoparticle technology, which we had developed earlier, and marrying it to this peptide nucleic acid technology that Raman has perfected,” he said.

Because the treatment is localized to the tumor site, Bahal noted that both the synthesized nucleic acids and the nanoparticles that deliver them to the tumor site are nontoxic. Also critical to the treatment’s success is that the particles and the agent it releases remain at the tumor site for about 40 days. Conventional site-specific treatments tend to wash away fairly quickly.

“ These are high-binding molecules that are scalable and effective simultaneously,” Bahal said. “It’s targeted and stays there. Traditional molecules have had many challenges in terms of toxicity.”

Ideally, the delivery system would be applied as part of a larger treatment regimen.

“ We designed it to be an add-on to what physicians do already,” Saltzman said. “They would do a surgery, then they infuse our nanoparticles, and then they give chemotherapy and/or radiation in the way that they normally do. We're expecting that this would lead to a better result because the nanoparticle/anti-microRNA is sensitizing the cells to the chemotherapy and the radiation therapy.”

The study’s other authors are, from Yale, Yazhe Wang, Hee-Won Suh, Yong Xiao, Yanxiang Deng, Rong Fan, Anita Huttner, and Ranjit S. Bindra; and from UConn, Shipra Malik and Vijender Singh.

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Customized drug to kill brain cancer cells

At a glance.

Researchers designed a new type of drug that causes lethal DNA damage in a type of brain cancer called glioblastoma, but not in normal cells.
In preliminary studies in mice, the most effective of the experimental drugs suppressed tumor growth without causing side effects.

Illustration of DNA helix broken in the middle

A type of tumor called glioblastoma is the most common brain cancer in adults. It’s also one of the most lethal tumor types overall. Only about 5% of people with glioblastoma will be alive five years after diagnosis.

When DNA gets damaged, cells use specialized molecular pathways to fix it. But about half of glioblastomas have low levels of a protein that’s important for DNA repair called O6-methylguanine methyl transferase (MGMT). Loss of MGMT makes these tumors sensitive to a combination of radiation therapy and a DNA-damaging drug called temozolomide (TMZ). However, tumor cells often quickly develop resistance to TMZ. This resistance is driven by mutations in the genes that control another DNA-repair pathway known as the mismatch repair pathway.

An NIH-funded research team led by Drs. Ranjit Bindra and Seth Herzon from Yale University have been looking for new ways to turn glioblastoma’s loss of MGMT into a vulnerability. They created a new type of drug, similar in structure to TMZ, that was designed to selectively kill cells that lack MGMT while sparing normal cells.

The new drugs, like TMZ, create a type of DNA damage that can be quickly repaired by MGMT. But if a cell lacks MGMT, the drugs then cause a further type of DNA damage, known as an interstrand cross-link, that kills cancer cells regardless of whether the mismatch repair pathway is altered. Healthy cells should be able to use MGMT to repair the early damage and remain unaffected.

The team reasoned that this approach could specifically kill TMZ-resistant glioblastoma cells while sparing normal cells. They tested their experimental compounds in human glioblastoma cells and then in mouse models of brain cancer. The study results were published on July 29, 2022, in Science .

In the laboratory, the compounds selectively killed cells that lacked MGMT. The most potent of the compounds, called KL-50, killed MGMT-deficient cells regardless of how well the mismatch repair pathway worked. But the compound was not toxic to normal human cells.

Further experiments showed that KL-50 was working as expected, producing interstrand cross-links in cells that lacked MGMT. Other types of DNA damage didn’t seem to affect how or whether KL-50 killed cells.

The researchers then tested KL-50 in mice with human glioblastoma cells implanted in their brains. While TMZ had no effect, KL-50 effectively suppressed tumor growth, whether given orally or as an injection. At all but the highest doses tested, no toxicity was observed, indicating that normal cells weren’t being damaged by KL-50.

More work in animals is needed before this concept can be tested in people. But many cancer types bypass specific types of DNA repair to resist treatment, so similar drugs may have the potential to improve the treatment of other types of tumors as well. The researchers have founded a company called Modifi Bio that aims to conduct clinical trials of these new compounds.

“These molecules are particularly promising as therapeutics because of their ability to directly modify the DNA of cancer cells, which we believe will not only be effective in fighting cancer but will also allow us to overcome key resistance mechanisms,” Herzon says.

—by Sharon Reynolds

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Powerful chemotherapy drug reaches brain tumors using novel ultrasound technology

Feinberg School of Medicine

A major impediment to treating the deadly brain cancer glioblastoma has been that the most potent chemotherapy can’t permeate the blood-brain barrier to reach the aggressive brain tumor.

But now Northwestern Medicine scientists report results of the first in-human clinical trial in which they used a novel, skull-implantable ultrasound device to open the blood-brain barrier and repeatedly permeate large, critical regions of the human brain to deliver chemotherapy that was injected intravenously.

The four-minute procedure to open the blood-brain barrier is performed with the patient awake, and patients go home after a few hours. The results show the treatment is safe and well tolerated, with some patients getting up to six cycles of treatment.

This is the first study to successfully quantify the effect of ultrasound-based blood-brain barrier opening on the concentrations of chemotherapy in the human brain. Opening the blood-brain barrier led to an approximately four- to six-fold increase in drug concentrations in the human brain, the results showed.

Scientists observed this increase with two different powerful chemotherapy drugs, paclitaxel and carboplatin. The drugs are not used to treat these patients because they do not cross blood-brain barrier in normal circumstances.

In addition, this is the first study to describe how quickly the blood-brain barrier closes after sonication. Most of the blood-brain barrier restoration happens in the first 30 to 60 minutes after sonication, the scientists discovered. The findings will allow optimization of the sequence of drug delivery and ultrasound activation to maximize the drug penetration into the human brain, the authors said.

“This is potentially a huge advance for glioblastoma patients,” said lead investigator Dr. Adam Sonabend , an associate professor of neurological surgery at Northwestern University Feinberg School of Medicine and a Northwestern Medicine neurosurgeon.

Temozolomide, the current chemotherapy used for glioblastoma, does cross the blood-brain barrier, but is a weak drug, Sonabend said.

The paper was published May 2 in The Lancet Oncology.

The blood-brain barrier is a microscopic structure that shields the brain from the vast majority of circulating drugs. As a result, the repertoire of drugs that can be used to treat brain diseases is very limited. Patients with brain cancer cannot be treated with most drugs that are otherwise effective for cancer elsewhere in the body, as these do not cross the blood-brain barrier. Effective repurposing of drugs to treat brain pathology and cancer require their delivery to the brain.

In the past, studies that injected paclitaxel directly into the brain of patients with these tumors observed promising signs of efficacy, but the direct injection was associated with toxicity such as brain irritation and meningitis, Sonabend said.

Blood-brain barrier recloses after an hour

The scientists discovered that the use of ultrasound and microbubble-based opening of the blood-brain barrier is transient, and most of the blood-brain barrier integrity is restored within one hour after this procedure in humans.

“There is a critical time window after sonification when the brain is permeable to drugs circulating in the bloodstream,” said Sonabend, also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Previous human studies showed that the blood-brain barrier is completely restored 24 hours after brain sonication, and based on some animal studies, the field assumed that the blood-brain barrier is open for the first six hours or so. The Northwestern study shows that this time window might be shorter.

In another first, the study reports that using a novel skull-implantable grid of nine ultrasound emitters designed by French biotech company Carthera opens the blood-brain barrier in a volume of brain that is nine times larger than the initial device (a small single-ultrasound emitter implant). This is important because to be effective, this approach requires coverage of a large region of the brain adjacent to the cavity that remains in the brain after removal of glioblastoma tumors.

Clinical trial for patients with recurrent glioblastoma

The findings of the study are the basis for an ongoing phase 2 clinical trial the scientists are conducting for patients with recurrent glioblastoma. The objective of the trial — in which participants receive a combination of paclitaxel and carboplatin delivered to their brain with the ultrasound technique — is to investigate whether this treatment prolongs survival of these patients. A combination of these two drugs is used in other cancers, which is the basis for combining them in the phase 2 trial.

In the phase 1 clinical trial reported in this paper, patients underwent surgery for resection of their tumors and implantation of the ultrasound device. They started treatment within a few weeks after the implantation.

Scientists escalated the dose of paclitaxel delivered every three weeks with the accompanying ultrasound-based blood-brain barrier opening. In subsets of patients, studies were performed during surgery to investigate the effect of this ultrasound device on drug concentrations. The blood-brain barrier was visualized and mapped in the operating room using a fluorescent dye called fluorescein and by MRI obtained after ultrasound therapy.

“While we have focused on brain cancer (for which there are approximately 30,000 gliomas in the U.S.), this opens the door to investigate novel drug-based treatments for millions of patients who suffer from various brain diseases,” Sonabend said.

Other Northwestern authors include: A. Gould, C. Amidei, R. Ward, K. A. Schmidt, D.Y. Zhang, C. Gomez, J.F. Bebawy, B.P. Liu, I.B. Helenowski, R.V. Lukas, K. Dixit, P. Kumthekar, V. A. Arrieta. Lesniak, H. Zhang and R. Stupp.

The work is funded by the National Cancer Institute of the National Institutes of Health, the Lou and Jean Malnati Brain Tumor Institute of the Lurie Cancer Center and SPORE support from the Moceri Family Foundation and the Panattoni family.

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A new branch of oncology, cancer neuroscience, offers hope for hard-to-treat brain tumors

To drive their growth, many tumors hijack nervous system signals, including those needed for brain plasticity. Stanford Medicine discoveries are opening a promising new branch of oncology research.

November 1, 2023 - By Erin Digitale

Michelle Monje's team has found that brain tumors can exploit the biological machinery of brain plasticity to drive their own growth. Timothy Archibald

Cancer cells hijack normal biological processes, allowing them to multiply. For example, tumors spur construction of new blood vessels, building themselves “highways” to supply nutrients.

Researchers have known about cancer’s blood vessel infiltration for decades, but it was only in the past few years that Stanford Medicine scientists and their colleagues discovered that tumors don’t just tap the body’s highway system; they can also infiltrate and exploit its “telecommunications.”

To put it in physiologic terms, tumors don’t just grow blood vessels; they also wire themselves into the nervous system. Certain brain cancers form working electrical connections with nearby nerves, then use the nerves’ electrical signals for their own purposes, the research has shown. The latest findings , published Nov. 1 in Nature , demonstrate that these tumors can even hijack the biological machinery of brain plasticity — which enables learning — to drive their own growth.

The discoveries have opened a novel field of medicine called cancer neuroscience. It offers new opportunities to target some of the deadliest forms of cancer, including brain tumors that are almost always lethal. Scientists are especially intrigued by the cancer treatment potential of FDA-approved drugs developed for other neurological disorders, such as epilepsy. It turns out that several such medications interrupt neural signals now understood to fuel certain cancers.

“Since 2015, when we first published that neuronal activity actually drives the growth of cancer in multiple brain tumor types, there has been a very exciting explosion of studies on these interactions,” said Michelle Monje , MD, PhD, a professor of neurology and neurological sciences and senior author of the new Nature study, whose team’s discoveries form the foundation of cancer neuroscience. “This is clearly a major set of interactions crucial to tumor biology that we had missed.”

Tumors’ hidden talent

Why did cancer’s ability to twine into the nervous system stay hidden from researchers for so long? A focus on how malignant and healthy cells differ may provide an explanation.

“People tend to think of cancer as more like an infectious disease, something that’s occurring but has nothing really to do with our body,” said Kathryn Taylor , PhD, lead author of the Nature study and a postdoctoral scholar in neurology and neurological sciences. “Whereas really, particularly in pediatric tumors, it’s a developmental disease.”

Kathryn Taylor

Small missteps in development underlie some of the worst childhood tumors, Monje’s team has shown.

This is true of one especially horrible type of brain cancer, diffuse intrinsic pontine glioma. Known as a high-grade glioma, DIPG arises in the brainstem that controls essential body functions such as breathing and heartbeat. It entwines with healthy cells, meaning it can’t be removed surgically. The five-year survival rate is 1%.

In 2011, Monje showed that DIPG arises from a type of healthy brain cells called oligodendrocyte precursor cells. Normally, OPCs develop into brain cells that produce insulating myelin, a substance that coats nerves and speeds up their electrical signals. This “neuron maintenance” job requires the healthy cells to stay in close communication with adjacent neurons, receiving and responding to neurons’ electrical and chemical signals.

DIPG cells respond to the same signals, but use them to fuel malignant growth, Monje’s team has demonstrated.

“The cancer is diffusely and widely invading the nervous system because that’s advantageous for it,” Monje said. “It integrates into neural circuits.”

Hardwired into the brain

In 2019, Monje’s team published a groundbreaking study showing that DIPG and similar cancers form working synapses with neurons. Synapses are the nervous-system widgets that allow electrical signals to cross the gaps between one cell and the next. Via these connections and additional means of electrical signaling, about half of all glioma cells in a given tumor have some type of electrical response to signals from healthy neurons, the research showed.

Adjacent brain cells also signal to each other with proteins that cross the space between cells to trigger complex intracellular responses. Such responses include molecular signals that underlie the neural plasticity needed for learning and memory. (The brain physically changes as we learn; these signals are part of that change.)

The new study investigates tumor responses to brain-derived neurotrophic factor, or BDNF, a protein that helps enable brain plasticity. With BDNF, the brain can strengthen synaptic connections between cells, enforcing a neural circuit that’s built as we learn.

The tumors use BDNF the same way healthy brain cells do, the researchers showed: BDNF travels from neurons to tumor cells to trigger a chain reaction inside the tumor that ultimately helps the tumor form more and stronger synapses.

During the studies of BDNF, which Taylor led, one key experiment showed that when the cell machinery triggered by BDNF was activated more strongly, the tumor cells responded with stronger electrical currents, which then fueled their growth. In other words, cancer uses the brain’s learning machinery to grow.

“We looked at the electrophysiological recordings and seeing this increase was … I will never forget that. It was pretty incredible,” Taylor said. “What was so striking about that finding was that not only can the cells connect, they also dynamically respond to input from healthy brain cells. The tumor cell is not only plugging into the network, it’s increasing its connection to that plug.”

Prior research by Monje’s team showed that another mechanism involved in neural plasticity, driven by a signaling molecule called neuroligin 3, works independently of BDNF to also increase neuron-to-glioma synapses.

It’s unsettling that tumors use brain activity to grow, Taylor admits. “It’s the same electrical activity that helps us think, move, feel, touch and see,” she said. “Cancer is plugging into that and using that to grow, invade and even occur in the first place.”

Hope for treatment

But understanding these unsettling interactions between tumors and the healthy nervous system presents new options for cancer treatment.

In the Nature study, Taylor, Monje and their team showed that medications aimed at the BDNF receptor, which were developed for other forms of cancer that have mutations affecting the receptor, work surprisingly well at slowing the growth of DIPG and other gliomas that do not typically have genetic alterations in that receptor.

We understand enough about this disease now to have lots of really rational ways to try to fight it.

Other drugs, including certain painkillers, anti-seizure medications and blood pressure medications also have potential as cancer fighters. A detailed understanding of how the tumors tap nerve signals to grow provides a huge leg up in cancer treatment research, as scientists can match what’s in the “medicine cabinet” of FDA-approved neuroactive drugs with their new knowledge of how cancers operate.

Stopping the worst gliomas, including DIPG, will require a mixture of tactics, from cancer neuroscience and from other oncology specialties, Monje said. Perhaps doctors can start treatment with neurological medications that slow the tumors’ growth, then give immunotherapies — such as specially engineered immune cells called CAR-T cells, which her team is also studying as a treatment for DIPG — as a second line of attack. Such a strategy might give immunotherapy treatments enough of a head start to enable them to outpace the rapidly growing tumors.

Monje’s team also plans to learn more about how electrical currents prompt tumor growth. “As we uncover granular details of those voltage-sensitive mechanisms, that will open up a whole additional realm of potential therapeutic targets,” she said.

Cancer neuroscience is also offering clues about how to tackle tumors outside the brain. Nerves normally send signals to stem cells that help regulate healthy organ development and repair, and research is increasingly documenting that these signals can fuel cancer. “There are critically important roles for the nervous system in pancreas, prostate, breast, colon, gastric, skin, and head and neck cancers — a very long list,” Monje said, adding that there’s also evidence that tumors that began outside the nervous system can piggyback on normal nerve signals once they invade the brain.

Hope for the future

For Monje, who was inspired to study DIPG more than 20 years ago, at a time when the biology of the disease was completely unknown, the new options are heartening. The old way of trying to treat the deadly tumor — a sort of throw-the-spaghetti-at-the-wall approach, using drugs not fitted to how the tumor grows — is obsolete, she said.

“This is a connected tumor; it’s connecting to the entire nervous system. We have to disconnect it,” she said. “We understand enough about this disease now to have lots of really rational ways to try to fight it.”

Researchers contributed to the new study from the Weizmann Institute of Science in Rehovot, Israel; Massachusetts General Hospital; Harvard Medical School; and the Broad Institute, a collaboration of the Massachusetts Institute of Technology and Harvard.

The study was funded by grants from the National Institute of Neurological Disorders and Stroke (grant R01NS092597), the NIH Director’s Pioneer Award (DP1NS111132), the National Cancer Institute (P50CA165962, R01CA258384 and U19CA265404), Abbie’s Army, the Robert J. Kleberg Jr. and Helen C. Kleberg Foundation, the Gatsby Charitable Foundation, Cancer Research UK, Damon Runyon Cancer Research, ChadTough Defeat DIPG, the Stanford Maternal and Child Health Research Institute, N8 Foundation, the McKenna Claire Foundation, the Kyle O’Connell Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the Waxman Family Research Fun, and the Will Irwin Research Fund.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu .

Hope amid crisis

Psychiatry’s new frontiers

Stanford Medicine magazine: Mental health

Experimental vaccine shows promise in delaying the return of aggressive brain tumor

John Wishman was diagnosed with the deadliest form of brain cancer, glioblastoma , in fall 2020.

Two and a half years later, he’s still traveling and enjoying life — a rarity for a cancer with an average survival time of just 12 to 18 months.

Wishman, 61, of Buffalo, New York, attributes that to an experimental vaccine that’s designed to delay the progression of the tumor. The vaccine, called SurVaxM, targets a protein found in tumors called survivin, named for the role it’s thought to play in the survival of cancer cells. Get rid of survivin, the thinking goes, and the cancer cells will die.

It sounds like a far-fetched dream: a vaccine that can delay the return of glioblastoma, one of the deadliest and treatment-resistant cancers. More than 14,000 people in the U.S. were diagnosed last year, according to Tom Halkin, a spokesperson for the National Brain Tumor Society , a nonprofit group. It accounts for almost half of all malignant brain tumors. The disease is devastating for patients and families; the five-year survival rate is 6.8%.

Wishman got the vaccine through an expanded access program — sometimes called compassionate use — that allows seriously ill patients to gain access to experimental medicines. His daughter Lydia is a nurse at Roswell Park Comprehensive Cancer Center, where researchers are studying the drug.

In an early clinical trial, SurVaxM was found to extend survival time for people diagnosed with the brain cancer to 26 months, on average. Now the drugmaker, New York-based MimiVax, is enrolling patients in a larger trial, hoping to confirm the results. The expanded access program is no longer available.

The new trial will enroll up to 270 patients. It is expected to take place at more than 10 sites in the U.S. and China and will compare the shot to patients who receive standard care.

Tracey Kassman, 65, enrolled in April 2022, three months after being diagnosed with glioblastoma. That same month, she received her first shot.

Kassman, a retired lawyer from Buffalo, now gets a shot once every two months. But because the trial is randomized and double-blinded, neither Kassman nor her doctors know if she’s getting the vaccine or a placebo.

“It’s been at times a leap of faith,” she said, “because right before I get the shot, I have this MRI, and every time I have the MRI, I’m like, ‘OK, well this could be it.’”

Why is glioblastoma so hard to treat?

Glioblastomas are aggressive cancers: They grow quickly and tend to have invaded other parts of the brain and spinal cord by the time a person is diagnosed.

Surgical removal of the entire tumor is almost impossible.

“It’s like octopus tentacles reaching into other parts of the brain,” said Honggang Cui, an associate professor of chemical and biomolecular engineering at Johns Hopkins Whiting School of Engineering.

Treatment typically involves surgery, chemotherapy and radiation, Cui said. But unless every cancer cell is eliminated, the tumor often comes back in what’s referred to as recurrence.

SurVaxM works by training the immune system to target and attack the cancer cells, so if they do return, the body can pick them off, preventing a new tumor from growing, said Michael Ciesielski, the CEO of MimiVax.

Tracey Kassman was diagnosed with glioblastoma in January 2022.

The approach is “promising,” Cui said. “This could bring hope to people who are impacted by GBM.”

Participants in the trial will first have surgery to remove as much of the tumor as possible, followed by radiation and chemotherapy, with a drug called temozolomide, said Dr. Robert Fenstermaker, the chair of the neurosurgery department at the Roswell Park Comprehensive Cancer Center and co-creator of SurVaxM.

“There’s usually a hiatus of about a month while radiation is still working, and it’s during that phase that we like to start the vaccination because that’s when the immune system has been rejuvenated,” he said.

The vaccine — given in the arm just like a flu shot or Covid shot — consists of four doses, spread out over two months, followed by a booster dose every two months. Participants in the trial will either get the real vaccine for each shot or a shot of a placebo every time. Participants will also get a brain scan every two months to monitor for signs of progression.

A need for different approaches

SurVaxM isn’t the first attempt to create a vaccine to delay the recurrence of glioblastoma. Other cancer vaccines have targeted survivin, but none of them so far have reached mid- to late-stage clinical trials, according to Ciesielski.

Dr. Alyx Porter, a neuro-oncologist at the Mayo Clinic in Phoenix, said the approach is different from what’s been tried in the past.

Targeted therapies like checkpoint inhibitors , for example, have grown in popularity in recent years, improving survival in people with cancer including those with breast or lung cancers. But these drugs are far less effective for brain tumors, because they can’t cross the blood-brain barrier, a network of blood vessels that keeps foreign substances from entering the brain.

The belief, Porter said, is that the antibodies generated by a vaccine would be able to reach the brain. But, she added, “the proof will be in the pudding with the trial.”

Results are still a ways off: According to Ciesielski, the company doesn’t expect its earliest results from the Phase 2b trial until mid-2024, and the trial likely won’t be completed for another 18 to 24 months after that. If successful, the company will have to conduct a larger Phase 3 clinical trial.

The high mortality rates of glioblastoma “warrants people pressing the edge and seeking out new treatments and allowing us to really maximize where immunotherapy may benefit,” said Porter, who is not involved with the SurVaxM trial.

So far, the drug appears to be safe, Fenstermaker said. Known side effects from the vaccine include fever, itching, redness and muscle aches.

Ciesielski said the company is also looking to use the vaccine on other forms of cancer, including multiple myeloma and neuroendocrine tumors , a rare form of cancer that can develop wherever there are neuroendocrine cells, which are found in various organs including the lungs, pancreas and gastrointestinal tract.

For Kassman, of Buffalo, New York, she feels “incredibly lucky” for a chance at a possible treatment.

“I could have ignored this whole thing again for a couple of weeks,” she said, “and I might not be here to talk about this with you.”

Follow NBC HEALTH on Twitter & Facebook .

Berkeley Lovelace Jr. is a health and medical reporter for NBC News. He covers the Food and Drug Administration, with a special focus on Covid vaccines, prescription drug pricing and health care. He previously covered the biotech and pharmaceutical industry with CNBC.

National Cancer Institute - Cancer.gov

A New Vaccine to Target Treatment-Resistant Glioblastoma

CD4 and CD8 staining of mouse brain tumor tissue confirming that immune cells called CD4+ T cells and CD8+ T cells are both increased in the vaccine group.

The rWTC-MBTA vaccine extended survival and prevented tumor recurrence in preclinical brain tumor models.

Raleigh mcelvery, scientific communications editor, march 8, 2024.

Glioblastoma is the most common primary brain cancer in adults and remains one of the most challenging cancers to treat. People with these tumors usually undergo surgery, followed by radiation and chemotherapy. However, glioblastomas often resist treatment. For decades, there’s been little improvement in disease outcomes. The median length of survival is eight months , and the five-year relative survival rate is just 6.9 percent .

One problem is that the immune system doesn’t automatically view glioblastomas as a threat. In fact, it takes a lot to elicit an immune response in the brain. That’s because the stakes are high: If the body mistakenly attacks its own healthy tissue, the impact on brain function could be catastrophic. As a result, immune cells don’t usually target the tumor, allowing it to grow.

To boost the immune system’s response, researchers at the NCI Center for Cancer Research’s Neuro-Oncology Branch (NOB) have created a cancer vaccine that can activate immune cells to recognize and attack glioblastomas. In a recent study published in Advanced Science , they showed that their vaccine (called the rWTC-MBTA vaccine) could extend survival and prevent tumor recurrence in mouse models. Eventually, they hope this vaccine could supplement conventional treatments to improve care for people with glioblastoma.

The researchers previously tested their vaccine in preclinical models of breast cancer and melanoma , but this is the first time they’ve applied it to brain tumors.

“We were very excited to see how well the rWTC-MBTA vaccine performed in glioblastoma models,” says Zhengping Zhuang, M.D., Ph.D. , the study’s senior author and head of the NOB’s Cancer Stem Cell Biology Research Program . “Our vaccine has the potential to enhance more traditional therapies to extend survival in people with glioblastoma. It could also be applied to address other hard-to-treat tumors.”

Boosting the Immune System to Attack Glioblastomas

Immunotherapies are treatments that harness the immune system to target tumors. At the moment, there are only a handful of immunotherapies being tested in clinical trials for brain cancers , including immune checkpoint inhibitors and CAR T-cell therapies. Although these immunotherapies show promise for treating multiple cancers, they have been relatively ineffective against glioblastoma. Immune checkpoint inhibitors are often unable to trigger an immune response because of the brain’s unique environment that suppresses immune cell activity. CAR T-cell therapies often fail because glioblastomas lack a universal identifying feature that the treatment can target across all tumors.

To address these limitations, many researchers are exploring cancer vaccines that help the immune system recognize and eliminate glioblastomas. One of these vaccines, called DCVax-L, was recently tested in a phase 3 clinical trial . Dr. Zhuang was inspired by this work and decided to create a vaccine that was less time-consuming and less expensive to produce.

His team’s rWTC-MBTA vaccine contains two main components. The first, rWTC, stands for “irradiated whole tumor cells.” The researchers took glioblastoma cells and exposed them to enough radiation treatment that the cells could no longer grow, but not so much that they died immediately. The researchers then mixed the irradiated cells with the second component: MBTA.

MBTA consists of a cocktail of ingredients. One of them is a sugar found in yeast. During the mixing process, it becomes embedded in the irradiated tumor cells and acts like bait to attract immune cells, including one type called dendritic cells. The immune cells are drawn to it because they are programmed to kill microorganisms, including yeast.

The rest of the MBTA ingredients help to boost the immune system’s response once the immune cells home in on the irradiated cells. If the yeast sugar is the baited hook, then the rest of the MBTA components are the bucket of “chum” that draws even more curious fish. This two-pronged approach helps establish both innate immunity (an immediate, general immune response) and adaptive immunity (a more specialized and sustained response) against the tumor.

Other researchers have tried using MBTA alone to treat tumors. While this does boost the immune response, it doesn’t direct the immune cells to target glioblastomas specifically.

The study’s first author, NOB Staff Scientist Herui Wang, Ph.D., saw only modest results when he treated mouse models of glioblastoma with just MBTA. Treating them with just the rWTC component only had a weak effect as well. This indicated that both the rWTC and MBTA components were needed to initiate a potent immune response and improve survival. In fact, the cancer completely disappeared in seven out of 10 mice who received the rWTC-MBTA vaccine three times a week for four weeks. The vaccine even extended survival in a specific mouse model of glioblastoma that is highly resistant to immunotherapy.

“We were thrilled to see the brain tumors regress in our glioblastoma models,” Dr. Wang says. “In many cases, we were able to kill and remove the tumor instead of simply delaying growth by a few months. I hope the same outcome can be achieved in a clinical setting.”

The vaccine also helped prevent the tumors from coming back. After several months, the researchers reimplanted tumor cells back into the mice whose tumors had completely disappeared. This time, though, their immune cells remembered the tumor and stopped it from regrowing.

Illustration showing that irradiated whole tumor cells (rWTC) are mixed with MBTA to make the vaccine.

Advancing to Clinical Trials

Dr. Zhuang’s team is now making plans to help develop a clinical trial to test their rWTC-MBTA vaccine. The researchers hope to take tumor cells from the patient during surgery, treat the cells with radiation in the lab, combine them with MBTA, and inject them into the patient’s arm.

Dr. Zhuang believes their vaccine would be especially effective in combination with other conventional treatments. For example, it could be injected after chemotherapy to remove any residual tumor cells. It could also help convert immunogenically “cold” tumors that don’t trigger an immune response to “hot” tumors that allow immune checkpoint inhibitors to work. One of the next steps, the researchers explain, will be to test whether the brain’s protective blood-brain barrier affects the vaccine’s ability to reach the tumor site.

“Our vaccine is not a cure-all,” Dr. Zhuang says, “but it does have the potential to address the shortcomings in our current treatment strategies for glioblastoma—and hopefully prevent recurrence.”

Top image caption: CD4 and CD8 staining results confirmed that immune cells called CD4+ T cells (A) and CD8+ T cells (B) are both increased in the brain tumors of the vaccine group. Credit: Courtesy of the researchers

Researchers create 'chameleon' compound that targets drug-resistant brain cancers

by Jim Shelton, Yale University

In a new study, Yale researchers describe how a novel chemical compound attacks drug-resistant brain tumors without harming healthy surrounding tissue.

The research, published in the Journal of the American Chemical Society , is a crucial step in the development of so-called "chameleon compounds" that may be used to target an array of pernicious cancers.

Every year, an estimated 20,000 Americans are diagnosed with glioma, a malignant tumor in the brain and spinal cord. Of those cases, about 13,000 are glioblastomas, the most aggressive subtype of malignant brain tumor among adults.

For decades, glioblastoma patients have been treated with a drug called temozolomide. However, the majority of patients develop resistance to temozolomide within a year. The five-year survival rate for glioblastoma patients is less than 5%.

In 2022, Yale chemist Seth Herzon and Yale radiation oncologist Dr. Ranjit Bindra developed a new strategy for targeting glioblastomas more effectively. They created a class of cancer-fighting molecules—chameleon compounds—that exploit a defect in a DNA repair protein known as O6-methylguanine DNA methyltransferase (MGMT).

In many cancer cells , including glioblastomas, the MGMT protein is missing. The new chameleon compounds are designed to damage DNA in tumor cells that lack MGMT.

The chameleon compounds initiate DNA damage by depositing primary lesions on DNA that evolve over time into highly toxic secondary lesions known as interstrand cross-links. MGMT protects the DNA of healthy tissue by repairing the primary lesions before they can transform into the deadly interstrand cross-links.

For their new study, co-corresponding authors Herzon and Bindra focused on their lead chameleon, KL-50.

"We used a combination of synthetic chemistry and molecular biology studies to elucidate the molecular basis for our earlier observations, as well as the chemical kinetics that give rise to the unique selectivity of these compounds," said Herzon, the Milton Harris '29 Ph.D. Professor of Chemistry in Yale's Faculty of Arts and Sciences. "We show that KL-50 is unique in that it forms DNA interstrand cross-links only in a DNA repair defective tumor. It spares healthy tissue."

It is an essential distinction, the researchers said. A number of other cancer-fighting compounds have been developed that trigger interstrand cross-links—but they are not selective for tumor cells, which limits their utility.

The secret to KL-50's success is in its timing, the researchers said. KL-50 generates interstrand cross-links more slowly than other cross-linking agents. This delay gives healthy cells enough time to use MGMT to prevent the cross-links from occurring.

"This unique profile suggests its potential for the treatment of drug-resistant glioblastoma, an area of great unmet need in the clinic," said Bindra, the Harvey and Kate Cushing Professor of Therapeutic Radiology at Yale School of Medicine. Bindra is also scientific director of the Chênevert Family Brain Tumor Center at Smilow Cancer Hospital.

Herzon and Bindra said that more broadly, their research underscores the importance of considering the rates of chemical DNA modification and biochemical DNA repair. They say they can use this strategy to develop treatment for other cancers harboring specific, tumor-associated DNA repair defects.

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8 innovations in neuroscience and brain research at Mayo Clinic

Mayo Clinic Staff

Researchers discover new molecular drug targets for progressive neurological disorder

Progressive supranuclear palsy (PSP) is an uncurable brain disorder marked by walking and balance difficulties. Its symptoms mimic Parkinson's disease and dementia. Mayo researchers and collaborators have outlined new therapeutic targets that may lead to future treatments for PSP as well as Alzheimer's disease and related disorders.

"This research enhances our understanding of progressive supranuclear palsy and other related, incurable neurological disorders," says the study's senior author, Nilufer Ertekin-Taner, M.D., Ph.D., a Mayo Clinic neurologist and neuroscientist. "Moving forward, we can target these specific genes or others that are biologically related to them to develop a potential treatment for this untreatable disease."

The researchers profiled 313 tumor biopsies from 68 high-grade glioma (HGG) patients. This image is a representation of the 3-dimensional relationship of multiple tissue biopsies from a single patient’s HGG tumor. The different colors depict different versions of genetic mutations relative to the epidermal growth factor receptor gene.

Mapping cell behaviors in high-grade glioma to improve treatment

High-grade gliomas are cancerous tumors that spread quickly in the brain or spinal cord. Mayo Clinic researchers found invasive brain tumor margins of high-grade glioma contain biologically distinct genetic and molecular alterations that indicate aggressive behavior and disease recurrence. They also found that MRI techniques, such as dynamic susceptibility contrast and diffusion tensor imaging, can help distinguish between the genetic and molecular alterations of invasive tumors, which is important for clinically characterizing areas that are difficult to surgically biopsy.

"We need to understand what is driving tumor progression," says lead author Leland Hu, M.D. , a neuroradiologist at Mayo Clinic. "Our results demonstrate an expanded role of advanced MRI for clinical decision-making for high-grade glioma."

Physician, holding a pencil, viewing medical images of brain scans on a monitor.

Researchers identify new criteria to detect rapidly progressive dementia

Rapidly progressive dementia (RPD) is caused by several disorders that quickly impair intellectual functioning and interfere with normal activities and relationships. If patients' symptoms appear suddenly causing rapid decline, a physician may diagnose RPD. These patients can progress from initial symptoms of dementia to complete incapacitation, requiring full-time care, in less than two years. Mayo Clinic researchers have identified new scoring criteria allowing for the detection of treatable forms of RPD with reasonably high confidence during a patient's first clinical visit. This scoring criteria may allow physicians to substantially reduce the time it takes to begin treatment.

"Many conditions that cause rapidly progressive dementia can be treated and even reversed. We found that more than half of the patients in our study with rapidly progressive dementia had a treatable underlying condition. We may be able to identify many of these patients early in the symptomatic course by intentionally searching for key clinical symptoms and exam findings and integrating these with results of a brain MRI and spinal tap," says the study's senior author, Gregg Day, M.D. , a clinical researcher at Mayo Clinic.

Global consortium to study Pick’s disease, rare form of early-onset dementia

Pick's disease , a neurodegenerative disease of unknown genetic origin, is a rare type of frontotemporal dementia that affects people under the age of 65. The condition causes changes in personality, behavior and sometimes language impairment. In patients with the disease, tau proteins build up and form abnormal clumps called Pick bodies, which restrict nutrients to the brain and cause neurodegeneration. Researchers at Mayo Clinic and collaborators worldwide have established the Pick's Disease International Consortium to study a specific MAPT gene variation known as MAPT H2 that makes the tau protein and acts as a driver of disease. They investigated a connection between the gene and disease risk, age at onset and duration of Pick's disease. "We found that the MAPT H2 genetic variant is associated with an increased risk of Pick's disease in people of European descent," says Owen Ross, Ph.D. , a Mayo Clinic neuroscientist and senior author of the paper. "We were only able to determine that because of the global consortium, which greatly increased the sample size of pathology cases to study Pick's disease."

Moments of clarity in the fog of dementia

Researchers define lucid episodes as unexpected, spontaneous, meaningful and relevant communication from a person who is assumed to have permanently lost the capacity for coherent interactions, either verbally or through gestures and actions. A study surveyed family caregivers of people living with dementia and asked them about witnessing lucid episodes.

"We have found in our research and stories from caregivers that these kinds of episodes change how they interact with and support their loved ones — usually for the better," says lead author Joan Griffin, Ph.D. "These episodes can serve as reminders that caregiving is challenging, but we can always try to care with a little more humanity and grace."

Microscopy image of TMEM106B with protein in green, cell nuclei in blue and neurons in red.

Untangling the threads of early-onset dementia

Changes in personality, behavior and language are hallmarks of frontotemporal dementia (FTD) , the most common form of dementia in patients under the age of 65. New research provides insight into the role a specific gene and the protein it produces play in the development and progression of FTD, which is associated with degeneration of the frontal and temporal lobes of the brain. The researchers think the key may lie in the formation of fibrils, or tiny fiber-like structures produced by part of this protein, that sometimes get tangled up in the brain.

"We also think that these fibrils could one day serve as biomarkers to help clinicians determine FTD prognosis or severity, " says Jordan Marks, an M.D.–Ph.D. student with the Mayo Clinic Graduate School of Biomedical Sciences .

A brain imaging MRI scan is shown with a blue and red reflection covering half.

Mayo Clinic researchers' new tool links Alzheimer's disease types to rate of cognitive decline

Through a new corticolimbic index tool that identifies changes in specific areas of the brain, Mayo Clinic researchers discovered a series of brain changes characterized by unique clinical features and immune cell behaviors for Alzheimer's disease , a leading cause of dementia .

"By combining our expertise in the fields of neuropathology, biostatistics, neuroscience, neuroimaging and neurology to address Alzheimer's disease from all angles, we've made significant strides in understanding how it affects the brain," says Melissa E. Murray, Ph.D. , a translational neuropathologist at Mayo Clinic. "The corticolimbic index is a score that could encourage a paradigm shift toward understanding the individuality of this complex disease and broaden our perspective. This study marks a significant step toward personalized care, offering hope for more effective future therapies."

The brain is a critical, complex organ and intricate diseases affect it.

New research platform assesses brain cancer mutations during surgery

Brain cancer is difficult to treat when it starts growing, and a prevalent type, known as a glioma , has a poor five-year survival rate. Mayo Clinic researchers report on a new surgical platform used during surgery that informs critical decision-making about tumor treatment within minutes. Time is of the utmost importance when dealing with aggressive malignant tumors.

The researchers say that, in addition to enabling real-time diagnosis, the platform allows surgeons to determine a patient's prognosis and perform tumor resection to improve patient outcomes.

“We will be able to bring the fight against cancer to the operating room, before chemotherapy and radiation treatments begin, and before the disease has progressed and invaded further," says the study's senior author, Alfredo Quiñones-Hinojosa, M.D.

Comprehensive testing leads to targeted treatment for rare autoimmune encephalitis antibody Mayo Clinic Minute: Types of brain tumors and treatments

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Editorial: Brain Cancers: New Perspectives and Therapies

1 Toxicology Unit, Laboratory of Clinical and Experimental Toxicology, Pavia Poison Centre, National Toxicology Information Centre, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy

Maria Grazia Bottone

2 Department of Biology and Biotechnology “L. Spallanzani, ” University of Pavia, Pavia, Italy

Brain diseases come in many different forms. It is estimated that these pathologies affect the lives of 1 in 6 people, and cost over a trillion dollars in annual treatment. The major categories of brain diseases include diverse brain cancers. Brain tumors are the most primitive, invasive and malignant in humans with poor survival after diagnosis (Mckinney, 2004 ; Laquintana et al., 2009 ). Although in recent years, numerous studies have been carried out to identify novel therapeutic protocols and tumor molecular markers capable to predict survival and response to treatment, the life expectancy of neuro-oncological patients is still very limited (24–36 months) (Aldape et al., 2019 ; Liang et al., 2020 ).

About 33% of all brain tumors are gliomas, accounting for about 80% of the total malignant central nervous system (CNS) tumors in adults (Hanif et al., 2017 ). Glioma is a broad category of glial brain and spinal cord tumors which originate in the glial cells that surround and support neurons in the brain, including astrocytes, oligodendrocytes, and ependymal cells. Among these, glioblastoma (GBM) is one of the most common and aggressive primary brain tumors (van Tellingen et al., 2015 ; Davis, 2016 ; Taylor et al., 2019 ; Birzu et al., 2021 ), characterized by diffuse infiltration of the adjacent brain parenchyma and development of drug resistance to standard treatment (Chen et al., 2018 ; Shergalis et al., 2018 ). So far, GBM remains associated with an extremely aggressive clinical course, and only 0.05–4.7% of patients survive 5 years from diagnosis (Ostrom et al., 2018 ). Cellular pleomorphism with nuclear atypia, high mitotic activity, and microvascular proliferation distinguish GBM from other lower-grade gliomas (Hambardzumyan and Bergers, 2015 ). In addition, the inter- and intra-patient tumor heterogeneity causes several obstacles, limiting the improvement of an early diagnosis and treatment protocols.

The tumor microenvironment (TME) plays a crucial role in mediating tumor progression and invasiveness, contributing to brain tumor aggression and poor prognosis ( Di Cintio et al. ; Yekula et al., 2020 ). Recent studies showed that differentiated tumor cells may have the ability to dedifferentiate acquiring a stem-like phenotype in response to microenvironment stresses such as hypoxia. Acidic extracellular pH and nitric oxide were also shown to be involved in stemness preservation (Dahan et al., 2014 ). Currently, the standard of care consists of surgical resection followed by radiotherapy (RT) and concomitant and adjuvant chemotherapy. Despite this aggressive treatment regimen, the median survival is only around 15 months, and the 2-year survival rate is only 26.5% (von Neubeck et al., 2015 ; Chen et al., 2018 ). Indeed, due to the location of gliomas origin and infiltrative growth (Urbańska et al., 2014 ), complete surgical resection of the tumor is often not possible other than with a high risk of neurological damages for the patient (Goldbrunner et al., 2018 ). Treating patients with primary brain tumors and brain metastases can be challenging. This is primarily due to the presence of the blood–brain barrier (BBB), posing an obstacle to overcome for most systemic treatments (van Tellingen et al., 2015 ; Brahm et al., 2020 ). Despite initial benefits, chemotherapy, using conventional agents, e.g., alkylating agents such as temozolomide, platinum-based drugs, or VEGF inhibitors (Dasari and Tchounwou, 2014 ; Pérez et al., 2019 ; Senbabaoglu et al. ; Strobel et al., 2019 ), is often associated with severe systemic toxicity, which occurs especially after long-term treatment (Karasawa and Steyger, 2015 ; Chovanec et al., 2017 ). Among these adverse side effects, neurotoxicity assumed increasing clinical importance as it is dose-cumulative and becomes limiting in long-lasting therapies, and also to the severe side effects (Chovanec et al., 2017 ; Staff et al., 2019 ). Therefore, high-grade gliomas or GBM are currently considered incurable and all patients inevitably experience and succumb to tumor recurrence, highlighting the urgent need to identify, validate and apply new therapeutic options (Ravanpay et al., 2019 ; Taylor et al., 2019 ; Maggs et al. ; Ghouzlani et al., 2021 ).

This Frontiers Research Topic Proposal on “ Brain Cancers: New Perspectives and Therapies ” joined contributions from scientists and physicians who investigate on etiopathogenesis and treatment of brain cancers. In fact, studies exploiting the existing link between enhancing the knowledge of cellular and molecular pathways involved in the onset/progression of these pathologies and the development of innovative therapies, improving patient prognosis and quality of life, need further in-depth investigations.

The published articles are based on neuro-oncological research and deal with proposing novel effective therapeutic strategies, focusing on different targets and aspects typical of brain tumors: tumor heterogeneity and microenvironment, cancer cell response to new chemotherapeutics and innovative radiotherapy treatments settings (often tested in combined protocols), immune-mediated gene therapies, which may involve blockade of immune checkpoint inhibitors, and other targeted therapies such virotherapy, CAR-T cells, dendritic cells' vaccines, or nanoparticle-mediated vaccination technologies ( Alghamri et al. ; Brandalise et al. ; Chen et al. ; Di Cintio et al. ; Ferrari et al. ; Lange et al. ; Maggs et al. ; Pasi et al. ; Senbabaoglu et al. ).

The joint mechanisms of neuro-inflammation, tumor microenvironment and BBB leakage status, which have been shown to trigger the tumor onset, invasion and progression, often mediated by the deregulation of a number of channel proteins and ion pumps ( Brandalise et al. ), have been also explored as promising targets for personalized pharmacological interventions ( Alghamri et al. ; Di Cintio et al. ; Lee et al., 2020 ). Another exploited key mechanism is cell death, a crucial multifaceted process dependent on signal transduction pathways, in which several Hsp90 client proteins, frequently abnormally expressed, may be involved ( Cao et al. ; Chen et al. ). It widely accepted that in cancer cells, particularly in gliomas cells, cell death pathways can be deactivated or defective for various causes, thus promoting cancer formation, proliferation, invasiveness, and even the induction of resistance to the drugs treatment. Particular effort has been devoted to the repositioning of old drugs as potent therapeutics for GMB and/or to exploit the combined effects of novel drugs in synergism with different irradiation protocols ( Chen et al. ; Lange et al. ; Ferrari et al. ; Pasi et al. ).

In summary, clinical evidences highlights the urgent medical need to further comprehend and delineate the complex mechanisms/interactions between cancer cells, immune cells, tumor stroma, resident healthy brain cells, and tumor vasculature, to develop innovative effective treatment strategies through the identification of novel targets. A multidisciplinary approach, taking into consideration all brain tumors aspects, including the modulation of the communication processes between cancer niche and tumor microenvironment and also the potential reactivation of defective cell death mechanisms, can currently be considered as a promising strategy.

This Frontiers Research Topic had the ultimate goal to apply new knowledges coming from multitiered approaches, to identify novel effective therapeutic strategies to be used in the field of clinical neuro-oncology, to improve the patient prognosis and quality of life, also reducing adverse side effects due to conventional treatments, in view of a focused, personalized medicine. The published contributions may play a crucial role, laying the groundwork to translate the experimental findings to clinical setting, turning them into new clinical therapeutic protocols, facing the challenges in this field and developing new healing perspectives.

Author Contributions

Both authors equally contributed to the work, giving a substantial, direct, and intellectual contribution, and they both approved the work for publication.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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New A.I. Tool Diagnoses Brain Tumors on the Operating Table

A new study describes a method for faster and more precise diagnoses, which can help surgeons decide how aggressively to operate.

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A surgeon holds a tool over the exposed brain of a surgery patient covered in blue sheets in an operating room under a spotlight.

By Benjamin Mueller

Once their scalpels reach the edge of a brain tumor, surgeons are faced with an agonizing decision: cut away some healthy brain tissue to ensure the entire tumor is removed, or give the healthy tissue a wide berth and risk leaving some of the menacing cells behind.

Now scientists in the Netherlands report using artificial intelligence to arm surgeons with knowledge about the tumor that may help them make that choice.

The method, described in a study published on Wednesday in the journal Nature , involves a computer scanning segments of a tumor’s DNA and alighting on certain chemical modifications that can yield a detailed diagnosis of the type and even subtype of the brain tumor.

That diagnosis, generated during the early stages of an hours-long surgery, can help surgeons decide how aggressively to operate, the researchers said. In the future, the method may also help steer doctors toward treatments tailored for a specific subtype of tumor.

“It’s imperative that the tumor subtype is known at the time of surgery,” said Jeroen de Ridder, an associate professor in the Center for Molecular Medicine at UMC Utrecht, a Dutch hospital, who helped lead the study. “What we have now uniquely enabled is to allow this very fine-grained, robust, detailed diagnosis to be performed already during the surgery.”

Their deep learning system, called Sturgeon, was first tested on frozen tumor samples from previous brain cancer operations. It accurately diagnosed 45 of 50 cases within 40 minutes of starting genetic sequencing. In the other five cases, it refrained from offering a diagnosis because the information was unclear.

The system was then tested during 25 live brain surgeries, most of them on children, alongside the standard method of examining tumor samples under a microscope. The new approach delivered 18 correct diagnoses and failed to reach the needed confidence threshold in the other seven cases. It turned around its diagnoses in less than 90 minutes, the study reported — short enough for it to inform decisions during an operation.

Currently, in addition to examining brain tumor samples under a microscope, doctors can send them for more thorough genetic sequencing.

But not every hospital has access to that technology. And even for those that do, it can take several weeks to receive results, said Dr. Alan Cohen, the director of the Johns Hopkins Division of Pediatric Neurosurgery and a cancer specialist.

“We have to start treatment without knowing what we’re treating,” Dr. Cohen said.

The new method uses a faster genetic sequencing technique and applies it only to a small slice of the cellular genome, allowing it to return results before a surgeon has started operating on the edges of a tumor.

Dr. de Ridder said that the model was powerful enough to deliver a diagnosis with sparse genetic data, akin to someone recognizing an image based on only one percent of its pixels, and from an unknown portion of the image.

“It can figure out itself what it’s looking at and make a robust classification,” said Dr. de Ridder, who is also a principal investigator at Oncode Institute, a cancer research center in the Netherlands.

But some tumors are still difficult to diagnose. The samples taken during surgery are about the size of a kernel of corn, and if they include some healthy brain tissue, the deep learning system may struggle to pick out enough tumor-specific markers.

In the study, doctors dealt with that by asking the pathologists examining samples under a microscope to flag the ones with the most tumor for sequencing, said Marc Pagès-Gallego, a bioinformatician at UMC Utrecht and a co-author of the study.

There can also be differences within a single patient’s tumor cells, meaning that the small segment being sequenced may not be representative of the entire tumor. Some less common tumors may not correspond to those that have previously been classified. And some tumor types are easier to classify than others.

Other medical centers have already started applying the new method to surgical samples, the study’s authors said, suggesting that it can work in other people’s hands.

But Dr. Sebastian Brandner, a professor of neuropathology at University College London, said that sequencing and classifying tumor cells often still required significant expertise in bioinformatics as well as workers who are able to run, troubleshoot and repair the technology.

“Implementation itself is less straightforward than often suggested,” he said.

Brain tumors are also the most well-suited to being classified by the chemical modifications that the new method analyzes; not all cancers can be diagnosed that way.

The new method is part of a broad movement toward bringing molecular precision to diagnosing tumors, potentially allowing scientists to develop targeted treatments that are less damaging to the nervous system. But translating a deeper knowledge of tumors to new therapies has proved difficult.

“We’ve made some gains,” Dr. Cohen said, “but not as many in the treatment as in the understanding of the molecular profile of the tumors.”

Benjamin Mueller is a health and science reporter. Previously, he covered the coronavirus pandemic as a correspondent in London and the police in New York. More about Benjamin Mueller

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Google appears to have rolled back its new A.I. Overviews after the technology produced a litany of untruths and errors.

OpenAI said that it has begun training a new flagship A.I. model that would succeed the GPT-4 technology that drives its popular online chatbot, ChatGPT.

Elon Musk’s A.I. company, xAI, said that it had raised $6 billion , helping to close the funding gap with OpenAI, Anthropic and other rivals.

The Age of A.I.

After some trying years during which Mark Zuckerberg could do little right, many developers and technologists have embraced the Meta chief as their champion of “open-source” A.I.

D’Youville University in Buffalo had an A.I. robot speak at its commencement . Not everyone was happy about it.

A new program, backed by Cornell Tech, M.I.T. and U.C.L.A., helps prepare lower-income, Latina and Black female computing majors for A.I. careers.

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Published: 20 December 2019

Focusing on brain tumours and brain metastasis

Nature Reviews Cancer volume 20 , page 1 ( 2020 ) Cite this article

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This Focus issue highlights current research into the unique biology of brain tumours and brain metastasis and how this research might improve therapy of these often devastating diseases.

Survival for many types of malignant primary brain tumours has not improved much in the past 10 years, despite the introduction of some new treatments and despite our improved understanding of the biological bases of brain tumour development 1 , 2 . In addition, most malignant brain lesions are actually secondary brain tumours (brain metastases), and it is estimated that brain metastases will develop in up to 30% of adults who have a malignant primary tumour at another site 2 , 3 . Furthermore, brain tumours are the most common type of solid tumour in children and are the leading cause of cancer-related deaths in this population 1 , 4 . These statistics all indicate that better treatments for brain tumours and brain metastasis are a pressing need. We have therefore put together this Focus issue to highlight the diverse research in this field and the unique challenges posed by brain tumours and brain metastases.

Brain tumours are a heterogeneous group of diseases, but one important common feature is that they are subject to the unique biology of the brain and its microenvironment. The brain contains many cell types that are distinct from those found elsewhere in the body, making it challenging to extrapolate findings from cancers arising in other organs to those arising in the brain. Furthermore, the anatomy of the brain presents challenges for treating both brain tumours and brain metastases.

A prime example of both the unique biology and the anatomical challenges of treating brain tumours is the blood–brain barrier (BBB), the neurovascular unit that maintains brain homeostasis and acts as a ‘gatekeeper’, controlling the crossing of molecules and cells from the blood into the brain. Although the BBB is often disrupted in brain tumours, effective delivery of anticancer therapeutics through this blood–tumour barrier remains a challenge, as addressed by Arvanitis et al. 5 .

One aspect of the brain microenvironment that might not be as unique as initially presumed is the immune environment. The immune cell types of the brain differ from those in other organs, but, as discussed by Sampson et al. 6 , it is now becoming clear that this organ is not as ‘immune privileged’ as once thought, leading to hope that brain tumours and metastases might be successfully targeted with immunotherapies.

despite the challenges presented by brain tumours, progress is being made on many different fronts against these often devastating diseases

Gliomas account for ~80% of malignant brain tumours, and the highest grade glioma, glioblastoma, is one of the most lethal cancers in adults 3 . Interestingly, genomic sequencing efforts more than 10 years ago jump-started the field of glioma metabolism with their finding of recurrent mutations in the genes encoding the tricarboxylic acid cycle enzymes IDH1 and IDH2, but the role of metabolism in glioma pathogenesis goes beyond IDH, as discussed by Bi et al. 7 .

Medulloblastoma is one of the most common paediatric brain tumours 4 . Our understanding of this disease was advanced substantially by genomic studies reported in 2012. Since then, as discussed by Hovestadt et al. 8 , more genomic studies, as well as epigenomic, transcriptomic and proteomic profiling efforts, have provided new insights into medulloblastoma biology that will hopefully lead to improved diagnosis and therapy.

The prevalence of brain metastases in adults raises the question of what those working on primary brain tumours can learn from research on brain metastasis, and vice versa. This, and other important questions on brain metastasis, is pondered in a Viewpoint article written by four leading experts in this field 9 .

What has emerged from this collection of articles is that despite the challenges presented by brain tumours, progress is being made on many different fronts against these often devastating diseases, which will hopefully lead to improvements in survival in the next 10 years, if not sooner.

Jones, D. T. W. et al. Molecular characteristics and therapeutic vulnerabilities across paediatric solid tumours. Nat. Rev. Cancer 19 , 420–438 (2019).

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Lapointe, S. et al. Primary brain tumours in adults. Lancet 392 , 432–446 (2018).

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Weller, M. et al. Glioma. Nat. Rev. Dis. Primers 1 , 15017 (2015).

Liu, K. W. et al. Molecular mechanisms and therapeutic targets in pediatric brain tumors. Sci. Signal. 10 , eaaf7593 (2017).

Arvanitis, C. D. et al. The blood–brain barrier and blood–tumour barrier in brain tumours and metastases. Nat. Rev. Cancer https://doi.org/10.1038/s41568-019-0205-x (2019).

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Sampson, J. H. et al. Brain immunology and immunotherapy in brain tumours. Nat. Rev. Cancer https://doi.org/10.1038/s41568-019-0224-7 (2019).

Bi, J. et al. Altered cellular metabolism in gliomas — an emerging landscape of actionable co-dependency targets. Nat. Rev. Cancer https://doi.org/10.1038/s41568-019-0226-5 (2019).

Hovestadt, V. et al. Medulloblastomics revisited: biological and clinical insights from thousands of patients. Nat. Rev. Cancer https://doi.org/10.1038/s41568-019-0223-8 (2019).

Boire, A. et al. Brain metastasis. Nat. Rev. Cancer https://doi.org/10.1038/s41568-019-0220-y (2019).

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Cancer Center experts present research at national conference

Ovarian and blood cancer trials highlight uc’s asco abstracts.

University of Cincinnati Cancer Center experts will present research at the American Society of Clinical Oncology annual meeting May 31 to June 4 in Chicago.

Platform-predicted treatment leads to longer survival for patients with ovarian cancer

Thomas Herzog, MD. Photo/University of Cincinnati Cancer Center.

After an initial response to chemotherapy, many patients with ovarian cancer encounter a period of resistance to therapy that can lead to tumor regrowth.

The Cancer Center’s Thomas Herzog, MD, said this resistance is believed to be partially caused by cancer stem cells (CSCs) that rebuild and repair tumors after chemotherapy. In a recent trial, researchers used a diagnostic tool called ChemoID that determines how sensitive CSCs and bulk tumor cells are to various cancer-killing therapies.

“The goal of the test is to find the most effective chemotherapeutic agents that would reduce CSCs in ovarian cancer, thereby limiting recurrent disease potential to help improve patients’ outcomes,” said Herzog, a University of Cincinnati Cancer Center member, the Paul and Carolyn Flory Professor in Gynecologic Oncology in the UC College of Medicine, and director of UC Health’s Gynecologic Cancer Disease Center. “ChemoID provides a prioritized list of effective and ineffective chemotherapies after taking a tissue biopsy of the tumor.”

In a multisite clinical trial, patients with recurrent platinum-resistant epithelial ovarian cancer were randomized to have their chemotherapy regimens selected through the ChemoID platform or by their physician’s best choice.

Patients in the physician-choice arm had an overall response rate to their chemotherapy of 5%, while those in the ChemoID arm had a 55% overall response rate. The median progression-free survival, or time after treatment when the disease does not get worse, was three months for the physician-choice group and 11 months for the ChemoID group.

Moving forward, Herzog said a larger trial will be needed to validate these results.

Herzog will present the oral abstract Relationship of cancer stem cell functional assay and objective response rate of patients with recurrent platinum-resistant ovarian cancer in a randomized trial June 1 from 8-9:30 a.m. Co-authors include Thomas Krivak, John Diaz, Scott Lentz, Stephen Bush, Navya Nair, Nadim Bou Zgheib, Camille Gunderson Jackson, Abhijit Barve, Seth Lirette, Candace Howard, Jagan Valluri, Krista Denning and Pier Paolo Claudio.

Herzog will also present the poster Endometrial cancer (EC) by ERBB2 amplification (ERBB2amp) status: Differences in molecular subtypes, ancestry, and real-world outcomes June 3 from 9 a.m. to 12 p.m. Co-authors include Natalie Danziger, Douglas Lin, Julia Elvin, Andrew Kelly, Ryon Graf, Robert Coleman, Bhavana Pothuri, Ramez Eskander, Julia Quintanilha and Brian Slomovitz.

Trial tests drug’s ability to overcome resistance in lymphoma

The Cancer Center’s John Byrd, MD, will present information on a Phase 1 trial testing a new treatment for patients with non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) whose cancer has returned or stopped responding to treatment (relapsed/refractory).

On average, about a quarter of patients with NHL or CLL will relapse by 24 months. Each patient is unique, and the relapse can occur with different mutations, including a MALT mutation that promotes survival and proliferation of blood cancers.

Cancer cells can also sometimes develop resistance to currently-used drugs targeting other enzymes, creating the need for innovative new therapies.

The trial drug, ONO-7018, targets a protein called MALT1. Preclinical data showed the drug inhibits MALT1 activity and exhibited an antitumor effect with a good safety profile, giving it therapeutic potential to be effective and overcome resistance.

Erin Hertlein, PhD, left, and John Byrd, right, look at data in the Leukemia and Drug Development Lab. Photo/UC Foundation.

In the trial, patients will be given ONO-7018 orally in 21-day treatment cycles. The first group of up to 48 patients will be enrolled to receive increasing doses until the maximum tolerated dose is identified. Once this occurs, a second group of up to 60 patients will be enrolled to receive the optimal dose identified.

“We are excited to have this exciting new agent, ONO-7018, available for our patients with NHL and CLL who have exhausted available effective therapies available for their disease,” said Byrd, Gordon and Helen Hughes Taylor Professor and Chair of the Department of Internal Medicine at the UC College of Medicine. “MALT1 is an exciting target across all B-cell malignancies and potentially for other types of cancer.”

The trial, which is currently recruiting patients, will primarily assess the drug’s safety and tolerability.

Byrd will present the poster A phase I, first-in-human study of ONO-7018 in patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia June 3 from 9 a.m. to 12 p.m. Co-authors include Pierluigi Porcu, Thomas Sundermeier, Takashi Nakada, Takeyuki Iwata, Sergio Prados and Leo Gordon.

For more information on this and other blood cancer clinical trials at the Cancer Center, contact Michelle Marcum at [email protected] or 513-584-6628.

Research examines link between sleep disturbance and cancer-related cognitive impairment

Cancer-related cognitive impairment (CRCI), often called “chemo brain,” affects approximately 75% of individuals with cancer.

The Cancer Center’s cognitive clinical registry found that more than 83% of patients report experiencing sleep disturbances, leading researchers to ask the question of how sleep disturbances and sleep apnea contribute to CRCI.

“CRCI is complex and overlaps with risk factors associated with non-cancer cognitive impairment and neurodegenerative disease,” said Alique Topalian, PhD, a research scientist in Survivorship and Supportive Services at the Cancer Center. “Sleep is central to maintaining brain health. Understanding the relationship between sleep and cancer is important for mitigating CRCI and neurodegenerative disease.”

In patients who do not have cancer, impaired sleep contributes to executive dysfunction and enlarged brain ventricles, which disrupt cerebral spinal fluid (CSF) flow and drainage of waste material from the brain, Topalian said. The team hypothesized this same process may be a contributing factor to CRCI.

“Reduced removal of toxic byproducts of normal brain metabolism and inflammation that is induced by cancer and its treatment could explain one mechanism of action for CRCI and the increased risk of neurodegenerative disease in cancer survivors,” Topalian said.

A Cancer Center team will present findings on how sleep disturbances and sleep apnea affect cancer-related cognitive impairment. Photo/iStock/FG Trade.

The research team analyzed data from 135 patients in the cognitive clinic’s clinical registry and found sleep apnea and sleep disturbances to be highly prevalent in CRCI.

“There was a statistical trend toward a relationship between sleep disturbance severity in CRCI and enlarged ventricles,” Topalian said. “Sleep disturbances did not correlate with measures of cognitive impairment. However, ventricular size was significantly associated with impaired processing speed, sustained attention/inhibitory control and semantic fluency.”

Topalian said the novel finding of enlarged brain ventricles in these patients suggests treatment aimed at improving sleep disturbances may help regulate disrupted CSF flow, which could potentially improve CRCI cognitive symptoms.

“We are pursuing fundings for a CPAP and sleep health treatment trial for CRCI patients to investigate how treatment impacts cognitive, imaging and serum markers of CSF flow,” she said.

Additionally, the research team plans to form an ongoing translational working group to expand research on this topic.

Research assistant Sophie Kushman will present the poster “ Sleep apnea and glymphatic dysfunction as a mediator of executive dysfunction and neurodegenerative risk in cancer related cognitive impairment (CRCI) ” during the Symptom Science and Palliative Care session June 3 from 1:30 to 4:30 p.m. Abstract co-authors are Topalian and Rhonna Shatz, DO.

Unique approach aids elementary science education

As the University of Cincinnati Cancer Center is tackling how to reduce the suffering and mortality of cancer in the community today, it is also testing unique ways to encourage the next generation of cancer researchers.

William Barrett, MD, co-director of the Cancer Center, professor and chair of Radiation Oncology in UC’s College of Medicine, and medical director of the Barrett Center for Cancer Prevention, Treatment and Research, said elementary students, particularly those in socially and financially disadvantaged settings, encounter barriers to effective scientific learning.

With an aim to overcome these barriers, which include maintaining interest, concentration and focus, Barrett and his colleagues implemented a scientific educational program for children attending an urban community center’s after-school program.

During the program’s activities, five students at a time complete three-minute sessions at tutoring stations on human physiology, astronomy, geography, geology and cancer led by medical students or residents. Meanwhile, another group of five students goes through three-minute basketball drills with a coach on the court.

Cancer Center volunteers developed a scientific educational program that alternated basketball drills with educational stations at a community center's after-school program. Photo/Nik Shuliahin/Unsplash.

The groups alternate between basketball and tutoring until all students have participated in all five drills and tutoring stations. Then the kids are quizzed on what they learned, and an end-of-practice scrimmage begins with a score based on the quiz results.

“Within weeks, nearly every child could list the planets of the solar system in order; calculate their pulse and explain its importance; list the most common symptoms of the most prevalent cancers; correctly identify continents, oceans, countries and states on maps; and explain the origin of volcanoes, earthquakes, hurricanes and tsunamis,” Barrett and his coauthors wrote in the abstract.

The alternating of physical exertion with learning appears to maintain interest, focus and concentration, and the approach could be widely applied to students from diverse backgrounds.

Barrett is first author on the abstract Defeating cancer through education, prevention, and youth athletics. Sherwin Anderson, Andrew Frankart, Samuel Thompson and William Mackey are co-authors.

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Featured photo at top of ovarian cancer cells. Photo/OGPhoto/iStock.

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Leading Change in Cancer Clinical Research, Because Our Patients Can’t Wait

May 31, 2024 , by W. Kimryn Rathmell, M.D., Ph.D., and Shaalan Beg, M.D.

Middle-aged woman with cancer having a virtual appointment with doctor on the computer.

Greater use of technologies that can increase participation in cancer clinical trials is just one of the innovations that can help overcome some of the bottlenecks holding up progress in clinical research.

Thanks to advances in technology, data science, and infrastructure, the pace of discovery and innovation in cancer research has accelerated, producing an impressive range of potential new treatments and other interventions that are being tested in clinical studies . The extent of the innovative ideas that might help people live longer, improve our ability to detect cancer early, or otherwise transform care is staggering.

Our understanding of tumor biology is also evolving, and those gains in knowledge are being translated into the continued discovery of targets for potential interventions and the development of novel types of treatments. Some of these therapies are producing unprecedented clinical responses in studies, including in traditionally difficult-to-treat cancers.

These advances have contributed to a record number of Food and Drug Administration (FDA) approvals in recent years with, arguably, the most notable approvals being those for drugs that can be used for any cancer, regardless of where it is in the body .

In some instances, the activity of new agents has been so profound that clinical investigators are having to rethink their criteria for implementation in patient care and their definitions of treatment response.

For example, although HER2 has been a known therapeutic target in breast cancer for many decades, the new antibody-drug conjugates (ADCs) that target HER2 have proven to be vastly more effective than the original HER2-targeted therapies. This has forced researchers to rethink fundamental questions about how these ADCs are used in patient care: Can they be effective in people whose tumors have lower expression of HER2 than we previously thought was needed ? And, if so, do we need to redefine how we classify HER2-positive cancer?

As more innovative therapies like ADCs hit the clinic at a far more rapid cadence than ever before, the research community is being inundated with such fundamentally important questions.

However, the remarkable progress we're experiencing with novel new therapies is tempered by a critical bottleneck: the clinical research infrastructure can’t be expected to keep pace in this new landscape.

Currently, many studies struggle to enroll enough participants. At the same time, there are patients who don’t have ready access to studies from which they might benefit. Furthermore, ideas researchers have today for studies of innovative new interventions might not come to fruition for 2 or 3 years, or even longer—years that people with cancer don’t have.

The key to overcoming this bottleneck is to invite innovation to help reshape our clinical trials infrastructure. And here’s how we plan to accomplish that.

Testing Innovation in Cancer Clinical Trials

A transformation in cancer clinical research is already underway. That transformation has been led in part by the success of novel precision oncology approaches, such as those tested in the NCI-MATCH trial .

This innovative study ushered in novel ways of recruiting participants and involving oncologists at centers big and small. And NCI-MATCH has spawned several successor studies that are incorporating and building on its innovations and achievements.

An innovation that emerged from the COVID pandemic was the increase of remote work, even in the clinical trials domain. Indeed, staffing shortages have caused participation in NCI-funded trials to decline. In response, NCI is piloting a Virtual Clinical Trials Office to offer remote support staff to participating study sites. This support staff includes research nurses, clinical research associates, and data specialists, all of whom will help NCI-Designated Cancer Centers and community practices engaged in clinical research activities.

Such technology-enabled services can allow us to reimagine how clinical trials are designed and run. This includes developing technologies and processes for remotely identifying clinical trial participants, shipping medications to participants at home, having imaging performed in the health care settings where our patients live, and empowering local physicians to participate in clinical trials.

We also need mechanisms to test and implement innovations in designing and conducting clinical studies.

The Pragmatica-Lung Cancer Treatment Trial , an innovative phase 3 study launched by NCI’s National Clinical Trials Network (NCTN) , was designed to be easy to launch, enroll participants, and interpret its results.

NCI recently established Clinical Trials Innovation Unit (CTIU) to pressure test a variety of innovations. The CTIU, which includes leadership from FDA and NCTN, is already working on future innovations, including those that will streamline data collection and apply novel approaches to clinical studies, all with the goal of making them less burdensome to run and easier for patients to participate.

Data-Driven Solutions

The era of data-driven health care is here, providing still more opportunities to transform cancer clinical research.

The emergence of artificial intelligence (AI) solutions, large language models, and informatics brings real potential for wholesale changes in how we match patients to clinical studies, assess side effects, and monitor events like disease progression.

Recognizing this potential, NCI is offering funding opportunities and other resources that will fuel the development of AI tools for clinical research, allow us to carefully test their usefulness, and ultimately deploy them across the oncology community.

Creating Partnerships and Expanding Health Equity

To be sure, none of this will be, or can be, done by NCI alone. All these innovations require partnerships. We will increase our engagement with partners in the public- and private-sectors, including other government agencies and nonprofits.

That includes high-level engagement with the Office of the National Coordinator for Health Information Technology (ONC), with input from FDA, Centers for Medicare & Medicaid Services, and Centers for Disease Control and Prevention.

Dr. W. Kimryn Rathmell, M.D., Ph.D.

NCI Director

One example of such a partnership is the USCDI+ Cancer program . Conducted under the auspices of the ONC, this program will further the aims of the White House's reignited Cancer Moonshot SM by encouraging the adoption and utilization of interoperable cancer health IT standards, providing resources to support cancer-specific use cases, and promoting alignment between federal partners.

And just as importantly, the new partnerships we create must include those with patients, advocates, and communities in ways we have never considered before.

A central feature of this community engagement must involve intentional efforts to expand health equity, to create study designs that are inclusive and culturally appropriate. Far too many marginalized communities and populations today are further harmed by studies that fail to provide findings that apply to their unique situations and needs.

Very importantly, the future will require educating our next generation of clinical investigators and empowering them with the tools that enable new ways of managing clinical studies. By supporting initiatives spearheaded by FDA and professional groups like the American Society of Clinical Oncology, NCI is making it easier for community oncologists to participate in clinical trials and helping clarify previously misunderstood regulatory requirements.

These efforts must also ensure that we have a clinical research workforce that is representative of the people it is intended to serve. Far too many structural barriers have prevented this from taking place in the past, and it’s time for that to change.

Expanding our capacity doesn’t mean doing more of the same, it means challenging ourselves to work differently. This will let us move forward to a new state, one in which clinical research is integrated in everyday practice. It is only with more strategic partnerships and increased inclusivity that we can open the doors to seeing clinical investigation in new ways, with new standards for success.

A Collaborative Effort

Shaalan Beg, M.D.

Senior Advisor for Clinical Research

To make the kind of progress we all desire, we have to recognize that our clinical studies system needs to evolve.

There was a time when taking years to design, launch, and complete a clinical trial was acceptable. It isn’t acceptable anymore. We are in an era where we have the tools and the research talent to make far more rapid progress than we have in the past.

And we can do that by engaging with many different communities and stakeholders in unique and dynamic ways—making them partners in our effort to end cancer as we know it.

Together, our task is to capitalize on this work so we can move faster and enable cutting-edge research that benefits as many people as possible.

We also know that there are more good ideas in this space, and part of this transformation includes grass roots efforts to drive systemic change. So, we encourage you to share your ideas on how we can transform clinical research. Because achieving this goal can’t be done by any one group alone. We are all in this together.

Chromatin openness sheds new light on prostate cancer plasticity

Treatment resistance caused by cancer cell plasticity constitutes a major challenge in the treatment of prostate cancer. Published in Nucleic Acids Research , a recent study from the University of Eastern Finland Institute of Biomedicine suggests that the SIX2 protein may be a possible factor underlying increased plasticity of prostate cancer cells and treatment resistance.

Prostate cancer is the most common cancer in men and the second most common cause of cancer mortality in Western countries. Prostate cancer growth is promoted by androgens and can be treated with androgen receptor inhibition therapies, especially as regards aggressive or advanced prostate cancer. However, cancer cells can develop resistance to these therapies, resulting in castration-resistant prostate cancer.

One mechanism underlying treatment resistance may be the plasticity of cancer cells: they can change their degree of differentiation and revert to a stem cell-like state, which helps them avoid the effects of hormonal therapies. However, factors contributing to cell plasticity and the development of treatment resistance remain unclear.

"It is important to identify the key factors contributing to treatment resistance in prostate cancer and how cancer cells change their degree of differentiation to find new targets for therapies. This could even lead to the discovery of a cure for these currently lethal types of cancer," Academy Research Fellow, Adjunct Professor (Docent) Kirsi Ketola of the University of Eastern Finland says.

Inhibition of the androgen receptor opens up new genomic regions

The new study by the Ketola Lab explored new potential factors contributing to treatment resistance in prostate cancer.

In cells, DNA is packed into chromatin. In regions where gene expression is active, this packing is looser, meaning that chromatin is more open. The Ketola Lab studied chromatin openness in androgen-dependent prostate cancer cells, which were treated with enzalutamide, an inhibitor of the androgen receptor used for treating prostate cancer. The researchers found that following exposure to enzalutamide, the number of new opened chromatin sites was greater than that of new closed chromatin sites. These new opened sites occurred especially in DNA regions containing binding site of the SIX2 protein. The increased activity of the SIX2 protein may contribute to the increased plasticity of cells following drug therapy.

In other words, inhibiting the function of the androgen receptor alters the regulation of genes within cells, allowing for the expression of genes that are normally silenced and the alteration of the cell state.

SIX2 is necessary for embryogenesis, but increases cell plasticity and malignancy in prostate cancer cells

The SIX2 protein is normally active during embryogenesis, where it maintains cells as undifferentiated stem cells, preserving their ability to differentiate.

The study found that the SIX2 protein can regulate the degree of differentiation of even prostate cancer cells that do not have an androgen receptor. The activity of the SIX2 gene increased in cancer cells after exposure to enzalutamide. In particular, the expression of the SIX2 protein has increased in cancer cells that do not express the androgen receptor.

"Silencing of the SIX2 gene, on the other hand, significantly reduced the malignancy of cancer cells that are resistant to hormonal therapies," Doctoral Researcher Noora Leppänen of the University of Eastern Finland notes.

The stem cell-like state of cancer cells that do not express the androgen receptor, as well as their ability to migrate, invade and metastasize, were significantly reduced following the silencing of the SIX2 gene. Reduced cell division and cancer spread were also observed in experiments conducted on zebrafish. Therefore, inhibiting the activity of the SIX2 protein could be a potential target for drug development to treat or prevent the development of metastatic, hormone therapy-resistant types of cancer.

Prostate Cancer
Men's Health
Lung Cancer
Skin Cancer
Brain Tumor
Breast Cancer
Prostate cancer
Pernicious anemia
Breast cancer
Stomach cancer
Malignant melanoma
Embryonic stem cell

Story Source:

Materials provided by University of Eastern Finland . Note: Content may be edited for style and length.

Journal Reference :

Noora Leppänen, Heidi Kaljunen, Eerika Takala, Roosa Kaarijärvi, Petri I Mäkinen, Seppo Ylä-Herttuala, Ilkka Paatero, Ville Paakinaho, Kirsi Ketola. SIX2 promotes cell plasticity via Wnt/β-catenin signalling in androgen receptor independent prostate cancer . Nucleic Acids Research , 2024; DOI: 10.1093/nar/gkae206

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