Yale Advances in Treating Primary Brain Cancers Benefit Patients and Science

Ranjit Bindra, MD, PhD, Harvey and Kate Cushing Professor of Therapeutic Radiology and scientific director of the Chênevert Family Yale Brain Tumor Center, was frustrated.

Another one of his glioblastoma patients, like most people with this aggressive brain cancer, had become resistant to temozolomide (TMZ), still the only effective drug against the disease despite being decades old. Glioblastoma strikes about 13,000 people in the U.S. every year and kills 95 percent of them within five years.

“There was obviously an urgent unmet need,” says Bindra. He wondered if a retooled version of TMZ could overcome the cancer’s resistance mechanisms and prolong life. Because he is a physician-scientist at Yale, where cross-disciplinary collaborations are routine, he reached out to Seth Herzon, PhD, Milton Harris ’29 PhD Professor of Chemistry. Their labs used a creative combination of molecular biology and synthetic chemistry to develop and test new derivative molecules.

Approximately 50 percent of glioblastomas, and up to 80 percent of all lower-grade gliomas, lack a key protein called MGMT that repairs DNA in healthy cells, which induces sensitivity to TMZ. But many of them become resistant to this drug, via loss of another DNA pathway called mismatch repair. Working together, Herzon and Bindra developed a new class of molecules to target tumors that lack MGMT, but are not affected by mismatch repair status, thereby selectively killing the tumor while sparing normal tissue.

“We call this precision chemotherapy,” said Bindra. “It’s an entirely new way to treat glioblastoma.” He and Herzon published their findings in Science in summer 2022, and together they created a company, Modifi Bio, to translate their work from the lab into the clinic. Last October Modifi Bio was acquired by Merck, a pharmaceuticals company, for $30 million upfront for the rights to develop this innovative therapeutic. Because the new drug is built on the scaffolding of an FDA-approved medication (temozolomide), Bindra and Herzon expect this therapy to reach the clinic quickly, as early as the first half of 2026.

Are there other new treatments for glioblastomas?

Another project that excites Bindra also exploits defects in DNA repair. He and Peter Glazer, MD, PhD, Robert E. Hunter Professor of Therapeutic Radiology and chair of Therapeutic Radiology, have been exploring mutations of the enzyme IDH, which disrupts cell metabolism and damages DNA. IDH mutations occur in most gliomas. The scientists established that such tumors have severe defects in DNA repair, making them lethally susceptible to PARP inhibitors, which prevent repair and lead to cell death. Glazer and Bindra published this work in a series of papers in Nature, Nature Genetics, and Science Translational Medicine.

These insights led to half a dozen clinical trials that tested PARP inhibitors against gliomas in adults and adolescents, which has also extended to tumors with IDH mutations outside of the central nervous system, and the results will be published soon. The trials were developed by other YCC members, including Patricia LoRusso, DO, Asher Marks, MD, and Michael Cecchini, MD, highlighting the cross-disciplinary collaborative spirit at YCC. The initial data are promising enough to advance trials based on their IDH work, and are about to launch at Yale and elsewhere, testing PARP inhibitors in combination with other drugs. “It’s another example of translating work from the bench to the bedside,” says Bindra.

He also has a cross-disciplinary collaboration with Mark Saltzman, PhD, Goizueta Foundation Professor of Biomedical Engineering. They have developed a way to encapsulate PARP inhibitors in nanoparticles that can bypass the blood-brain barrier and deliver drugs directly to brain cancers that are otherwise difficult to treat, particularly medulloblastomas, the most common brain cancer in children. These tumors grow fast and often enter the cerebrospinal fluid (CSF).

“When that happens, it's very difficult to treat them,” says Bindra. “Systemic drugs can't reach the CSF. With radiation therapy, you have to radiate the entire brain and spine. And when you inject free drug into the CSF, it just washes away. Our drugs are sustained-release nanoparticles that stick along the meninges and slowly release drug for more than three weeks.”

Using a mouse model of medulloblastoma, Bindra and Saltzman found that a single dose of an encapsulated PARP inhibitor (BMN-673), either alone or combined with temozolomide, significantly improved survival. They are refining this breakthrough and expect that it will soon help children who now have no effective treatment for their disease. Their work was recently published in a Science Translational Medicine cover article. They are currently bringing this work to the clinic through their latest biotechnology spin-out company, B3 Therapeutics.

“Overall, there's just a lot of great translational momentum on brain cancer here at Yale,” says Bindra.

How are meningioma brain tumors treated?

A new contributor to that momentum is Sylvia Kurz, MD, PhD, associate professor of neurology and neuro-oncology, who arrived at Yale last summer. Her recent research on meningiomas has caused a stir. These are the most common intracranial tumors, with 41,000 new cases every year, though about 80 percent are benign. The other 20 percent—12,000 cases—are malignant, aggressive, and likely to recur even after surgery and radiotherapy, with a poor prognosis.

Almost all meningiomas overexpress the protein SSTR2, a biomarker that is also common in neuroendocrine tumors, which have been successfully stymied with a radiopharmaceutical drug named Lutathera (lutetium Lu 177-dotatate) that targets SSTR2. Kurz and colleagues tested Lutathera in a clinical trial enrolling meningioma patients whose disease had recurred despite prior surgery and radiation. Among such patients, only 26 to 29 percent typically live beyond six months, so the trial’s primary measure was progression-free survival (PFS) at that interval. In an interim analysis published in 2024 in Clinical Cancer Research, half of the trial’s patients met the mark, comparing favorably to historical data.

“Instead of a chemical warhead, Lutathera has a radioactive warhead,” explains Kurz. “The agent recognizes SSTR2 on the meningioma cell’s surface, gets internalized, and radiates the cell from within. Because of the radio-specific properties of this drug, the radioactivity effects are limited to the targeted cells with maximum protection of normal structures around it.”

Kurz is now the principal investigator on an impending randomized open-label Phase II trial that will evaluate Lutathera compared to best standard of care medical therapy in patients with advanced meningioma. The multi-center national clinical study will be co-sponsored by the Radiation Therapy Oncology Group (RTOG) Foundation and Novartis and will include up to 130 patients at 35 institutions. “We don't often have clinical trials to offer to meningioma patients, so this is huge,” she says.

Can radiotherapy be combined with other therapies to treat primary brain cancer?

In another main project at Yale, Kurz is the principal investigator for a national clinical trial evaluating the effects of blocking the protein biomarker TIGIT and PD-1 that help tumor cells evade the immune system. The therapy aims to reawaken the immune cells within the tumor to improve their attacks on cancer cells.

Some tumors develop resistance to a single immunotherapy, which researchers are trying to overcome by deploying combination treatments. Kurz’s trial will build on studies that showed strong anti-tumor effects against glioblastomas in animals when two immunotherapies were given together—an anti-TIGIT drug (domvanalimab) and an anti- PD-1/PD-L1 drug (zimberelimab). Since both drugs are already FDA-approved, the combination could help glioblastoma patients fairly soon if the trial is successful.

The role of surgery in treating brain cancers

Yale’s advanced brain cancer research and clinical investigations are complemented by state-of-the-art neurosurgery and postsurgical care. Specialized brain surgeons at Smilow Cancer Hospital offer patients every advanced technology and microsurgical techniques and approaches. “The goal in brain tumor surgery is to remove as much tumor as safely as possible, while best preserving neurological function. A large component of success really comes down to surgical skill, talent, and expertise, and that is what we offer at Yale,” says Jennifer Moliterno, MD, FAANS, professor of neurosurgery, chief of neurosurgical oncology, and clinical director of the Chênevert Family Brain Tumor Center.

Smilow is also the only hospital in Connecticut with a 3T MRI right in the operating room. The machine produces sharp real-time images that allow surgeons to immediately see and remove as much tumor as possible, as well as any residual tumor. During most surgeries, neurophysiologists use sophisticated brain-mapping technology to monitor the patient’s neurological responses, including motor and language function, which allows the surgeon to excise more tumor while minimizing the risk of damage to functional brain tissue.

Patients benefit from the combination of experienced surgical expertise and cutting-edge technology because they “allow for the safest, maximal extent of resection which has been repeatedly shown to positively impact patient survival,” Moliterno says, adding that Smilow is a major referral center for brain tumor patients in need of surgical expertise, particularly complex cases. “Cancer centers with high volumes of brain cancer surgery, such as Yale, are truly unsurpassed for providing the best patient outcomes and experience, including the neuroscience intensive care unit and post-operative care."

“But no new technology or gizmo can substitute for surgical expertise and surgical experience,” Moliterno adds. “Those are the only things shown to really affect patient survival or outcome. It comes down to being a master surgeon who can remove all the tumor and preserve function. That obviously requires an enormous amount of skill and concentration and understanding and technical ability—and you only get those by doing a large volume of surgeries, which we certainly do at Yale”—about 1,000 per year. Moliterno herself does several hundred.

Another crucial component of Yale’s brain surgery program, she says, is compassionate support for patients frightened by their life-changing diagnosis and pending operation. “We are very much focused on helping our patients in every possible way we can,” Moliterno says. “We are fortunate to have a large team of individuals who help patients navigate through this incredibly challenging time and offer a monthly support group and other activities. We’re privileged and honored to do what we do in every realm of our work.”