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“Dr. Mischel made a number of critical discoveries as part of the National Brain Tumor Society’s Defeat GBM Research Collaborative, a concentrated six-year effort that helped improve the landscape of glioblastoma research and treatment development, as well as the Sharpe/NBTS GBM Research Awards,” said NBTS Chief Executive Officer, David Arons. “We are excited to continue supporting the Mischel lab’s efforts to translate and bring forward a new class of treatments for glioblastoma and other malignant brain tumor patients.”
The grant builds on previous findings from the Mischel lab on how the profoundly altered metabolism of GBM tumors leaves cancerous cells critically dependent on key enzymes to maintain their survival. These dependencies leave the tumor vulnerable to targeted drugs, which Dr. Mischel believes can potentially improve GBM survival rates. Dr. Mischel and his collaborators have demonstrated this through preclinical research and real-world evidence, and his collaborators will now seek to further develop these existing, highly brain-penetrant drugs and test additional treatments and combinations.
“GBM is a major unmet medical need,” said Dr. Mischel. “Building on our work from Defeat GBM with the goal of translating science for the benefit of patients, this integrated research effort leverages an interactive and highly interdisciplinary collaboration between my laboratory – with expertise in GBM metabolism, genetics, signaling, and modeling – and Dr. Ben Cravatt’s team, which specializes in bridging biology and chemistry with CNS drug development. The strength of this grant is that it continues to follow cutting-edge science and is coupled with a development strategy that lacks the impediments that have typically held back GBM R&D. By targeting a series of enzymes in the cholesterol, phospholipid, and sphingolipid synthesis pathways, upon which GBMs are exquisitely dependent for survival, we are seeking to open up an entirely new window for discovery and drug development with the promise of new and more effective treatments for patients.”
Specific aims will include further testing and development of the drug fluoxetine (Prozac) as a potent inhibitor of the enzyme SMPD1, which is involved in lipid metabolism and plasma membrane structure. Previous findings have shown that when given at a higher, but clinically safe and achievable dose, combined with standard of care temozolomide, fluoxetine can selectively block the aggressive growth of GBMs and improve survival for GBM patients. In addition to continuing to shed light on which patients are most likely to respond to fluoxetine and advancing toward clinical studies, the team will also seek to determine whether it can be combined with LXR inhibition – based on additional, prior studies from the Mischel lab regarding cholesterol metabolism and the role the enzyme LXR plays – for an even greater potential treatment effect. The second aim advances the lab’s recent discovery of an enzyme, known as LPCAT1, that regulates plasma membrane activity. Finally, the Mischel and Cravatt labs will use novel laboratory tests to identify drugs that block this pathway, prepare them for biotech development, and simultaneously search for new and promising GBM metabolic co-dependency drug targets.
“The tiered development strategy will enable testing of promising drugs in the near term and could yield exciting new brain-penetrant, precision treatments in the intermediate-term with the potential to be highly transformative therapies for GBM patients,” Dr. Mischel continued.
Glioblastoma is the most common malignant (cancerous) brain tumor, accounting for approximately half of all primary malignant brain tumors. These tumors are also the most aggressive, complex, difficult to treat, and deadly type of brain tumor. Approximately 13,460 new cases of glioblastoma will be diagnosed in the United States in 2022, and it’s estimated that more than 10,000 individuals in the United States will succumb to their disease this year. The five-year survival rate for glioblastoma patients is only 6.8 percent, and the median length of survival is only 8 months. These rates have changed little during the past 30 years.
About the National Brain Tumor Society
Building on over 30 years of experience, the National Brain Tumor Society (NBTS) unrelentingly invests in, mobilizes, and unites the brain tumor community to discover a cure, deliver effective treatments, and advocate for patients and caregivers. Our focus on defeating brain tumors and improving the quality of patients’ lives is powered by our partnerships across science, health care, policy, and business sectors. We fund treatments-focused research and convene those most critical to curing brain tumors once and for all. Join us at BrainTumor.org.