Our Approach
Brain Tumors
IDH Mutant Tumors
Brain cancers, including isocitrate dehydrogenase (IDH) mutant brain tumors, represent a key unmet need. Around 30,000 people in the United States are estimated to be living with one of these tumors (astrocytoma or oligodendroglioma).1 Because of their indolent nature, patients can survive with an IDH mutant brain tumor for a decade or longer. However, they are almost invariably fatal, and suffer from a lack of modern cytotoxic approaches.
- The standard-of-care for all IDH mutant brain tumors is radiation therapy followed by alkylating agents. The most commonly used alkylating agent is temozolomide, which received FDA approval in 1999.
- Sometimes, PCV triple therapy is used instead, incorporating three drugs which received their initial U.S. FDA approvals between 1963 and 1976.
These approaches have been shown to effectively improve survival. However, they work by non-specifically killing rapidly dividing cells, with the hope that the tumor is less able to quickly recover than rapidly dividing healthy tissues (bone marrow, lining of the gastrointestinal tract, hair follicles, gonadal cells). However, since these other tissues are still affected, side effects can be widespread and severe. For this reason, many patients will delay initial therapy.
With the approval of vorasidenib in 2024, some patients now have another option.
- Vorasidenib works by targeting the IDH mutation directly to prevent the production of the oncometabolite 2-HG and has been shown to delay tumor progression. While much needed as a new option, it is a cytostatic approach, limited to first line therapy and only approved in low grade tumors.
We believe that dihydroorotate dehydrogenase (DHODH) inhibition combines the strength of both approaches2:
- a cytotoxic mechanism
- with the power to selectively kill cancer cells by targeting the IDH mutation
Animal models, including ones using patient-derived tumor cells, suggest strong activity in improving overall survival in both low grade and higher grade tumors, as well as in tumors that have been heavily pretreated. We believe our lead candidate GLIO-1 holds strong potential across the breadth of the patient spectrum.
Childhood Tumors
Better therapies are also needed in many forms of childhood brain cancer. Fortunately, our academic collaborators have identified that DHODH inhibition also causes genetically-targeted, highly potent and selective cytotoxicity in cancer cells, with sparing of wildtype cells, in preclinical models of diffuse midline glioma, medulloblastoma and neuroblastoma. We are actively exploring potential application of our drug candidates in these very important populations, too.