Targeted Therapy for Idh-Mutant Brain Cancer

Title: Expenditure Responsibility Grant to Test Brain Cancer Therapies Being Developed
Grantee: Agios Pharmaceuticals

Mutations in genes known as IDH1 and IDH2 are quite common in human glioma. The vast majority of low-grade gliomas, along with some secondary gliomas, have mutations in one or both of these genes – meaning that finding drugs that counteract the effects of these mutations could help treat a significant segment of the glioma population.

Scientists at Agios Pharmaceuticals, a leading biopharmaceutical company that develops drugs directed against cancer metabolism, recently took strides toward this goal by discovering how IDH mutations may actually cause glioma.  The IDH genes normally make enzymes that help cells break down nutrients and generate energy.  When these genes are mutated in human glioma, however, they make IDH enzymes that don’t work properly.  Rather than generating energy, the mutant enzymes instead create a chemical that alters a brain cell’s genetic programming and makes the cell divide too quickly.  IDH mutations in brain cells, therefore, cause brain tumors.

Recognizing the significance of this discovery for glioma treatment, ABC2 funded Agios to accelerate the early-stage development of IDH-targeted therapies for use in human glioma.  Specifically, the ABC2 funding allowed Agios to pursue a two-armed project devoted to 1) identifying biomarkers for glioma that, using signals from the mutant IDH enzymes and the chemical they produce, would permit rapid diagnosis and therefore earlier treatment of glioma and 2) generating new laboratory models of IDH-mutant glioma in which to test drugs targeting the mutant, dysfunctional IDH enzymes.

Following the success of both the funded project by ABC2 and ensuing IDH-directed research at Agios, Agios established a partnership with the global biopharmaceutical company Celgene to move its IDH-targeting drugs into clinical trials for human glioma.  The Agios/Celgene partnership sponsored the first clinical trial of a targeted therapy for IDH-mutant glioma as well as two subsequent trials of IDH-targeting drugs in the same patient population.  Preliminary data from all three trials suggest that those IDH-targeting drugs are well-tolerated and produce durable clinical activity in humans.  These drugs are currently undergoing ongoing clinical development and may soon lead to new treatment options for IDH-mutant glioma.