Targeting Genetic Changes in IDH-Mutant Gliomas with a Novel Use of an FDA-Approved Drug

Gliomas account for nearly 80% of all malignant brain tumors, and they are rarely curable. Current treatment consists of brain surgery to remove the tumor, followed by radiation and chemotherapy. While this strategy may prolong survival, it does not target the genetic changes which lead to recurrence of these fatal tumors. Our novel use of a currently FDA-approved drug to treat a subset of universally fatal gliomas -isocitrate dehydrogenase(IDH)-mutant gliomas –facilitates genetic changes that flag cancer cells as targets for the immune system. Following treatment, we observed reduction of tumor size and severity in both mice and human subjects. These results suggest that our novel use of this drug for patients with IDH-mutant gliomas will lead to significantly improved outcomes.

These MRI brain scans display a patient with diffuse IDH mutant glioma treated before (A) and after (B) three months of treatment.

Description

Our novel use of the drug works by reversing the immune-evasive properties of IDH-mutant gliomas. The immunotherapeutic properties of this compound are due to activation of immune target receptors specifically in cancer cells, rendering them significantly more susceptible to killing by NK cells and T cells. In addition, treatment reduces tumor size and growth by modulating IDH-mutant cancer cell death and differentiation. Compared to current broad-spectrum treatments like tumor resection, radiation, and chemotherapy, our genetically targeted immunotherapeutic approach may avert tumor recurrence.

Applications

· Immunotherapy adjuvant with surgery, chemotherapy, and radiation treatment
· Prevention of recurrence and treatment resistance
· Treatment of cancer cells and tumor boundaries unreachable by surgery

Advantages

· Safety profile established: the drug is FDA-approved and currently in use for other therapeutic purposes
· Specific to IDH-mutant genetic changes in cancer cells
· Regulates biological processes which reduce tumor size and growth

Invention Readiness

In vivo mouse and human data

IP Status

https://patents.google.com/patent/US10821091B2

Related Publication(s)

Amankulor, N. M., Kim, Y., Arora, S., Kargl, J., Szulzewsky, F., Hanke, M., Margineantu, D. H., Rao, A., Bolouri, H., Delrow, J., Hockenbery, D., Houghton, A. M., & Holland, E. C. (2017). Mutant IDH1 regulates the tumor-associated immune system in gliomas. Genes & Development, 31(8), 774–786. https://doi.org/10.1101/gad.294991.116

Zhang, X., Rao, A., Sette, P., Deibert, C., Pomerantz, A., Kim, W. J., Kohanbash, G., Chang, Y., Park, Y., Engh, J., Choi, J., Chan, T., Okada, H., Lotze, M., Grandi, P., & Amankulor, N. (2016). IDH mutant gliomas escape natural killer cell immune surveillance by downregulation of NKG2D ligand expression. Neuro-Oncology, 18(10), 1402–1412. https://doi.org/10.1093/neuonc/now061