Enzyme Inhibitor Promotes Anticancer Immune Response

This novel enzyme inhibitor is a promising immunotherapy target that promotes antitumor immune response and increases tumor control when used with a tumor vaccine. Immunotherapy is one of the fastest growing, most promising forms of cancer treatment, and new immunotherapy drugs are consistently being approved and effectively used to treat a variety of cancers. Immunotherapy is already successfully used to treat lung and bladder cancer, leukemia, and melanoma. However, many forms of cancer, such as ovarian cancer, remain unaffected by currently available immunotherapy drugs. New immunotherapy targets are needed to develop drugs that impact cancers that have not been previously treatable with immunotherapy.

Description

Researchers at the University of Pittsburgh have identified a novel enzyme inhibitor that promotes antitumor immune response. This inhibitor blocks activity of aldehyde dehydrogenase-1A enzymes. These enzymes synthesize retinoic acid to regulate multiple cellular processes. When applied to immune cells, this enzyme inhibitor enhanced dendritic proliferation and drove T cell differentiation away from immunosuppressive regulatory T cells and towards cytotoxic T cells. Treatment of cancer cells induced immunogenic cell death. When applied in vivo along with a tumor vaccine this enzyme inhibitor significantly increased tumor control. These successes make this novel enzyme inhibitor a promising candidate for developing immunotherapies that act on aldehyde dehydrogenase-1A to treat cancers that have yet to be successfully treated with immunotherapy.

Applications

· Induces antitumor immune response and increases tumor control in difficult-to-treat forms of cancer

Advantages

· Induces anticancer immune response
· Targets immune cells rather than cancer cells
· Novel aldehyde dehydrogenase-1A family inhibitor

Invention Readiness

In vivo data

IP Status

https://patents.google.com/patent/WO2023059884A1

Related Publication(s)

Grimley, E., Cole, A. J., Luong, T. T., McGonigal, S. C., Sinno, S., Yang, D., Bernstein, K. A., & Buckanovich, R. J. (2021). Aldehyde dehydrogenase inhibitors promote DNA damage in ovarian cancer and synergize with ATM/ATR inhibitors. Theranostics, 11(8), 3540–3551. https://doi.org/10.7150/thno.51885

Huddle, B. C., Grimley, E., Chtcherbinine, M., Buchman, C. D., Takahashi, C., Debnath, B., McGonigal, S. C., Mao, S., Li, S., Felton, J., Pan, S., Wen, B., Sun, D., Neamati, N., Buckanovich, R. J., Hurley, T. D., & Larsen, S. D. (2021). Development of 2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one inhibitors of aldehyde dehydrogenase 1A (ALDH1A) as potential adjuncts to ovarian cancer chemotherapy. European Journal of Medicinal Chemistry, 211, 113060. https://doi.org/10.1016/j.ejmech.2020.113060

Chefetz, I., Grimley, E., Yang, K., Hong, L., Vinogradova, E. V., Suciu, R., Kovalenko, I., Karnak, D., Morgan, C. A., Chtcherbinine, M., Buchman, C., Huddle, B., Barraza, S., Morgan, M., Bernstein, K. A., Yoon, E., Lombard, D. B., Bild, A., Mehta, G., … Buckanovich, R. J. (2019). A Pan-ALDH1A Inhibitor Induces Necroptosis in Ovarian Cancer Stem-like Cells. Cell Reports, 26(11), 3061-3075.e6. https://doi.org/10.1016/j.celrep.2019.02.032

McLean, K., Tan, L., Bolland, D. E., Coffman, L. G., Peterson, L. F., Talpaz, M., Neamati, N., & Buckanovich, R. J. (2018). Leukemia inhibitory factor functions in parallel with interleukin-6 to promote ovarian cancer growth. Oncogene, 38(9), 1576–1584. https://doi.org/10.1038/s41388-018-0523-6