The investigators have discovered a unique class of gamma-secretase inhibitors that have demonstrated significant anti-cancer activity. Using a proprietary, high-throughput screening assay, the investigators identified GSI-34, a class of compounds structurally distinct from other GSIs currently utilized in clinical trials. Gamma-secretase inhibitors disrupt the Notch signaling pathway, which is involved in cell-to-cell communication and gene regulation, and is abnormally activated in many types of cancers, including chronic lymphocytic leukemia, diffuse large B-cell lymphoma, and breast cancer.
Studies have demonstrated that GSI-34 effectively blocks the migration and invasion of aggressive breast cancer cell lines. Furthermore, GSI-34 reduced primary tumor burden in a breast cancer mouse model, and had a profound effect on lung metastasis. The investigators are now planning preclinical toxicity/tolerance studies to support IND application.
GSI-34 outperforms other GSIs currently in development in terms of anti-tumor activity
The breast cancer market size is approximately $10.2B. The leukemia therapeutics market (ALL, CLL, AML, CLL) is approximately $4.0B, projected to reach $7.6B by 2018.
A number of GSIs, such as RO04929097, MK-0752, and PF3084014, are in early-stage clinical trials for the treatment of leukemia, lymphoma, and advanced solid tumors, however, no GSIs are currently on the market.
Leukemia, lymphoma, breast cancer
PCT application number PCT/US2009/068937 filed on December 21, 2009; National Stage filings pending in Europe, Japan, and Hong Kong; U.S. issued patent 9,056,857 (June 2015)
Dr. Yueming Li, PhD, Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering