Breast cancer is the most diagnosed cancer and the second leading cause of mortality. Triple-negative breast cancer (TNBC) is characterized by the absence of receptors for estrogen and progesterone as well as lack of HER-2 gene. These tumors are enriched in cancer stems cells and exhibit resistance to most treatments and chemotherapy. TNBC is more prevalent in younger females and accounts for about 10% to 20% of breast cancer incidence with poor prognosis._ Importantly, to date, no efficient therapy exists for this type of cancer._ In addition, it was reported that the chemotherapy drugs enriched CSCs in TNBC patients. Hence it is crucial to define new treatment options for these patients to prevent cancer relapse, drug resistance and metastasis.
We recently uncovered new role for CDK4-dependent in regulating cancer stemness and as a novel prognostic marker in TNBCs. The expression of CDK4 in TNBC patients correlates with worse clinical outcome. Moreover, we found that blocking this pathway, using a specific inhibitor of CDK4/6 (Palbociclib) could eliminate breast cancer stem cells (CSC) but also chemotherapy resistant breast cancer cells in TNBCs. These exciting results highlight CDK4 as promising therapeutic targets for the development of new therapies against TNBCs.
We are working on the design and development of small inhibitor compounds targeting CDK4 and Cox-2, based on their therapeutic value against cancer stem cells and chemotherapy-resistant cells in TNBCs. These new small molecules are tested in a variety of in vitro assays but also in vivo, using preclinical xenograft transplantation models of TNBCs. A second aspect of the project is dedicated to the development of new therapeutic approaches specifically targeting cancer stem cells, using combi-molecules that will target both CDK4 and Cox2.
To ensure the successful completion of this project, we are collaborating with Dr. Bertrand Jean-Claude. He is the Director of the Drug Discovery platform and the Co-Director of the McGill CIHR Drug Development Training Program. His research has pioneered the combi-molecule research field and his expertise and contribution will be invaluable.
The MUHC-RI drug design and development platforms are equipped with the best instrumentations. Of note, and relevant to this project, the MUHC-RI has acquired the full license for the Molecular Operating Environment (MOE) software, which will be instrumental for the completion of the computational modeling part it.