Partnership for the Advancement of Cancer Research Project
Doxorubicin is one of the most effective and widely used chemotherapy agents for breast cancer. However, resistance to this anthracycline agent is common, leading to treatment failure and poor prognosis. Triple negative breast cancer (TNBC), a clinical subtype type seen disproportionately in African American and Latina women is characterized by higher recurrence and lower overall survival following anthracycline treatment. Developing targeted therapies for TNBC, especially those that do not respond to doxorubicin, is the most urgent priority for the clinical treatment of this aggressive disease. The tumor suppressor p53 is mutated in 43-62% of breast cancers, so therapies designed to increase the sensitivity of p53 mutant breast cancer cells to genotoxic therapy would be immensely beneficial. We have identified several candidate gene targets that when depleted sensitized p53 mutant cancer cells to doxorubicin. We hypothesize that targeting these doxorubicin survival genes will lead to p53 independent apoptotic or mitotic cell death and will sensitize breast tumors to doxorubicin. Our partnership combines expertise in DNA repair, cancer biology, and functional genetics together with the outstanding research environments of Fred Hutch and NMSU. Our objectives in this pilot proposal are:
1. Identify mechanisms leading to p53 independent cell death.
2. Valudate candidate therapeutic targets in preclinical models of breast cancer.
Because doxorubicin resistance leads to treatment failure and subsequent mortality, these findings will elucidate new strategies to treat these unresponsive aggressive tumors.