P2-02-10: Differential Targeting of the RB-Pathway To Expand the Therapeutic Index in the Treatment of Triple Negative Breast Cancer.

Abstract

Abstract Background: The retinoblastoma tumor suppressor (RB) is inactivated in a significant fraction of triple negative breast cancers (TNBC). RB loss is believed to contribute to tumor initiation and progression, and provocative data suggest that RB loss is associated with improved response to cytotoxic chemotherapy. Unfortunately, such therapies have significant side effects that impinge on patient quality of life. Here we explored the ability to specifically target RB loss in TNBC to expand the therapeutic index by protecting against undesired side-effects of chemotherapy. Experimental Design: A combination of cell culture and xenograft models of triple negative breast cancer were used to evaluate how RB-status impinges on sensitivity to chemotherapy. These models were complemented by the analyses of clinical specimens from patients treated with chemotherapy. Parallel use of agents that activate RB function with high specificity were interrogated as potential tissue protectors to ameliorate side effect of chemotherapy. Results: RB loss in preclinical models is associated with increased sensitivity to conventional cytotoxic chemotherapies that are frequently employed in the treatment of TNBC. The findings were recapitulated through the analyses of clinical specimens, and suggest that the loss of RB could be particularly useful in defining TNBC patients with improved response to chemotherapy. Combination studies of pharmacological activation of the RB pathway and cytotoxic chemotherapies commonly used to treat TNBC demonstrated that activation of RB can modulate the efficacy of cytotoxic compounds in the treatment of TNBC. Importantly, functional studies indicated that RB pathway activation limits cardiotoxicity associated with anthracycline based treatments and correspondingly improve cardiac function in animal studies. Conclusions: Combined, these studies indicate that RB pathway status could be utilized in the clinic to direct combination treatments that would exploit the sensitivity of RB-deficient tumors to cytotoxic chemotherapies while simultaneously providing protection for normal tissues. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-02-10.