Abstract 591: Expanding the therapeutic window through pharmacological activation of the RB pathway in breast cancer treatment

Triple negative breast cancer (TNBC) is a highly aggressive disease that is most often treated with cytotoxic chemotherapies, such as anthracyclines and platinum compounds. While effective for certain tumors, these therapies are known to cause severe toxicities in numerous tissues. Thus, targeting pathways to both exploit therapy-sensitive tumors and ameliorate tissue toxicity is of utmost significance. Loss of the retinoblastoma tumor suppressor (RB) protein is a frequent event in TNBC, and is expected to alter therapeutic sensitivity by perturbing cell cycle checkpoints and yielding a predilection towards cell death. Conversely, it is possible that the same principles that drive sensitivity to cytotoxic agents in an RB-deficient setting could be used to prevent toxicities in an RB-proficient setting (i.e. normal tissues). Thus, modulation of the RB pathway could be critical for expanding the therapeutic window in the treatment of breast cancer. To address this hypothesis, combination studies of pharmacological activation of the RB pathway and cytotoxic chemotherapies commonly used to treat TNBC were performed in vitro and in vivo. Results indicate that activation of the RB pathway can modulate the efficacy of cytotoxic compounds in the treatment of TNBC. The mechanisms behind these observations were attributed directly to RB-mediated regulation of DNA damage and repair signaling pathways, as well as apoptosis. RB-deficiency resulted in bypass of these mechanisms and thus enhanced sensitivity to cytotoxic therapies. These results were supported by in silico data demonstrating that RB-deficient TNBC is associated with better clinical outcome in response to chemotherapy. Importantly, functional studies indicated that RB pathway activation can provide protection against the toxicity of frequently used chemotherapeutic compounds in normal tissue. Combined, these studies suggest 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 Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 591. doi:10.1158/1538-7445.AM2011-591

Duke Scholars

Author Walter J. Koch Surgery, Cardiovascular and Thoracic Surgery