Targeting the mTOR Pathway for the Prevention of Breast Cancer

Despite advances in its early detection and improved treatment options, breast cancer remains a significant health problem. Although breast cancer mortality is declining, preventing breast cancer or its progression is the most effective way of reducing breast cancer deaths. For women with estrogen receptor (ER)-positive breast cancers, anti-estrogen drugs are effective for both treatment and prevention. For women with HER2-positive breast cancer, anti-HER2 targeted therapies have been found to be effective for the treatment and are now being tested for the prevention of HER2-positive breast cancers. However, for women whose tumors lack ER, progesterone receptor (PR), and HER2 (aka triple negative breast cancer, TNBC), there are few options for targeted therapy. TNBC, which accounts for 10-20% of invasive breast cancers, is known to be more aggressive with poor prognosis, and is resistant to anti-estrogen or anti-HER2 therapies. The p53-mutant TNBCs are typically high grade with poorer prognosis even if treated with chemotherapy. TNBC tumors also frequently harbor BRCA1 gene mutations, especially in women with a family history of breast cancer. Evidently, there is a clear need for the clinical development of new agents with novel mechanisms of action, documented/established efficacy and minimal toxicity for the prevention of ER negative and Triple negative breast cancers. Accumulating data suggest that mTOR (mammalian target of rapamycin) is a crucial mediator of tumor progression and may be a promising target in a significant proportion of breast cancer patients. Deregulation of mTOR has been found in TNBCs and a mutation of the BRCA1 gene increases the phosphorylation and kinase activity of AKT1 and mTOR signaling pathways. Everolimus (mTOR inhibitor) is a second generation rapalog approved by the U.S. Food and Drug Administration to be used in combination with other agents to treat advanced-stage, hormone-receptor-positive, HER2-negative breast cancer in postmenopausal women. Further, everolimus is used to treat ER-positive tumors that have become resistant to anti-estrogen therapy. This drug is now being tested in clinical trials for the treatment of ER-negative breast cancer. Such “clinical-ready” agents, already in clinical use for treatment of cancer and other diseases, offer prevention options that may be primed for clinical translation within a much shorter timeframe, if favorable toxicity profiles can be established in the prevention setting. Alternative modes of administration of these clinical-ready agents - including lower, potentially less toxic doses, represent a viable approach to drug development for prevention of breast cancer. The overarching goal of this task order is to evaluate an mTOR inhibitor, Everolimus, for its chemopreventive efficacy in preclinical models with loss of BRCA1 and P53, and p53-mutant TNBC.