Abstract MS1-3: Clinical Development of mTOR Inhibitors in Breast Cancer

Abstract

Abstract mTOR is a serine/threonine kinase involved in cancer cell metabolism and protein synthesis. mTOR induces phosphorylation of estrogen receptor and resistance to endocrine therapy in preclinical models. Based on this rationale, clinical trials have evaluated whether first generation of mTOR inhibitors could reverse resistance to endocrine therapy. Two randomized trials, including one registration trial, have reported that everolimus improves progression-free survival in patients resistant to non-steroidal aromatase inhibitors. These data are consistent with a phase II randomized trial performed in the neoadjuvant setting. One large phase III trial performed with temsirolimus failed, mainly due to dose intensity of the drug and patient population. Overall, these finding suggest that rapalogs could reverse resistance to endocrine therapy. These data open several avenues in the field of breast cancer. First, two trials are starting that evaluate the efficacy of everolimus in the adjuvant setting. These trials evaluate everolimus either frontline or after 2–3 years of endocrine therapy. Second, rapalogs are being tested in other breast cancer subtypes including Her2-overexpressing breast cancers and triple negative breast cancers. Indeed, mTOR has been shown to be involved in trastuzumab resistance in preclinical studies. Early trials have suggested that mTOR inhibition could reverse trastuzumab resistance. mTOR inhibitors have also been shown to synergize with cisplatin in preclinical models, and this combination is currently being evaluated in a phase II randomized trial. Finally, several mechanisms of resistance to rapalogs have been identified. This includes positive feedback loops and lack of optimal bioactivity on p4EBP1. Rapalogs indeed mediate activating feedback loops that in turn induce a paradoxical activation of kinase pathways. Based on this observation, several trials have started that evaluate the combination between Rapalogs and IGF1R inhibitors. Preliminary results from phase I trial suggest that this combination is active in ER+/highly proliferative disease. Although they induce optimal inhibition of pS6K, several studies have reported that rapalogs could be suboptimal to inhibit p4EBP1, a protein downstream of mTORC1. 4EBP1 is involved in protein synthesis. Second generation mTOR inhibitors (mTORC1/C2 inhibitors) present an increased bioactivity on 4EBP1, in addition to avoid mTORC2-mediated feedback loop. This second generation mTOR inhibitor is being tested in early phase trials. Overall, rapalogs have opened the path for the development of mTOR inhibitors in the field of breast cancer. This will further improve outcome by exploring new indications and by developing strategies to reverse resistance. Finally, the development of mTOR inhibitors will dramatically increase our knowledge on the role of metabolism and protein translation in cancer progression. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr MS1-3.