IGF::OT::IGF EVALUATION OF 'CLINICAL-READY' AGENTS (BAZEDOXIFENE AND LAPATINIB) IN COMBINATION FOR THE PREVENTION OF ER+ AND ER- MAMMARY CANCERSPOP 6/19/2017 - 6/18/2019

University Of Alabama At Birmingham, Birmingham AL

Investigators

Abstract

Multiple agents are in development to prevent breast cancer. Selective estrogen modulators (SERMs, specifically tamoxifen and raloxifene) and third-generation aromatase inhibitors are either FDA-approved and/or have been demonstrated in phase 3 trials to reduce breast cancer incidence significantly. The efficacy of these estrogen antagonizing agents is limited to prevention of ER+ breast cancers, however. Although other, more broadly applicable (ER+, ER-, triple negative) breast cancer prevention agents are currently being tested, these agents remain at early stages of development, with no immediate translational applicability to the clinic. Yet, a need exists for a broader spectrum of effective breast cancer prevention agents, with documented/established efficacy and minimal toxicity. Such ?clinical-ready? agents, already in clinical use for treatment of cancer and other diseases, offer prevention options that are poised for translation within a much shorter timeframe. Alternative modes of administration of these clinical-ready agents - including lower, potentially less toxic, doses, and combinations to enhance efficacy ? represent a viable approach to drug development for prevention. Two such agents are bazedoxifene and lapatinib. Bazedoxifene, a third-generation SERM, is approved in Europe for prevention and treatment of osteoporosis. In Europe and the United States, it is approved in combination with conjugated equine estrogens (CEE), as Duavee, for treatment of osteoporosis and vasomotor symptoms associated with menopause. As expected of a SERM, bazedoxifene inhibits growth of hormone-dependent (ER+) breast cancer cells, down-regulating the ER alpha protein, but without stimulating the uterine endometrium. In addition, bazedoxifene inhibits hormone-independent breast cancer cell growth and exhibits additional mechanistic activities such as down-regulation of cyclin D1 and inhibition of IL-6/GP130 protein-protein interactions resulting in induction of apoptosis and reduction of tumor growth. Such observations, together with a low toxicity profile, support the testing of bazedoxifene specifically for prevention of breast cancer. Lapatinib, a small molecule dual receptor tyrosine kinase inhibitor (RTKI) of both the epidermal growth factor receptor (EGFR/HER1) and human epidermal growth factor receptor-2 (HER2), is FDA-approved and is commonly used to treat patients with HER2-positive (HER2+) breast cancer. Lapatinib has been shown to inhibit development of ER+ tumors that develop in the Sprague-Dawley rat treated with the carcinogen methynitrosourea (MNU). Additionally, lapatinib suppresses abundance of HER2, phosphorylated HER2, and phosphorylated EGFR in this rat model and modulates a number of downstream signaling molecules associated with proliferation, apoptosis and cell-cycle arrest. Although lapatinib has specific toxicities, primarily diarrhea and rash, the drug is generally well tolerated at dose levels used in treatment of metastatic cancer. Early studies of the clinical efficacy of lapatinib as a breast cancer prevention agent are ongoing. Both bazedoxifene and lapatinib are approved for human use with minimal toxicity at the approved treatment doses. For this reason, they are poised to be rapidly incorporated into a cancer prevention trial once preclinical studies support such translation. These drugs work through different mechanisms and thus may complement each other?s activity resulting in synergistic or additive effects. The hypothesis emerging from these observations is that combination treatment with the two agents should enable the use of lower, presumably less toxic, doses and simultaneously lead to enhanced efficacy in inhibition of breast carcinogenesis. The overall objective of this task order is to test the efficacy of two FDA-approved drugs, Bazedoxifene and Lapatinib, at lower doses, alone and in combination, for prevention of breast cancers in rodent models of ER+ and ER- breast cancer.