Novel targeted combination therapies based on PIM kinase

Triple-negative breast cancer (TNBC) represents the BC subtype with the poorest clinical outcome. No targeted therapy has been FDA-approved to treat the vast majority of TNBC patients. We previously found that the oncoprotein MYC was activated in 50% of TNBC tumors. However, clinical development of small molecules MYC inhibitors has remained challenging. We took an alternative approach, known as the synthetic lethal approach, to identify druggable targets required for MYC-driven tumor viability, but that are not essential in healthy cells. Our MYC synthetic lethal screen identified PIM1 as a promising target. We found that PIM1 expression was elevated in clinical TNBC samples and was associated with poor outcomes. Preclinical PIM inhibitors showed activity in mouse models of TNBC. The goal of this study is to identify the treatment schemes in which the anti-tumor effects of PIM inhibition could be maximized without compromising safety. We have made a surprising observation that a PIM inhibitor, when combined with another inhibitor that targets the estrogen receptor subtype beta (ER-beta), can elicit significant anti-tumor effects in TNBC cells. Unlike the ER-alpha subtype, which is clinically and biologically well characterized as the major therapeutic target in ER positive (non- TNBC) tumors, ER-beta has been underappreciated especially clinically. We have also made yet another surprising observation that ER-beta, unlike ER-alpha, is abundantly and predominantly expressed in TNBC and it co-exists with MYC and PIM in clinical samples. The goals of our study are to determine the mechanism of drug synergy and the in vivo efficacy of the identified combination therapy.