FoXM1 inhibition: a novel therapeutic avenue to treat breast cancers

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Abstract The training goal of this diversity supplement grant is for Daisy Medina to gain valuable skills in translational research methods and further her career development in such a way that will allow her to become a successful independent researcher. The research goal of this diversity supplement award will be to investigate the role of FOXM1-associated signaling in supporting rescue DNA repair pathways (e.g. alt-NHEJ) and consequently breast cancer growth, progression and drug resistance through the use of FOXM1 inhibitor that we have developed. A significant proportion of ER+ BCs, which account for ~70% of all BCs, initially respond to antiestrogens or aromatase inhibitors, but become therapy resistant and progress to incurable metastases. Furthermore, TNBC accounts for 10-20% of BC cases, commonly occur in younger women, have higher propensity to relapse and contribute to disproportionate number of deaths in BC. FOXM1 is a proto-oncogene that is highly expressed in ER+ and TNBCs and promotes tumor growth, progression as well as therapy resistance. As part of the parent grant, we propose that FOXM1 may promote ER+ and TNBC growth and therapy resistance by supporting alternative (backup) DNA repair pathways; and a novel FOXM1 inhibitor (Imipramine Blue; IB) that we recently developed, will block FOXM1’s DNA repair ability and sensitize breast cancer cells to standard of care therapies. To achieve these goals, the trainee will focus her efforts on the following aims as part of the contributions to this supplement. Aim 1. To characterize the IB-target protein interactions and determine the mechanism(s) by which IB regulates its target genes in TNBC and ER+BC. In this aim, we will establish whether IB treatment depletes FOXM1 by directly binding to the protein or whether it acts downstream and disrupts positive feedback activation of FOXM1 using biophysical, structure-based and molecular biology approaches. Mechanistic studies will also determine whether IB has FOXM1-independent effects. Aim 2. To elucidate the mechanism(s) by which IB inhibits TNBC and ER+BCs growth/metastasis and sensitizes chemotherapy and anti-endocrine therapy response. In this aim, we will test the hypothesis that IB inhibits TNBC and ER+BCs growth, metastasis, and enhances therapy response by inhibiting alternative/backup DNA repair pathways that these cancers employ to survive and progress. To accomplish these goals, we will use target gene overexpression, knockdown cell models, biochemical, immunofluorescence, radiolabeled ligand binding, confocal microscopy and DNA repair assays. Aim 3. To test the hypothesis that IB is a safe and viable therapeutic for treating TNBC and ER+BC. In this aim, we will rigorously test the therapeutic potential of IB in blocking the growth and progression of TNBC and ER+BC; by which improving the efficacy of chemotherapy using patient derived xenografts (PDX) in humanized mice and by using human breast cancer explant (PDEx) studies. Successful completion of this study will contribute significantly to a better understanding of the DNA repair mechanisms that TNBC and therapy resistant ER+ breast cancer cells employ to survive and progress. This study will also set the stage for a new way of treating TNBC and therapy resistant ER+BC using IB as a therapeutic.