Breast cancer (BC) is the most prevalent and second most lethal malignancy in females. Development of novel effective therapies for patients with therapy-resistant BCa (TR- BC) and triple negative BCa (TNBC) remains the highest unmet need in improving survival outcomes. Proline-, glutamic acid, and leucine-rich protein 1 (PELP1), is a proto-oncogene that plays a critical role in multiple nuclear receptor (NR) functions leading to BC progression. PELP1 expression is upregulated in BCa, promotes epigenetic changes through histone modification, is a prognostic indicator of poor BCa survival, and contributes to drug therapy-resistance and metastases. The focus of my F31 dissertation research is to develop a First-in- Class small molecule inhibitor targeting oncogenic PELP1 (SMIPs) and elucidate the efficacy as an advanced BC therapy. I hypothesize that PELP1 couples NRs with epigenetic modifiers and targeting this axis with SMIPs will have therapeutic utility in treating both TR-BC and TNBC. My preliminary data indicates lead compound, SMIP34, inhibits proliferation in an established panel of BCa cell lines with an IC50 between 3-10?M. Results indicate that SMIP34 has ability to block PELP1 oncogenic functions including reduction of cell viability and invasiveness and promotion of apoptosis.
Aim 1 will define the mechanisms by which SMIP34 functions as a PELP1 inhibitor. I will use multiple biophysical methods to confirm the direct interaction of SMIP34 with PELP1. I will further confirm specificity using conditional CRISPR knockout of PELP1. I will evaluate the ability of SMIP34 to inhibit the PELP1 oncogenic interactome and assess modulation of downstream signaling pathways using genome wide approaches including ChIP-Seq and Mass Spec analyses. The effects of SMIP34 treatment on gene expression will be determined by RNA-Seq and further analyzed in order to identify potential correlative biomarkers.
Aim 2 will evaluate the utility of SMIP 34 in treating advanced breast cancer using preclinical and PDX models. Immuno-competent CD1 mouse models will be used to study toxicity and to determine the maximum tolerated dose of SMIP34. Patient derived explant (PDEX) models will be utilized to characterize the ex vivo effects of SMIP34 on growth of human BC tumor explants. Both TR-BC and TNBC syngenic models, in addition to PDX orthotopic xenograft models, will be utilized to test the effects of treatment on tumor volume, disease progression, maximum tolerated dose, and observable toxicity. I will use IHC analyses of tumor tissues to confirm mechanism of action and efficacy. My long-term career objective is elucidating the mechanistic contributions oncogenic signaling in breast and gynecological cancers for the purpose of developing targeted therapies. Ultimately, the F31 Fellowship will provide multiple opportunities to develop my career as an independent extramurally funded investigator focused on novel translational advances in women's cancer therapeutics.
This proposal has the potential to benefit public health as I am committed to improving our understanding of the role of epigenetic modifiers and hormonal signaling in women's cancers with a goal of developing novel translational cancer therapeutics to positively affect disease-free interval and survival outcomes. My dissertation research focuses on development of a First-in-Class inhibitor of oncogenic PELP1 for the treatment of advanced BC. This proposal details a rigorous training plan for my development as an independent, translational, and collaborative cancer biologist with a passion for investigating knowledge gaps in the interrelated fields of epigenetics, endocrinology, and women's cancers.
