Novel STAT3 inhibitor for overcoming chemoresistant ovarian cancer .

Abstract/Summary Epithelial ovarian cancer (OC) is the fifth leading cause of death in women and the most lethal gynecological malignancy in the United States. OC is mostly diagnosed at an advanced stage. Patients undergo debulking surgery and chemotherapy or neoadjuvant chemotherapy and interval debulking surgery. Conventional drugs are carboplatin and paclitaxel. Despite the recent introduction of FDA-approved PARP- and VEGF-inhibitors for OC, the vast majority of patients will experience disease recurrence that requires additional treatment and recurrent OC is essentially incurable. New therapeutics to improve patient outcomes are needed. Transcriptional profiles have demonstrated that the master transcriptional regulator STAT3 to be highly active in OC, determined by increased phosphorylation in SH2-dimerization domain (pSTAT3-Y705) and induction of oncogenic factors. Active STAT3 in metastatic and chemoresistant OC correlates with poor patient survival, and inhibiting STAT3 with shRNA, or small molecules inhibited OC progression, supporting the objective of targeting STAT3 as a viable therapeutic strategy. Additionally, we demonstrate significant upregulation of STAT3 activity in OC cells is strongly associated with increased platinum resistance. We hypothesize that targeting STAT3 will block multiple oncogenic pathways and sensitize OC cells to chemotherapy. Although transcriptions factors (TF) like STAT3 are attractive therapeutic targets, TFs are challenging to target with small molecules due to lack of clear small molecule binding pockets, large surface areas important for protein-protein interactions and large intrinsically disordered domains. At Altay Therapeutics, we developed a platform that enables identification of small molecule binding pockets within intrinsically disordered domains in previously undruggable TFs, allowing a novel approach for specific targeting of STAT3 and development of potent STAT3 inhibitors (STAT3i). Using our platform, we identified inhibitors that reduced STAT3 DNA binding by targeting the disordered DNA binding domain. Importantly, these STAT3i have minimal STAT1 inhibitory activity, low cytotoxicity and when used in combination with CDDP, synergized and increased platinum sensitivity across OC cell lines. We propose three aims based on quantitative metrics that will clearly define the top candidate(s) which inhibit STAT3 compared to existing STAT3is and block OC progression. In Aim 1, we will determine STAT3 target gene inhibition and measure effects on secreted inflammatory factors with Altay’s novel STAT3is. In Aim 2, we will carry out in vitro phenotypic studies with human and transgenic mouse OC cells using STAT3is in combination with platinum chemotherapy. In Aim 3, we will determine antitumor activity of STAT3i using OC cells in orthotopic and intraperitoneal in vivo models alone and in combination with platinum chemotherapy. The proposed studies will establish the potential for targeting STAT3 in treating chemoresistant OC and guide new therapeutic strategies in this setting. We will then pursue an SBIR phase 2 grant that will include medicinal chemistry efforts and additional animal studies and ultimately commercialization of a first-in-class STAT3 inhibitor for OC.