Novel targeted therapy for treating Ovarian Cancer

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PROJECT SUMMARY: Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States. Patients with OCa initially respond to standard combinations of surgical and cytotoxic therapy; however, nearly 90% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. OCa stem cells are implicated in the tumor re- initiation and therapy resistance. Lack of targeted therapies that promote apoptosis of tumor cells and eliminate cancer stem cells in OCa represents a critical barrier. The goal of this Academic-Industry Partnership (AIP) grant application is to develop a novel targeted therapy for treating OCa. Through this AIP grant, we will establish a collaborative framework between the University of Texas Health at San Antonio and Evestra Inc., a San Antonio based biotech to create a novel targeted therapy for treating OCa. With Evestra Inc.'s expertise in developing novel small molecule inhibitors that disrupt protein-protein interactions, we have rationally designed and synthesized a first-in-class leukemia inhibitory factor receptor (LIFR) inhibitor, EC359. Our preliminary studies have shown that EC359 reduces the growth of OCa cells with high potency, promote apoptosis, reduce stemness, sensitize therapy resistant OCa cells and has in vivo activity with favorable PK parameters. The objective of this AIP proposal is to synthesize EC359 in grams using GLP protocol, establish its mechanisms, identify biomarkers, conduct efficacy studies using PDX models, and perform off target screening studies that are needed to file the Investigational New Drug (IND) Application to FDA. Our overarching hypothesis is that LIFR signaling plays a critical role in OCa progression, and disruption of LIF/LIFR signaling with small molecule inhibitor EC359 will have a therapeutic effect by promoting apoptosis of OCa cells, reducing stemness, and promoting anti-tumor immunity by altering the tumor microenvironment. Our AIP team is unique due to synergistic expertise in drug development, availability of GMP facility, experience with OCa biology, preclinical models and geographic proximity. In Aim1, we will evaluate translatability of EC359 by determining maximum tolerated dose, toxicity, biodistribution, in vivo efficacy using xenografts and PDX models and test the utility of EC359 in combination with standard of care chemotherapy. In Aim 2, we will define EC359 mechanisms, establish molecular correlates of EC359 activity using unbiased genomic and proteomic approaches, define the role and mechanism by which EC359 reduces stemness and determine the role of EC359 in reprogramming the anti-OCa immunity, including macrophages, in syngeneic and humanized mouse models. In Aim 3, we will synthesize EC359 using multi-gram scale, conduct metabolite studies, perform cardiovascular safety screens, and establish formulation and chemistry manufacturing controls. The studies proposed in this AIP proposal will establish a novel targeted therapy that will eliminate local tumor growth, reduce recurrence, and enhance the survival of OCa patients. EC359 could be utilized as a monotherapy, or in combination therapy or as a maintenance therapy, thus creating a new paradigm of novel targeted therapy for the treatment of OCa.