Abstract 5875: Development of LIFR inhibitor EC359 as a novel therapeutic for ovarian cancer
Authors: Suryavathi Viswanadhapalli, Hareesh B Nair, Bindu Santhamma, Gangadhara R Sareddy, Yiliao Luo, Xinlei Pan, Edward R Kost, Ramachandran Murali, Rajeshwar Rao Tekmal, Klaus J Nickisch, Ratna K Vadlamudi
Journal: Cancer Research (2018)

Abstract Background: Ovarian cancer (OCa) is the deadliest of all gynecologic cancers. OCa patients initially respond to standard combinations of surgical and cytotoxic therapy; however, ~80% will develop recurrence and inevitably succumb to chemotherapy-resistant disease. OCa stem cells are implicated in the tumor initiation and therapy resistance. LIFR signaling plays a critical role in OCa progression and stemness. Further, high circulating LIF levels correlate with tumor recurrence and chemoresistance. The autocrine loop involving LIF, LIFR and STAT3 axis drives sustained fibroblast production of inflammatory mediators. This represents a significant problem and a critical need exists for development of novel therapies targeting the LIFR axis for treating OCa. Methods: We have rationally designed and synthesized a small organic molecule (EC359) that emulates the LIF-LIFR binding site and functions as a LIFR inhibitor from a library of compounds. In silico docking studies were used to identify the putative interaction of the EC359 and LIF/LIFR complex. Binding of EC359 to LIFR was confirmed using surface plasmon resonance (SPR) and IP assays. Mechanistic studies were conducted using Western, RT-qPCR, and RNA-Seq analysis. Xenograft models were used for preclinical evaluation and toxicity. The efficacy of EC359 was tested using Patient-Derived eXplants (PDeX). Results: Global analysis of online databases revealed negative correlation of OCa survival with LIFR expression. Molecular docking studies showed EC359 interacts at the LIF-LIFR binding interface. SPR studies confirmed interaction of EC359 to LIFR. Western analysis of eight cells that represent four subtypes of OCa confirmed higher expression of LIF and LIFR. EC359 reduced the growth of eight OCa cells with high potency (IC50 10-50 nM) and promoted apoptosis. EC359 treatment reduced stemness of OCa cells. EC359 activity is dependent on the level of expression of LIFR with little activity on cells that do not express LIFR. EC359 significantly reduced the viability of carboplatin- and taxol-resistant OCa cells. Mechanistic studies showed EC359 interacts with LIFR and block its interaction with LIF. EC359 treatment reduced the STAT3 phosphorylation, mTOR and downstream survival signaling cascades. RNA sequencing revealed unique pathways blocked by EC359. Treatment of xenograft tumors with EC359 significantly reduced the tumor volume compared to control. Further, using PDeX of OCa, we demonstrated that EC359 has potential to reduce the proliferation. Pharmacologically, EC359 exhibited high oral bioavailability and long half-life with a wide therapeutic window. Conclusions: EC359 is a novel agent that targets LIF-LIFR axis and has activity against chemotherapy-resistant and primary OCa tumors. EC359 has the distinct pharmacologic advantages of oral bioavailability, in vivo stability, and is associated with minimal systemic side effects. Citation Format: Suryavathi Viswanadhapalli, Hareesh B Nair, Bindu Santhamma, Gangadhara R Sareddy, Yiliao Luo, Xinlei Pan, Edward R Kost, Ramachandran Murali, Rajeshwar Rao Tekmal, Klaus J Nickisch, Ratna K Vadlamudi. Development of LIFR inhibitor EC359 as a novel therapeutic for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5875.