Targeted Inhibition of Leukemia Inhibitory Factor (LIF)/LIFR Axis for the Treatment of Triple-Negative Breast Cancer
Abstract
Triple-negative breast cancer (TNBC) tumors are associated with young age at diagnosis (<40 years), advanced disease, and African-American ethnicity, are more aggressive, have a higher propensity to metastasize to visceral site, and have the worst prognosis, contributing a disproportional share of the overall mortality from breast cancer. Standard chemotherapy regimens are only effective for patients with early TNBC; however, patients with advanced disease respond poorly to chemotherapy. At present, there are no proven effective targeted agents for treating TNBC. This application proposes to develop a novel first-in-class small molecule drug for the treatment of TNBC. Leukemia inhibitory factor (LIF) is a secreted cytokine that plays a critical role in promoting cytokine signaling that is needed for optimal survival of TNBC cells. Recent studies suggested that TNBC tumors induce expression of LIF in an autocrine and paracrine manner and that LIF-LIF receptor (LIFR)-associated signaling contribute to progression of TNBC to metastases and therapy resistance. We reasoned that interruption of LIF-LIFR signaling by a small molecule inhibitor impairs the growth of TNBC. This project address two overarching challenges: (1) Revolutionize treatment regimens by replacing them with ones that are more effective and less toxic and (2) eliminate the mortality associated with metastatic breast cancer. With our expertise in developing novel small molecule inhibitors that disrupt protein-protein interactions, we have rationally designed and synthesized a lead small organic molecule that can emulate the LIF–LIFR binding site and that function as LIF inhibitor (EC359) from a library of compounds. EC359 represent an exciting new mechanism to modulate LIF-LIFR oncogenic functions. We have validated that EC359 blocks the interaction between LIF and LIFR. In preliminary studies, EC359 blocked LIF-LIFR signaling and reduced cell viability of TNBC breast cancer cells both in vitro and in vivo. The objective of this proposal is to confirm the specificity, test in vivo activity and establish the mechanism, and conduct safety, efficacy, and off-target screening studies. Our hypothesis is that LIF signaling via LIFR play a critical role in TNBC progression and that disruption of LIF-LIFR interaction with the small molecule inhibitor EC359 will have a therapeutic effect. In this proposal, we will establish mechanism and complete safety, efficacy, and off-target effects that are needed to file the Investigational New Drug (IND) application for clinical development. The proposed studies will also test the therapeutic potential of EC359 to inhibit TNBC progression using preclinical models. The experiments testing the EC359 using the PDX models will provide clinically relevant information as to whether the disruption of the LIF-LIFR can be exploited to develop new therapeutic strategies against TNBC progression to metastases and therapy resistance. Further, LIF inhibitor EC359 may also have utility in treating other breast cancers subtypes such as therapy-resistant and metastatic ER+ve BCa that exhibit LIFR signaling. Since EC359 is a small, stable molecule, it is amenable to translation to clinical trials in patients with TNBC as monotherapy or in combination with current standard of care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810016
Entities
People
- Ratna K Vadlamudi
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio