THE RNA HELICASE EIF4A IS A THERAPEUTIC VULNERABILITY IN TRIPLE-NEGATIVE BREAST CANCER

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1 This application is being submitted in response to the Notice of Special Interest (NOSI) 2 identified as NOT-CA-22-039. Triple negative breast cancer (TNBC) is a biologically 3 heterogeneous and clinically important breast cancer subtype because if it were considered a 4 distinct disease, TNBC would rank as the 5th leading cause of cancer deaths in women. TNBC 5 also is more prevalent in younger premenopausal women especially Black or African Americans. 6 Protein translational regulation has been demonstrated to be a potential vulnerability in cancer 7 including TNBC. The eIF4A RNA helicase is a key regulator of translation initiation as part of the 8 eIF4F translation initiation complex. Interestingly, eIF4A selectively inhibits the translation of many 9 oncogene and growth factor mRNAs with highly structured 5’UTRs and is an essential gene in 10 many cancer cell lines. eFFECTOR Therapeutics has developed an improved eIF4A inhibitor, 11 Zotatifin (eFT226), that is currently being evaluated in a Phase I clinical trial (NCT04092673) in 12 patients with advanced solid tumor malignancies. In collaboration with eFFECTOR, we have 13 performed studies to determine the efficacy of Zotatifin in syngeneic genetically engineered 14 mouse (GEM) TNBC models developed in our laboratory. In these models a marked improvement 15 in tumor regression and time to end point was observed following combination treatment of 16 Zotatifin with standard-of-care either carboplatin or docetaxel. We now propose to expand these 17 studies to a series of racially and ethnically diverse TNBC PDX models with a special focus on 18 those derived from underserved populations in order to better identify which patients might benefit 19 from combination therapy in future clinical trials. Analysis of eIF4A protein expression across 20 TNBC PDX models has identified models with markedly different levels of Zotatifin target 21 expression. We now propose to optimize and elucidate mechanisms of single agent and 22 combination therapy with Zotatifin and chemotherapy across several high and low eIF4A PDX 23 models and to develop biomarkers to predict response. Our previous studies in GEM models 24 identified changes in the myeloid immune microenvironment including decreased infiltration of 25 neutrophils and repolarization of tumor associated macrophages to a less immunosuppressive 26 and more tumor inhibitory phenotype. Thus, we will also study effects of Zotatifin and 27 chemotherapy on circulating and tumor associated myeloid cells in these PDX models. In 28 summary, these preclinical studies may help provide key information to inform the design of future 29 clinical trials. Although these studies are initially focused on TNBC they may have a broader 30 application to other solid cancers.