1125 - Targeting Breast Cancer-Obesity Axis to Overcome Treatment Resistance

Purpose/Objective(s): Estrogen Receptor-positive (ER+) breast cancer (BC) is the most common obesity-associated cancer in the United States. Obesity in BC patients increases risk of endocrine therapy (ET) resistance, increases risk of toxicity from cancer treatments, and increases risk of BC recurrence and mortality. Cytokines secreted by adipocytes, referred to as adipokines, are key mediators of the effects of adipocytes on cancer cells and the surrounding tumor microenvironment. Leptin and endotrophin are two such adipokines, which link obesity to BC progression and treatment resistance. High serum and intratumoral leptin levels are associated with poor clinical outcomes in BC. Endotrophin, a collagen type VI–derived peptide, drives epithelial mesenchymal transition. High plasma endotrophin levels in BC patients are associated with worse BC-specific survival.

Materials/Methods: Recombinant leptin and endotrophin were used to assess the impact of adipokine stimulation on the growth of ET-resistant and CDK4/6 inhibitor (CDK4/6i)-resistant BC cells. Monoclonal humanized antibodies were developed against leptin and endotrophin and employed in xenograft studies to assess their therapeutic potential in targeting resistance to ET and CDK4/6i in BC.

Results: Treatment of ER+ MCF-7 and T-47D cells harboring ESR1 Y537S mutation (which confers resistance to ET) with 0.1 µg/mL of recombinant leptin and endotrophin was sufficient to cause more than 2-fold increase in proliferation relative to vehicle treated cells (p < 0.005 by unpaired t-test). We developed first-in-class humanized monoclonal antibodies against leptin and endotrophin and demonstrated high affinity (K_d < 10 nM) to the respective targets. Both leptin and endotrophin antibodies (200 µg, sub-q injection, 2x/week) caused significant inhibition in the growth of MCF-7 ESR1 Y537S xenograft growth as single agents, and caused complete xenograft growth inhibition when administered together. When combined with palbociclib, both leptin and endotrophin antibodies caused regression of MCF-7 ESR1 Y537S xenografts (all p< 0.005 by ANOVA with Dunnett’s test). Combination of leptin and endotrophin antibodies also caused complete inhibition of growth of CDK4/6i-resistant MCF-7 RB1-/- xenografts.

Conclusion: Both leptin and endotrophin are necessary and sufficient to promote the growth of treatment-resistant BC cells. First-in-class neutralizing antibodies against leptin and endotrophin show synergy in overcoming treatment resistance in BC xenografts. Our study offers a novel therapeutic approach for targeting the Obesity-BC axis, which is highly significant given that ER+ BC is the most common obesity-associated cancer in the U.S.