Abstract 1684: Combination of L-NMMA and sacituzumab govitecan as a novel targeted therapy for inflammatory breast cancer

Abstract Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer characterized by rapid progression, early metastatic potential, and distinct clinical and pathological features. The main treatment includes systemic cytotoxic therapy, surgery, and radiation. There is a need for novel targeted therapies to improve patients’outcomes. Inducible nitric oxide synthase (iNOS) is a mediator of various cancers including breast cancer. The pan-NOS inhibitor L-NMMA has been studied in preclinical and clinical settings, primarily focusing on cancers with high iNOS expression. Our preclinical studies provided the rationale for a recently completed phase I/II clinical trial of L-NMMA plus taxane for treating patients with triple-negative breast cancer (TNBC), with favorable toxicity and robust responses. Exploring the interaction between iNOS and IBC could identify novel therapeutic strategies, improving management approaches for this aggressive and highly lethal breast cancer subtype. Hypothesis: we hypothesize that, in combination with sacituzumab govitecan, the inhibition of iNOS by L-NMMA will significantly reduce tumor progression and survival in preclinical models of IBC. Sacituzumab govitecan is an antibody-drug conjugate where SN-38, a topoisomerase I inhibitor, is coupled to an anti-trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody, currently used in the treatment of TNBC. Experimental Procedures: The IBC xenograft SUM149 was orthotopically established in the mammary fat pad of female NSG mice by injection of 2x106 cells/mouse. Once tumors reached 200 mm3 in size, mice were randomly assigned into the following groups (n=7 mice per group): 1) Control (Saline, administered via i.p. injection); 2) Sacituzumab (administered at 5 mg/kg via i.v. injection weekly); 3) L-NMMA plus the calcium channel blocker amlodipine (LNMMA administered at 400 mg/kg on day 1 followed by 200 mg/kg per subsequent day by daily oral gavage; amlodipine administered at 10 mg/kg via i.p. injection daily); 4) Combination of Sacituzumab, L-NMMA, and amlodipine (Combo). Animals were treated as indicated for 21 days. Tumor size was monitored twice per week using caliper measurements. Results: The Combo treatment was more effective at reducing tumor volume than each individual drug (adj p value = 0.0010 by one-way ANOVA). Conclusions: Treatment with the Combo significantly reduced tumor growth compared to single drugs and control group. There was no statistically significant difference between the L-NMMA group and sacituzumab govitecan-treated mice. Overall, our findings demonstrate the synergism between L-NMMA and sacituzumab govitecan, highlighting the potential use of these drugs in future clinical trials. Citation Format: Karina A. Ortega Martinez, Maria F. Chervo, Wei Qian, Jianying Zhou, Liliana Guzman-Rojas, Ivonne D. Uzair, Gianmarco Melone, Mailin Li, Christoforos Thomas, Jenny C. Chang. Combination of L-NMMA and sacituzumab govitecan as a novel targeted therapy for inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1684.