R44CA272064

PROJECT SUMMARY Metabolic reprogramming plays a critical role in carcinogenesis, in part due its ability to promote immune suppressive properties within tumors. It remains unclear whether inhibition of fatty acid metabolism in tumors affects their immunogenicity. We show that inhibition of stearoyl CoA desaturase 1 (SCD1), the rate limiting enzyme involved in fatty-acid synthesis converting saturated acids (SFA) to monounsaturated fatty acids (MUFAs), increases the immunogenicity of poorly immunogenic tumors. Our results indicate that inhibition of tumorigenic de novo lipogenesis represents a novel approach to enhance T cell-based cancer immunotherapy. In so doing, our novel lead SCD1 inhibitor (MTI-301; aka SSI-4) singly, and in combination with immune checkpoint inhibitors (ICIs) using immune competent mouse models demonstrates anti-tumor synergy sensitizing tumors to ICIs, as a prelude to an early phase clinical trial. We will also optimize efficacy and seek predictive biomarkers of response that could be useful for the design and stratification of patients in the critical Phase III clinical trial. SCD1 is universally upregulated in aggressive cancers and validated by MTI-301 antitumor activity across a broad range of cancer cell lines and tumor mouse models. Mechanistically, MUFA deprivation in addicted cancer cells leads to endoplasmic reticulum (ER) stress mediating apoptotic cell death. We discovered using immune competent mouse cancer models that MTI-301 activates the adaptive immune response via calreticulin/PERK arm of the ER stress pathway enhancing activated T cell tumor infiltration and thereby promoting anti-PD1 antibody therapy. Combined with anti-PD1 inhibitor, MTI-301 sensitizes tumors to immune checkpoint inhibitors in mouse triple negative breast cancer (TNBC) and HER2 breast cancer mouse models. Based upon these data, our central hypothesis is that aberrant de novo lipogenesis is linked to attenuation of tumor immunogenicity. Three aims are proposed in this fast-track Phase 1/2 SBIR proposal. In Aim 1 (Milestone 1, Phase I SBIR), GLP dog toxicology study will be completed to identify the No-observed- adverse-effect level (NOAEL) enabling calculation of the first in human dose for the phase I clinical trial. In Aim 2 (Milestone 2, Phase II SBIR), GMP MTI-301 will be synthesized and capsulated along with submission of the investigation of new drug (IND) application for FDA Phase I trial approval. In Aim 3 (Milestone 3, Phase II SBIR), a Phase I clinical trial will be performed and exploratory biomarkers including identification of immune infiltrates into the tumor site will be assessed. In summary, we envision SCD1 as a broad-spectrum anti-cancer target overexpressed in aggressive malignancies. Therapeutically useful, MTI-301 increases the immunogenicity of poorly immunogenic tumors thereby sensitizing to immune checkpoint blockade, leading to dramatic adaptive immune mediated tumor cell killing. This combination therapy should enhance patient response rates and be well tolerated in patients.