Development of a Novel Approach to Immunotherapy.

PROJECT SUMMARY/ABSTRACT. This phase 1 SBIR project proposes development of a new type of drug to improve the treatment of cancer. This new approach offers potential in many forms of the disease, including breast cancer, which is second only to cancer of the lung in terms of mortality. In particular, triple negative breast cancer (TNBC) is very challenging to treat as there are fewer therapeutic options compared to other forms of breast cancer. Recent additions to the oncology armamentarium include immunotherapies, such as immune checkpoint inhibitors (ICBi) targeting PD-1, PD-L1 or CTLA4, which offer great promise but still only benefit a minority of TNBC patients. Acetyl CoA synthetase 2 (ACSS2) is a nucleocytoplasmic enzyme that is involved in the conversion of acetate to acetyl CoA for use as a substrate for fatty acid biosynthesis and for acetylation of nuclear proteins. ACSS2 is commonly upregulated in tumor cells and high expression predicts poor outcomes in multiple cancer types including TNBC. Tumor cells use acetate derived from the gut microbiome as a substrate to support their ongoing proliferation and metabolic needs. In contrast, the related enzymes ACSS1 and ACSS3 are both mitochondrially located and thereby regulate a different pool of Acetyl CoA from ACSS2 and are rarely upregulated in cancer. Consistent with its association with human disease outcomes, genetic deletion of ACSS2 impairs tumor growth in tumor models in animals and small molecule inhibitors of ACSS2 provide beneficial effects in mouse models, including TNBC models that are resistant to ICBi. The ACSS2 knockout mouse has a normal phenotype suggesting that inhibition of this enzyme is likely to have a good safety/tolerability profile. This SBIR project will explore the potential of ACSS2 inhibitors alone and in combination with other therapeutic mechanisms in models of TNBC and will further the development of a proprietary series of ACSS2 inhibitors towards the aim of an orally available drug candidate suitable for clinical development. If successful we hope to significantly improve the therapeutic options for TNBC patients, impacting directly on improved survival and quality of life. In addition, we believe that a well-tolerated ACSS2 inhibitor drug will impact therapeutic outcomes in many more cancer types in addition to TNBC.