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.
Public Health Relevance Statement: PROJECT NARRATIVE. Every year in the US about 600,000 people die of one form of cancer or another. In this Phase I SBIR, Cadre Bioscience seeks to develop a novel drug that will not only have direct anti-tumor effects but will improve the disappointing response rates of immune-boosting therapies currently available. We will initially target triple-negative breast cancer but this mechanism holds promise in a wide range of other cancer types.
Project Terms: Cytotoxic T-Lymphocyte-Associated Serine Esterase-4; cytotoxic T-lymphocyte antigen 4; programmed cell death protein 1; PD 1; PD-1; PD1; programmed cell death 1; programmed death 1; sle2; systemic lupus erythematosus susceptibility 2; Mammary Neoplasms; Breast Neoplasms; Breast Tumors; Mammary Cancer; mammary tumor; Breast Cancer Model; Breast tumor model; mammary cancer model; mammary tumor model; cytotoxic; Breast Cancer Cell; breast tumor cell; Immunocompetent; immune competent; Pre-Clinical Model; Preclinical Models; Prediction of Response to Therapy; predict therapeutic response; predict therapy response; predict treatment response; therapy prediction; treatment prediction; treatment response prediction; Proliferating; in vivo; Cancer Cell Growth; Cancer Patient; therapy outcome; therapeutic outcome; Patient-Focused Outcomes; Patient outcome; Patient-Centered Outcomes; patient oriented outcomes; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Tumor Immunity; anti-tumor immunity; antitumor immunity; cancer immunity; Tumor Promotion; Protein Acetylation; Knock-out; Knockout; Tracer; Cellular Metabolic Process; cell metabolism; cellular metabaolism; Enzyme Inhibition; Development; developmental; triple-negative invasive breast carcinoma; TNBC; triple-negative breast cancer; tumor microenvironment; cancer microenvironment; therapy resistant; resistance to therapy; resistant to therapy; therapeutic resistance; treatment resistance; Minority; new approaches; novel approaches; novel strategy; novel strategies; tumor xenograft; Outcome; Population; cancer type; Impairment; resistant; Resistance; human disease; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; murine model; mouse model; tumor; malignant phenotype; drug candidate; Breast Tumor Patient; Breast Cancer Patient; anti-tumor effect; antitumor effect; B7-H1; B7H1; CD274; PD-L1; PDL-1; PDL1; Programmed Cell Death 1 Ligand 1; Programmed Death Ligand 1; programmed cell death protein ligand 1; protein death-ligand 1; programmed cell death ligand 1; GI microbiome; digestive tract microbiome; enteric microbiome; gastrointestinal microbiome; gut-associated microbiome; intestinal biome; intestinal microbiome; gut microbiome; small molecule inhibitor; clinical development; check point blockade; checkpoint blockade; immune check point blockade; immune checkpoint blockade; Checkpoint inhibitor; immune check point inhibitor; Immune checkpoint inhibitor; antitumor immune response; anti-tumor immune response; lead optimization; scRNA-seq; single cell RNA-seq; single cell RNAseq; single cell expression profiling; single cell transcriptomic profiling; single-cell RNA sequencing; Hypoxic tumor; tumor hypoxia; inhibitor therapy; inhibitor drug; inhibitor therapeutic; pharmacologic; Nutrient availability; Acetates; Acetyl CoA; S-acetate Coenzyme A; Acetyl Coenzyme A; Acetate Thiokinase; Acetothiokinase; Acetyl Activating Enzyme; Acetyl CoA Synthetase; Acetyl Coenzyme A Synthetase; Acetate-CoA Ligase; Acetylation; Affect; Animals; inhibitor; Antibodies; accessory cell; Antigen-Presenting Cells; Biological Availability; Bioavailability; Physiologic Availability; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; malignant breast neoplasm; Breast Cancer; malignant breast tumor; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Carbon; Cell physiology; Cell Function; Cell Process; Cellular Function; Cellular Physiology; Cellular Process; Subcellular Process; Cells; Cell Body; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Enzymes; Enzyme Gene; Fatty Acids; Flow Cytometry; Flow Cytofluorometries; Flow Cytofluorometry; Flow Microfluorimetry; Flow Microfluorometry; flow cytophotometry; Goals; Immunotherapy; Immune mediated therapy; Immunologically Directed Therapy; immune therapeutic approach; immune therapeutic interventions; immune therapeutic regimens; immune therapeutic strategy; immune therapy; immune-based therapies; immune-based treatments; immuno therapy; Laboratories; Lead; Pb element; heavy metal Pb; heavy metal lead; Lipids; Metabolism; Intermediary Metabolism; Metabolic Processes; Mitochondria; mitochondrial; mortality; Mus; Mice; Mice Mammals; Murine; Persons; Nuclear Proteins; Oxygen; O element; O2 element; Phenotype; Production; Quality of life; QOL; Research Personnel; Investigators; Researchers; Safety; Starvation; Stress; T-Lymphocyte; T-Cells; thymus derived lymphocyte; Vascularization; CD27 Antigens; T-Cell Activation Antigen; TNFRSF7 Receptor; cytokine; Measures; Mediating; Label; improved; Phase; Series; KO mice; Knock-out Mice; Null Mouse; Knockout Mice; Hypoxic; Oxygen Deficiency; Hypoxia; Malignant Tumor of the Lung; Pulmonary Cancer; Pulmonary malignant Neoplasm; lung cancer; Malignant neoplasm of lung; analog; anti-cancer immunotherapy; anticancer immunotherapy; immune-based cancer therapies; immunotherapy for cancer; immunotherapy of cancer; cancer immunotherapy; Oncology Cancer; Oncology; Chemotactic Cytokines; Homologous Chemotactic Cytokines; Intercrines; SIS cytokines; chemoattractant cytokine; chemokine; Leucocytic infiltrate; Therapeutic; stable isotope; Metabolic; Effector Cell; Genetic; cancer cell; Malignant Cell; programs; Immune; Immunes; Oral; Source; Route; experience; fatty acid biosynthesis; neoplastic cell; Tumor Cell; tumor growth; synergism; T-Cell Depletion; T-cell depletion therapy; T-lymphocyte depletion therapy; Nutrient; Disease Outcome; novel; Pharmacodynamics; Modeling; Property; response; unpublished works; cancer therapy; Cancer Treatment; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; anti-cancer therapy; anticancer therapy; cancer-directed therapy; metabolomics; metabolism measurement; metabonomics; small molecule; CTLA4 gene; CD152; CD152 Antigen; CD152 Gene; CTLA 4; CTLA-4 Gene; CTLA4; CTLA4-TM; Cytotoxic T-Lymphocyte Protein 4; Cytotoxic T-Lymphocyte-Associated Antigen 4; Cytotoxic T-Lymphocyte-Associated Protein 4
