Triple Negative Breast Cancer (TNBC) is defined by the receptor status of the cells. TNBC does not express estrogen, progesterone, or Her-2 receptors. It is estimated that 1 million women worldwide are diagnosed with breast cancer each year. TNBC is the most deadly sub-type of breast cancer, accounting for ~15% of the breast cancer diagnoses and ~25% of breast cancer-related deaths. Median survival for 30% of the patients with TNBC is 1 year. TNBC arises more frequently in women younger than 60 years of age, particularly of African-American descent, and those who possess the BRAC1 mutation. Seventy-five percent (75%) of women, who have breast cancer with the BRAC1 mutation, will develop TNBC. TNBC has poor clinical outcomes because it is highly metastatic, resistant to chemotherapy, and lacks effective treatment options. Nirogyones approach is to develop small molecule MCT1/MCT4 dual inhibitors to shunt glycolysis, block metabolic symbiosis, prevent metastasis, and effectively treat TNBC. A novel lead molecule (NGT- 008) has already been synthesized, and evaluated in in vitro and in vivo pilot experiments. Preliminary data demonstrates that NGT-008 exhibits good potency against a TNBC cell lines, MDA-MB-231 and MDA-MB-468, good physicochemical properties, reasonable mouse pharmacokinetic profile, and modest in vivo efficacy. NGT-008 showed no cytotoxicity even at 10µM against several normal cell lines including muscle cells which are known to express MCTs. In this application, we propose to further characterize NGT-008 and its optimized analogs by conducting the following AIMS: (1) Develop analogs of NGT-008 with improved pharmacokinetic profile and potency by iterative synthesis and homology models of MCT1 and MCT4 to aid in the discovery of new improved lead compounds to increase in vivo efficacy (2) Extend in vitro cytotoxicity studies to other TNBC cell lines (3) Evaluate the in-vivo efficacy of the optimized analog in a mouse xenograft model of MDA-MB-231 while establishing a 3D co-culture system. The proposed work will determine the feasibility of NGT-008 or its optimized analog as a novel therapeutic agent to treat TNBC. Next steps will be to evaluate an optimized analog in additional in-vivo studies (orthotopic models, PDX models, dose response, dosing regimen, toxicology assessment, etc.) as determined by results from AIMS 1, 2, and 3 in order to nominate a pre-clinical candidate. This will be a part of Phase II application.
Public Health Relevance Statement: Project Narrative Triple Negative Breast Cancer (TNBC) is defined by the receptor status of cancer cells. TNBC does not express estrogen, progesterone, or Her-2 receptors. TNBC is the most deadly sub- type of breast cancer, accounting for ~15% of breast cancer diagnoses and ~25% of breast cancer-related deaths. Median survival for 30% of the patients with TNBC is only one year. TNBC has poor clinical outcomes because it is highly metastatic, resistant to chemotherapy, and lacks targeted treatment options. TNBC cells are highly glycolytic, and therefore over- express monocarboxylate (lactate) transporters (MCTs) that are crucial for the cancer cells to adapt to glycolysis for their survival. In this proposal we outline the development of small molecule MCT1/4 dual inhibitors as a new therapeutic approach to effectively treat TNBC.
Project Terms: Accounting; African American; Age-Years; American; analog; Animals; base; Biological Assay; Biological Models; Biological Process; Breast Cancer Cell; breast cancer diagnosis; c-myc Genes; cancer cell; Cancer cell line; Cause of Death; Cell Line; Cell membrane; Cells; Cessation of life; chemotherapy; Clinical; clinical candidate; Coculture Techniques; Consensus; Cytosol; cytotoxicity; Data; design; Development; Diagnosis; Docking; Dose; Drug Kinetics; effective therapy; efficacy study; Endothelial Cells; Energy-Generating Resources; Environment; Estrogens; Exhibits; experimental study; Failure; Family; Fibroblasts; Gene Expression Profile; Glucose; Glycolysis; Goals; Homology Modeling; Human; Hypoxia; hypoxia inducible factor 1; improved; In Vitro; in vivo; inhibitor/antagonist; insight; interest; Killings; Lactate Transporter; Lead; malignant breast neoplasm; Malignant Neoplasms; MDA MB 231; MDA-MB-468; Measures; Metabolic; Modeling; Molecular Profiling; mouse model; Mus; Muscle Cells; Mutation; Neoplasm Metastasis; Normal Cell; novel; novel strategies; novel therapeutic intervention; novel therapeutics; Outcome; overexpression; Oxygen; Patients; Pharmaceutical Chemistry; Phase; phase 1 study; Play; pre-clinical; prevent; Progesterone; Property; Protein Isoforms; Proteins; Pyruvate; receptor; Recurrence; Regimen; Resistance; response; scale up; screening; selective expression; Shunt Device; small molecule; Solid Neoplasm; Stromal Cells; success; Surveys; Symbiosis; System; targeted treatment; Testing; Therapeutic Agents; three dimensional cell culture; three-dimensional modeling; Toxicology; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; Umbilical vein; virtual; Woman; Work; Xenograft Model; Xenograft procedure
