This Small Business Innovation Research (SBIR) Phase I application is in response to Funding Opportunity Announcement PA-12-088. Tumor-stromal interactions are increasingly recognized as critical components of the progression of human neoplasias, including tumor invasion and metastasis. Utilizing a novel high- throughput screening approach developed by the applicants, compounds will be identified having superior anti- myeloma activity in the presence of bone marrow stromal cells. This system more closely replicates the interactions of tumors and non-malignant tissues in patients, allowing the discovery of more clinically effective therapeutics compared to cell autonomous approaches. This proposal, in collaboration with the Conrad Prebys Center for Chemical Genomics (CPCCG) at Sanford-Burnham Medical Research Institute, focuses on screening a large compound collection against multiple myeloma cancer cell lines in the presence and absence of non-malignant bone marrow stromal cells to identify compounds with superior activity in a tumor microenvironment context. Probes will be further evaluated against a larger panel of tumors and non-malignant stromal cells to examine their broader activity. This technology and approach is a revolutionary advancement over current cell autonomous systems and has the potential to identify new first-in-class, FDA-approved and marketed drugs missed using conventional drug discovery approaches.
Public Health Relevance Statement: Public Health Relevance: The approach outlined herein, utilizing a tumor-microenvironment platform, represents a paradigm shift in how drugs can be discovered and developed for cancer. Although genetic drivers are critical, the interactions between tumors and non-malignant tissues can dramatically affect the sensitivity of tumors to treatment. Until now these interactions have not been extensively modeled for preclinical drug discovery, especially considering the high-throughput features necessary to perform large scale primary screens. Our approach will increase the likelihood of a rapid and effective translation of therapeutics from discovery to market for multiple myeloma. Utilizing the platform, originally developed at the Dana-Farber Cancer Institute, Harvard Medical School and published in Nature Medicine1, the Investigators previously identified a novel agent active against multiple myeloma1 which was significantly more active against target tumor cells in the presence of bone marrow stromal cells than their absence. The compound was further shown to be active in an orthotopic mouse model recapitulating bone lesions observed in patients. By screening a larger compound collection, the proposed studies will identify additional novel probes with superior activity in a bone setting allowing for the generation of novel IP and more effective agents for translation to the clinic.
NIH Spending Category: Biotechnology; Cancer; Hematology; Orphan Drug; Rare Diseases
Project Terms: Affect; Biological Assay; bone; Bone Marrow; Cancer cell line; Cell Communication; Cells; Characteristics; Chemicals; Clinic; Collaborations; Collection; Dana-Farber Cancer Institute; Data; drug discovery; drug market; Exhibits; FDA approved; Funding Opportunities; Future; Generations; Genetic; Genomics; Health; high throughput screening; Human; In Vitro; Lesion; Luciferases; Malignant Neoplasms; Marketing; Medical Research; medical schools; mouse model; Multiple Myeloma; Nature; Neoplasm Metastasis; Neoplasms; neoplastic cell; Non-Malignant; novel; Patients; Performance; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Principal Investigator; programs; Publishing; Research Institute; Research Personnel; response; screening; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Stromal Cells; Stromal Neoplasm; System; technical report; Technology; Testing; Therapeutic; Tissues; Translations; tumor; Tumor Cell Invasion; Tumor Cell Line; tumor microenvironment; Tumor Tissue; Validation
