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Principal Investigator: BRIAN O BACHMANN
Organization: VANDERBILT UNIVERSITY
Fiscal Year: 2024
Award: $661,374
Funding agency: National Cancer Institute
PROJECT SUMMARY
Natural product therapeutics remain critically important in the treatment of cancer, with most patients diagnosed
with cancer receiving natural product-based chemotherapy, such as microtubule disrupting agents and DNA
intercalators. Select chemotherapeutic small molecules, the majority of which are natural products, have an
additional therapeutic benefit in their ability to stimulate a productive form of natural immunity against the cancer
cells that they injure or kill. For example, chemically induced damage associated molecular pattern expression
can recruit antigen presenting cells to phagocytose damaged cancer cells and display cancer cell antigens to
prime and activate T cells for adaptive immunity. Notably however, natural product induced anti-tumor immunity
properties of these select compounds were only discovered subsequent to their clinical application. We
hypothesize that the pathways by which such immunogenic natural products injure and kill cancer cells
determines the production of damage associated molecular patterns and ensuing innate and adaptive immune
responses against treated cells. We propose to develop and apply a high throughput, multiplexed, single cell
chemical biology assay platform for the discovery of chemically induced antitumor immunity. Using this system,
we will map the associations between regulated cell death and injury signaling in treated cells to functional
cellular markers of immunogenicity for several classes of known and new natural products. This goal will be
accomplished through three aims: (1) Discover and characterize secondary metabolites via regulated cell death
and injury cytometric phenotypes; (2) Define the relationships between cell injury and death signaling phenotypes
and damage associated molecular patterns, and immunogenic cell signaling in cancer and immune cells; (3)
Validate chemical agents inducing immunogenic cell injury and death via antigen cross priming assays and deep
cellular profiling using flow cytometry. Relevance: The successful completion of the proposed research is
relevant to human health because it will provide methods to accelerate the identification of potential anticancer
natural products, which have had and continue to have a large positive impact on human health. Furthermore,
the discovery of the multiplexed cell-targeting immuno-oncological structure-activity relationships within newly
discovered compounds and known but not commercially available compound families, may provide new targeted
therapeutics, with greater efficiency and reduced clinical toxicity.
Terms: <Acceleration><Adjuvant><Anti-cancer natural products><Anti-tumor Natural Products><Antigen Presentation><Antigen-Presenting Cells><Antigens><Assay><Bar Codes><Bioassay><Biological><Biological Assay><Biology><Cancer Induction><Cancer Treatment><Cancers><Cell Body><Cell Communication and Signaling><Cell Death><Cell Death Process><Cell Death Signaling><Cell Death Signaling Process><Cell Signaling><Cell-Mediated Lympholytic Cells><Cells><Cellular injury><Cessation of life><Chemical Agents><Chemicals><Chemistry><Clinical><Cross-Priming><Cultured Neoplastic Cells><Cultured Tumor Cells><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><DNA><DNA Intercalating Agent><Data><Death><Deoxyribonucleic Acid><Diagnosis><Drugs><Engraftment><Equilibrium><Exposure to><Family><Finding natural products><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Genome><Goals><Health><Human><Immune><Immune Modulation Therapy><Immune mediated therapy><Immunes><Immunity><Immunize><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologically Directed Therapy><Immunologics><Immunooncology><Immunotherapy><Injury><Innate Immune Response><Innate Immunity><Intercalating Agents><Intercalating Ligands><Intercalative Compounds><Intercalators><Intracellular Communication and Signaling><Lytotoxicity><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Maps><Measurement><Medication><Methods><Mice><Mice Mammals><Micro-tubule><Microtubules><Mining><Modality><Modern Man><Molecular><Murine><Mus><Native Immunity><Natural Immunity><Natural Products><Natural anti-cancer agents><Natural antineoplastic agents><Natural chemotherapeutic agents><Natural chemotherapeutic products><Natural product anti-neoplastics><Natural product discovery><Non-Specific Immunity><Nonspecific Immunity><Organism><Pathway interactions><Patients><Pattern><Pharmaceutical Preparations><Phenotype><Process><Production><Productivity><Property><Research><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Stimulus><Structure-Activity Relationship><System><T-Cell Activation><T-Cells><T-Lymphocyte><Therapeutic><Toxic effect><Toxicities><Treatment Efficacy><Tumor Antigens><Tumor Immunity><Tumor-Associated Antigen><Validation><Variant><Variation><Work><accessory cell><activate T cells><adaptive immune response><adaptive immunity><anti-cancer therapy><anti-tumor immunity><antitumor immunity><balance><balance function><barcode><biologic><biological signal transduction><cancer antigens><cancer cell><cancer immunity><cancer therapy><cancer-directed therapy><carcinogenesis><cell damage><cell injury><cellular damage><chemical structure function><chemotherapy><clinical applicability><clinical application><cytotoxic><cytotoxicity><damage to cells><drug/agent><flow cytophotometry><guided discovery><guided inquiry><immune modulating therapies><immune modulatory therapies><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immune-modulation treatment><immune-oncology><immuno oncology><immuno therapy><immunogen><immunogenic><immunogenic apoptosis><immunogenic cell death><immunogenicity><immunology oncology><immunomodulation therapy><immunomodulation treatment><immunomodulator therapies><immunomodulator treatment><immunomodulator-based therapies><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><injured><injuries><injury response><injury to cells><intervention efficacy><killer T cell><living system><malignancy><metabolism measurement><metabolome><metabolomics><metabonome><metabonomics><microbial><naturally occurring product><necrocytosis><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><next generation><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><oncoimmunology><pathway><recruit><response to injury><scaffold><scaffolding><secondary metabolite><small molecule therapeutics><structure function relationship><therapeutic efficacy><therapy efficacy><thymus derived lymphocyte><tumor><tumor-specific antigen><validations>