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Targeting M2-Tumor Associated Macrophages to overcome tumor immunity in metastatic castration-resistant prostate cancer

靶向 M2 肿瘤相关巨噬细胞克服转移性去势抵抗性前列腺癌的肿瘤免疫

基本信息

批准号：
9921343
负责人：
Jelani Chinelo Zarif
金额：
$ 15.36万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9921343
关键词：
Advisory Committees Autopsy Biometry Cancer Biology Cancer Cell Growth Cancer Patient Career Transition Award Castration Cell Proliferation Cells Cessation of life Clinical Coculture Techniques Cytotoxic T-Lymphocytes Data Dependence Disease Effectiveness Ensure Environment Etiology Faculty Foundations Glutamine Goals Grant Growth Growth Factor Health Human Immune Immune response Immune system Immunocompetent Immunologics Immunotherapy In Vitro Infiltration Institution K22 Award Knowledge Laboratories Lead Leadership Learning Lesion Life Malignant Neoplasms Malignant neoplasm of prostate Medical Membrane Glycoproteins Metabolism Mission Modeling Morbidity - disease rate Neoplasm Metastasis PC3 cell line Pathologist Peptides Postdoctoral Fellow Pre-Clinical Model Principal Investigator Prognostic Marker Prostate Cancer therapy Prostatic Neoplasms Public Health Research Research Personnel Research Proposals Resected Resistance Role Running Sampling Solid Neoplasm Surface T-Cell Activation Techniques Testing Tissues Training Tumor Immunity Tumor-associated macrophages Tumor-infiltrating immune cells United States Work Writing angiogenesis anti-CTLA4 anti-PD-1 anti-tumor immune response base cancer cell cancer diagnosis cancer immunotherapy cancer therapy castration resistant prostate cancer checkpoint therapy clinically relevant cytokine design effective therapy epithelial to mesenchymal transition fighting improved in vivo in vivo Model inhibitor/antagonist innovation macrophage mannose receptor men mouse model neoplastic cell novel outcome forecast prevent programs prostate cancer cell prostate cancer cell line prostate cancer model response single-cell RNA sequencing skills targeted treatment therapeutic target tumor tumor growth tumor immunology tumor metabolism tumor microenvironment tumor-immune system interactions tumorigenesis wound healing

项目摘要

Prostate cancer (PCa) is deadly once it metastasizes and continues to be an unmet medical need here in the United States. Increasing evidence has demonstrated that the prostate tumor microenvironment which, surrounds the cancer cells, significantly contributes to its progression, circumvention of current therapies, resistance to newer immune checkpoint therapies, and its survival. Using clinical samples, the principal investigator has found that the tumor microenvironment of metastatic castration-resistant prostate cancer (mCRPC) is infused with reactive stroma enriched with M2 macrophages known as M2-tumor-associated macrophages (M2-TAMs). His previous studies have partly elucidated how M2-TAMs and reactive stroma associate with primary and metastatic disease, identified five new surface-enriched markers on M2-TAMs, and has helped demonstrate that M2-TAMs are key regulators of PCa epithelial-to-mesenchymal transition (EMT) and tumorigenesis. Therefore, the need to design targeted therapies that target M2-TAMs within the tumor microenvironment is sorely needed. Other studies have demonstrated the importance of M2-TAMs in angiogenesis, metastasis, and their dependence on glutamine metabolism. Based on his data and that of other groups, the principal investigator hypothesizes that M2-TAMs are ideal therapeutic targets in mCRPC and help confer mCRPC resistant to immunotherapy. This proposal will determine novel M2-TAM marker expression in mCRPC (Specific Aim 1) and assess if the elimination of M2-TAMs in prostate cancer can reverse mCRPC immunotherapy resistance (Specific Aims 2, 3). This will be the first body of work using syngeneic mCRPC tumor models treated with either anti-CD206 peptide (RP182) or a novel glutamine antagonist, JHU083 followed by immunotherapy and a comprehensive immunological analysis of the tumor microenvironment. The principal investigator will also learn new techniques necessary to accomplish the proposed research under the advisement team (Drs. Drake, McConkey, Pardoll, Pienta, and Powell) and his pathologist consultant (Dr. De Marzo) all of whom have pioneering expertise in PCa biology, mCRPC treatment, cancer metabolism, single-cell RNA sequencing, and cancer immunotherapy. Importantly, his advisory committee collectively has a very strong track record of training both clinical and postdoctoral fellows who have been successful in transitioning into independent investigators at top tier research institutions. He will also engage in and present at national seminars, take coursework on laboratory biostatistics, cancer metabolism and immuno-metabolism, single cell RNA-sequencing, Jr. Faculty leadership program, grant-writing seminars, and training on running a laboratory. Combining these new skills learned during the K22 award period with his prior training in cancer biology and cancer immunology, will ensure a strong technical foundation to launch an independent laboratory dissecting and targeting innate immune cells and their mechanisms responsible for immunotherapy resistance, both of which are very poorly defined in mCRPC.

前列腺癌（PCa）一旦转移是致命的，并且在美国仍然是一个未满足的医疗需求