Immunometabolic pathways enabled by PARP inhibition in breast cancer

乳腺癌中 PARP 抑制启用的免疫代谢途径

• 批准号: 10417531
• 负责人: Jennifer L. Guerriero
• 金额: $ 47.05万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10417531
• 关键词: Address; Antineoplastic Agents; Antitumor Response; Bioenergetics; Breast Cancer Patient; Breast Cancer Treatment; Breast Oncology; CD8-Positive T-Lymphocytes; Cancer Patient; Cell Survival; Cell physiology; Cells; Cellular Metabolic Process; Cellular biology; Clinical; Clinical Trials; Cytotoxic T-Lymphocytes; DNA Damage; Data; Dependence; Development; Duct (organ) structure; Effectiveness; Equipoise; Excision; Exhibits; Goals; HMGA2 gene; Human; Immune; Immune checkpoint inhibitor; Immuno-Chemotherapy; In Vitro; Knowledge; Lead; Lipids; Mammary Neoplasms; Mediating; Metabolic; Metabolism; Mus; Neoplasm Metastasis; Nutrient; Outcome; Oxygen; PARP inhibition; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Poly(ADP-ribose) Polymerases; Positioning Attribute; Protein Biosynthesis; Proteomics; Regulation; Research; Resistance; SRE-1 binding protein; Sampling; Solid Neoplasm; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Translations; Treatment Efficacy; Tumor-associated macrophages; Work; adaptive immunity; angiogenesis; base; cancer therapy; cancer type; cellular imaging; clinical translation; design; early phase clinical trial; early phase trial; fitness; immune checkpoint blockade; improved; in vivo; inhibitor; inhibitor therapy; lipid biosynthesis; lipidomics; macrophage; malignant breast neoplasm; metabolic fitness; metabolomics; monocyte; mouse model; next generation; novel; novel therapeutic intervention; optimal treatments; programs; recruit; response; success; synergism; therapy resistant; trait; treatment response; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumorigenesis

PROJECT SUMMARY Tumor associated macrophages (TAMs) are abundant in solid tumors and drive tumorigenesis and resistance to therapy. Strikingly, a commonly used cancer drug, poly (ADP-ribose) polymerase inhibitors (PARPi), drive development of suppressive TAMs through metabolic remodeling and induction of lipogenesis that restrict T- cell activation and function. Conversely, T-cells treated with PARPi exhibit bioenergetic fitness, superior viabil- ity, and heightened effector function. While there is enthusiasm for combining PARPi with immune checkpoint blockade (ICB), based on potential synergy of T-cell activation of each class of drug, early phase clinical trials have not yet demonstrated the combination to be superior to PARPi monotherapy, suggesting lipogenic TAMs may limit PARPi + ICB responses. Thus, there is a critical need to elucidate the dichotomy of PARPi-induced metabolic remodeling to generate deleterious TAMs while promoting superior antitumor T-cells. In the absence of such knowledge successful strategies to harness the power of PARPi to benefit cancer patients are unlikely. The long-term goal is to design clinically effective strategies through TAM modulation to promote T-cell activa- tion and weaken the immune-suppressive TME to improve therapy in breast cancer patients. The central hy- pothesis is that lipogenic TAMs promote tumorigenesis in part through T-cell inhibition and are catalyzed by PARPi therapy, offering a unique therapeutic opportunity to enhance PARPi + ICB. The overall objectives are to (i) characterize TAM and T-cell metabolic regulation during PARPi and (ii) determine clinically effective strat- egies to regulate TAM metabolism to enhance T-cell activation and PARPi responses. The central hypothesis will be tested by pursing the following specific aims: 1) Define the mechanism of lipogenic macrophage de- velopment. Human and murine monocytes and macrophages will be used to formally define TAM lipogenesis catalyzed by PARPi and determine the mechanism by which TAM lipogenesis is induced during TNBC therapy using unbiased lipidomic as well as functional studies. 2) Test that lipogenic TAMs promote tumorigenesis through suppression of PARPi-mediated metabolic remodeling of adaptive immunity. Aim 2 will employ in vitro and in vivo protein synthesis, proteomics and metabolomic analysis to detail how PARPi induces T-cell metabolic fitness and define optimal metabolic perturbation for anti-tumor therapy. 3) Determine the optimal treatment strategy of PARPi and metabolic remodeling for rapid translation to breast cancer patients. Multiple TNBC mouse models will be employed to test if depletion of TAMs clears a path for T-cells with im- proved bioenergetic fitness fashioned by PARPi, metabolic remodeling, or the therapies combined. Unique clinical trial samples from patients treated with PARPi and PARPi + ICB will be assessed using state-of-the-art, single cell imaging to identify immune phenotype and function. Successful completion will reveal novel thera- peutic strategies to circumvent lipogenic TAMs while simultaneously activating metabolically superior antitumor T-cells and has potential for rapid clinical translation to increase the effectiveness of PARPi + ICB therapy.

项目总结