Precision whole-body imaging of pancreatic cancer senescence with ImmunoPET

使用ImmunoPET 对胰腺癌衰老进行精确的全身成像

• 批准号: 10712147
• 负责人: Edwin Charles Pratt
• 金额: $ 0.25万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2025-06-18
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712147
• 关键词: Antibodies; Antibody Specificity; Antibody Therapy; Biological; Blood Vessels; Cell Aging; Cells; Cessation of life; Chelating Agents; Clinical; Cytostatics; Detection; Diagnosis; Disease; Early Diagnosis; Fellowship; Fluorouracil; Future; Histology; Human; Image; ImmunoPET; Immunocompetent; Immunotherapy; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Isotopes; Leucovorin; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Modeling; Modification; Molecular Chaperones; Mus; Neoplasm Metastasis; Nude Mice; Oncogenes; P-Selectin; Pancreas; Patients; Pharmaceutical Preparations; Phenotype; Population; Positron-Emission Tomography; RANTES; Radiation; Regimen; Resistance; Specificity; Stains; Survival Rate; Testing; Therapeutic; Time; Tissues; Tracer; Tumor Tissue; VEGFA gene; Vascular Endothelial Growth Factors; Visualization; Work; beta-Galactosidase; bevacizumab; cancer cell; cancer therapy; carcinogenesis; cell type; chemotherapy; cytokine; effective therapy; gemcitabine; imaging agent; improved; in vivo; inflammatory marker; irinotecan; non-invasive imaging; novel therapeutics; oxaliplatin; pancreatic cancer model; pancreatic cancer patients; pancreatic neoplasm; patient derived xenograft model; phenotypic biomarker; precision medicine; preservation; radiotracer; refractory cancer; senescence; sex; small molecule; targeted imaging; targeted treatment; trafficking; tumor; tumor microenvironment; tumorigenesis; tumorigenic; uptake; whole body imaging

Project Summary Pancreatic cancer is the fourth most prevalent cancer death in both sexes with less than 10% overall survival over 5 years. In patients diagnosed with pancreatic cancer, first-line chemotherapy with gemcitabine often requires second-line therapies such as FOLFIRNOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin), with median survival ranging from 6 to 26 months. While the survival of pancreatic cancer has not dramatically progressed with new therapeutic combinations, most of the chemotherapeutic regimens used for pancreatic cancer induce senescence. Cells can undergo senescence through replication, oncogene induction, as well as targeted drug therapy. Senescent cells have been implicated in tumorigenesis via pro inflammatory factors secreted by senescent cells and modification of the tumor microenvironment. It is unknown to what degree senescence occurs in patient tumors and how the senescence-associated secretory phenotype (SASP) changes with therapy. Immunotherapy has revolutionized many cancer treatments with precision medicine and targeted antibody therapies, but these treatments have lent only a modest increase in survival time to pancreatic cancer patients. Newer methods to target pancreatic cancer and identify senescent pancreatic cancer during treatment are needed. Recent work from the Scott Lowe Lab demonstrated that pancreatic cancer senescence could be induced with the combination of trametinib and palbocicilib, leading to the release of cytokines that remodel the tumor microenvironment. The current gold standard method for identification of senescence cells has focused on a small molecule for lysosomal trafficking with beta- galactosidase activity. Specific markers for SASP using antibody-based agents are needed. Previously elevated SASP markers include VEGF, P-selectin, uPAR, CCl2 and CCL5, and Interleukins 1, 6, and 12. This fellowship proposes to use clinically available antibodies against known SASP markers to visualize and quantify SASP activity in vivo with ImmunoPET. By using an antibody-based approach, senescent cells can be selectively targeted with greater specificity than small molecules. This is extremely important work, allowing for the in vivo quantification of SASP under numerous models and therapeutic combinations and identifying how a senescent population could lead to resistance and metastasis. Future work with ImmunoPET tracers specific to senescent tissue could include conjugation with senolytic drugs as well as stand-alone antibody endoradiotherapy.

项目总结