Understanding tumorigenesis and metastasis of pancreatic cancer through precision whole-body imaging of senescence with ImmunoPET

通过使用免疫PET对衰老进行精确的全身成像来了解胰腺癌的肿瘤发生和转移

• 批准号: 10602415
• 负责人: Edwin Charles Pratt
• 金额: $ 7.2万
• 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: 2022-06-19 至 2025-06-18
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602415
• 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.

项目概要 胰腺癌是男女中第四大最常见的癌症死亡原因，总体死亡率不到 10% 生存超过5年。在诊断患有胰腺癌的患者中，一线化疗 吉西他滨通常需要二线治疗，例如 FOLFIRNOX（亚叶酸、氟尿嘧啶、 伊立替康和奥沙利铂），中位生存期为 6 至 26 个月。虽然生存 新的治疗组合并没有显着进展胰腺癌，大多数 用于胰腺癌的化疗方案会导致衰老。细胞可以经历 通过复制、癌基因诱导以及靶向药物治疗来预防衰老。衰老细胞 通过衰老细胞分泌的促炎因子参与肿瘤发生 改变肿瘤微环境。目前尚不清楚患者的衰老程度如何 肿瘤以及衰老相关分泌表型 (SASP) 如何随治疗而变化。 免疫疗法通过精准医学和靶向治疗彻底改变了许多癌症治疗方法 抗体疗法，但这些疗法仅略微延长了胰腺的生存时间 癌症患者。针对胰腺癌和识别衰老胰腺癌的新方法 治疗期间需要。斯科特·洛实验室 (Scott Lowe Lab) 最近的工作表明，胰腺 曲美替尼 (Trametinib) 和帕博西利布 (palbocicilib) 联合使用可诱导癌症衰老，从而导致 释放重塑肿瘤微环境的细胞因子。目前的黄金标准方法 衰老细胞的鉴定主要集中在一种用于溶酶体运输的小分子上 半乳糖苷酶活性。需要使用基于抗体的试剂进行 SASP 的特异性标记。之前 SASP 标记物升高，包括 VEGF、P-选择素、uPAR、CCl2 和 CCL5，以及白细胞介素 1、6 和 12. 该奖学金建议使用临床上可用的针对已知 SASP 标记的抗体来 使用ImmunoPET 可视化和量化体内SASP 活性。通过使用基于抗体的方法， 与小分子相比，可以以更高的特异性选择性地靶向衰老细胞。这是 极其重要的工作，允许在多种模型和条件下对 SASP 进行体内定量 治疗组合并确定衰老人群如何导致耐药性和 转移。未来针对衰老组织的免疫PET示踪剂的研究可能包括结合 与 senolytic 药物以及独立的抗体内放射治疗一起使用。