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.

项目摘要 胰腺癌是男女中第四大常见癌症死亡，总死亡率不到10 生存5年以上。在诊断为胰腺癌的患者中， 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。虽然生存的 胰腺癌在新的治疗组合中没有显著进展，大多数 用于胰腺癌的化疗方案诱导衰老。细胞可以经历 通过复制、癌基因诱导以及靶向药物治疗来延缓衰老。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 肿瘤以及衰老相关分泌表型（SASP）如何随治疗而变化。 免疫疗法已经彻底改变了许多癌症治疗与精准医学和靶向 抗体疗法，但这些治疗方法只增加了胰腺癌患者的生存时间， 癌症患者。靶向胰腺癌和识别衰老胰腺癌的新方法 在治疗过程中，需要。Scott Lowe实验室的最新研究表明，胰腺 曲美替尼和哌柏西尼联合使用可诱导癌症衰老， 释放细胞因子重塑肿瘤微环境。目前的金标准方法 衰老细胞的鉴定集中在用于溶酶体运输的小分子， 半乳糖苷酶活性需要使用基于抗体的试剂的SASP的特异性标志物。先前 升高的SASP标志物包括VEGF、P-选择素、uPAR、CCl 2和CCl 5，以及白细胞介素1、6和 12.该研究建议使用临床上可用的抗已知SASP标记物的抗体， 用ImmunoPET可视化和定量体内SASP活性。通过使用基于抗体的方法， 可以以比小分子更高的特异性选择性靶向衰老细胞。这是 非常重要的工作，允许在体内定量SASP在许多模型和 治疗组合，并确定衰老的人口如何可能导致耐药性， 转移对衰老组织特异性的免疫PET示踪剂的未来工作可能包括缀合 与抗衰老药物以及单独的抗体内放射疗法。