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.

项目摘要 胰腺癌是两性的第四大癌症死亡，总体癌症总体不到10％ 生存超过5年。在被诊断为胰腺癌的患者中 吉西他滨通常需要二线疗法，例如folfirnox（叶酸，氟尿嘧啶，， Irinotecan和Oxaliptin），中位生存期为6到26个月。而生存 胰腺癌并未随着新的治疗组合而显着进展，大多数 用于胰腺癌的化学治疗方案会诱导衰老。细胞可以进行 通过复制，癌基因诱导以及靶向药物治疗的衰老。衰老细胞 通过衰老细胞分泌的Pro炎症因子和 修饰肿瘤微环境。患者在多大程度上衰老是未知的 肿瘤以及衰老相关的分泌表型（SASP）如何随着治疗而变化。 免疫疗法用精确药物彻底改变了许多癌症治疗 抗体疗法，但这些治疗方法仅借出了胰腺的生存时间的适度增加 癌症患者。靶向胰腺癌并确定衰老胰腺癌的较新方法 需要在治疗期间。 Scott Lowe Lab的最新工作证明了胰腺 可以通过Trametinib和palbocicilib的组合诱导癌症衰老，从而导致 释放重塑肿瘤微环境的细胞因子。当前的黄金标准方法 衰老细胞的鉴定集中在一个小分子上，用于溶酶体运输，并具有β- 半乳糖苷酶活性。需要使用基于抗体的剂进行SASP的特定标记。之前 升高的SASP标记包括VEGF，P-选择蛋白，UPAR，CCL2和CCL5，以及列元1、6，以及 12.该研究金建议使用针对已知SASP标记的临床可用抗体 用免疫集在体内可视化和量化SASP活性。通过使用基于抗体的方法， 与小分子相比，衰老细胞可以选择性地靶向更特异性。这是 极其重要的工作，允许在许多模型下对SASP进行体内量化，并且 治疗组合并确定衰老人群如何导致抵抗和 转移。未来与特定于衰老组织的免疫示踪剂的未来工作可能包括共轭 塞溶剂药物以及独立的抗体内放射疗法。