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

项目摘要 胰腺癌是男性和女性的第四大癌症死亡病例，总体死亡率不到10%。 存活5年以上。在被诊断为胰腺癌的患者中，一线化疗包括 吉西他滨通常需要二线治疗，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。而人类的生存 胰腺癌在新的治疗组合中并没有显著进展，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而衰老。衰老细胞 通过衰老细胞分泌的促炎因子参与肿瘤的发生 改善肿瘤微环境。目前尚不清楚患者衰老的程度。 肿瘤以及衰老相关分泌表型(SASP)如何随治疗而改变。 免疫疗法用精确的医学和靶向技术彻底改变了许多癌症的治疗方法 抗体治疗，但这些治疗只略微增加了胰腺的存活时间 癌症患者。以胰腺癌为靶点和识别衰老胰腺癌的新方法 在治疗过程中是需要的。斯科特·洛实验室最近的研究表明，胰腺 曲美替尼和帕波西利联合使用可诱导癌症衰老，导致 释放细胞因子，重塑肿瘤微环境。现行的金本位法 对衰老细胞的鉴定主要集中在一个与溶酶体转运有关的小分子上。 半乳糖苷酶活性。需要使用基于抗体的试剂来检测SASP的特异性标记物。先前 升高的SASP标志物包括血管内皮生长因子、P-选择素、uPAR、CCL2和CCL5以及白细胞介素1、6和 12.该联谊会建议使用临床上可用的针对已知SASP标志物的抗体来 用免疫正电子发射计算机断层扫描技术对体内SASP活性进行可视化和定量。通过使用基于抗体的方法， 与小分子相比，衰老细胞可以有更高的特异性选择性地被靶向。这是 极其重要的工作，允许在体内量化SASP在多种模型和 治疗组合，并确定衰老人口如何导致耐药性和 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 使用抗衰老药物以及单独的抗体内放射治疗。

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.