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

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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.