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Disrupting Collagen-Mediated Pro-survival Pathways in Pancreatic Cancer

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Technical Report,01 Aug 2018,31 Jul 2019

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Wayne State University Detroit United States

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This application proposes to inhibit the Discoidin Domain Receptors both with a single agent and in conjunction with drugs targeting RASMEK-ERK as a new possible treatment for Pancreatic Ductal Adenocarcinoma PDAC. We hypothesize that DDRs mediate the crosstalk between mutant Kras addicted PDAC cells with collagen, and thereby activate signaling pathways that promote tumor cell survival and malignancy MEK resistance. Thus, disrupting DDR function by pharmacological or genetic means may attenuate PDAC pro-survivalfibrotic pathways and enhance therapeutic efficacy drugs targeting Kras-driven MEK signaling networks. In the first funding period, we examined the sensitivity of human PDAC cell lines to Trametinib, a MEK inhibitor. We also tested the role of overexpression and downregulation of DDR1 on Trametinib sensitivity. We found that downregulation of DDR1 in CFPAC-1 cells significantly increased the sensitivity of the cells to Trametinib, as determined in cell proliferation assays. In contrast, overexpression of DDR1b in MiaPaCa cells, which are devoid of endogenous DDR1, had no impact on Trametinib sensitivity. We were also expanding the KPC component mouse colonies KrasLSL-G12D, trp53LSL-R172H and Pdx1-Cre, for the conduct of the animal studies. We have also created over 50 organoids cultures, with appriximate 15 being bankable and expandable for the studies proposed.

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  • Medicine and Medical Research

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