Determining the mechanisms of heterogeneity of interpatient chemotherapy responsiveness in human pancreatic cancer organoids
Hematology, Oncology
Final Report Abstract
The aim of this project was to gain additional insights into the heterogeneous mechanisms of chemotherapy response in pancreatic cancer organoids. I used the organoids in pharmacokinetic studies for which I treated the organoids with the standard-of-care chemotherapies and subsequently collected media as well as the cells and subjected them to mass spectrometry analyses to detect the specific chemotherapy or metabolites. In a second step I investigated chemotherapy responses but as well alternative treatment options of pancreatic cancer organoids in a highthroughput drug screen. The screen consisted of 123 drugs including the 5 standardof-care chemotherapy drugs gemcitabine, paclitaxel, irinotecan (SN-38, active metabolite), 5-fluorouracil and oxaliplatin in combination. In an effort to further understand mechanism of response, I performed phospho-receptor tyrosine kinase arrays on 10 pancreatic cancer organoids to understand their kinase activation pattern and derived rational combination therapies from this approach that could effectively kill 5 of 10 tested organoids with low nanomolar concentrations. Finally, I overexpressed different mutants of KRAS in a set of organoids (KRASmut and KRASwt) and investigated their viability upon exposure to chemotherapies as well as a small set of targeted agents. My initially proposed experiment of performing an ORF screen in organoids turned out to be not feasible in organoids due to their low transfection and transduction efficiency.
