Functionalizing the genome to find novel pancreatic cancer treatments

Taped outside of the lab of Dr. Christopher Kemp, a professor in the Human Biology Division, hangs a piece of paper with an earlier version of the Fred Hutch logo- a DNA helix integrated between an “H” with the slogan, “Advancing Knowledge, Saving Lives”. Russell Moser, a research scientist in the Kemp Lab explains that this serves as motivation for his own research using functional genetic approaches to identify new ways to target RAS-driven cancers. One RAS-driven cancer that has been particularly challenging to treat is pancreatic ductal adenocarcinoma (PDAC). These cancers often are driven by co-mutations in KRAS and tumor suppressor p53 and typically present as metastatic by the time of diagnoses in 80% of patients. PDAC is a leading cause of cancer death, however patient survival and treatments have not improved substantially over the past several decades. In a recent Cancer Research study led by Moser, the Kemp team took an unbiased functional precision medicine approach to identify novel PDAC targets and therapeutic strategies.   

In collaboration with Dr. Dan Von Hoff of the TGEN Institute, the researchers first developed a PDAC patient-derived xenograft model following surgical removal of the tumor. Notably, the treatment of this pancreatic cancer patient ultimately failed and the patient died within a year, highlighting the aggressiveness of this cancer and dire need for better treatment options. The Kemp team then took these patient-derived PDAC cells and performed whole-exome sequencing to identify mutations, as well as a genome -scale siRNA screen to pinpoint genetic dependencies, in parallel with drug profiling to identify potential therapeutic strategies. Whole-exome sequencing of these PDAC cells identified 117 mutations in the coding region of genes, most notably an activating G12V mutation in the oncogene KRAS  and a truncating mutation in the tumor suppressor p53 (TP53).  As is the case for most cancers, this genomic characterization was insufficient to point to potential therapies, so the researchers turned to functional genetics, where they performed an unbiased functional genomic screen with a highly comprehensive RNAi library to knockdown ~6,700 target genes in order to find potential driver mutations and new cancer vulnerabilities. Importantly, many of these had “druggable signaling nodes” which enabled the researchers to validate these targets  as therapeutic strategies. “One of the most exciting parts about this study was the sheer list of novel targets we found, too much for one lab to follow up on” Kemp stated. The researchers sought out targets that had selective lethality when knocked down in PDAC patient cells compared to patient-derived non-cancerous pancreatic cells.

Read more here: Source link