Researchers at the University of Texas MD Anderson Cancer Center have developed a new method for rapid generation and analysis of patient-derived xenograft (PDX) models. The technique, dubbed “patient-based in vivo lethality to optimize treatment” (PILOT), applies large-scale functional genetic screening to PDX, and has already uncovered a new molecular driver for pancreatic ductal adenocarcinoma (PDAC).
Functional genetic screening is more commonly applied to laboratory cancer cell lines, but the researchers believe PDX more accurately models the genomic complexity of real tumors. The scientists boost efficiency from the start, by speeding up assessment of the tumor’s engraftment capability. Typically, engraftment efficiency is assessed by transplanting different numbers of cancer cells into mice to see how many cells it takes to generate a new tumor – a procedure that is slow and subject to variation. The PILOT researchers used lentivirus to deliver molecular “barcodes” that tag individual cells and track their fate, to get a more accurate picture of engraftment efficiency. Once the PDX model has been generated, a library of short hairpin RNAs (shRNAs) is used to identify expression of selected genes.
In their first published study, the team decided to focus on epigenetic factors driving PDAC, with a shRNA library targeting over 200 chromatin regulators (1). The top 15–30 percent emerging from screening were evaluated with multiple methods, and the most robust “hit” was WDR5, a key regulator of chromatin function. WDR5 was highly expressed in pancreatic cancer cells compared with normal pancreatic tissue, and gene knockout studies revealed impaired tumor growth and increased survival in mice. Further studies gave additional clues into the mechanisms of action – it appears that WDR5 works with the known cancer-promoter Myc to improve tumor cell survival. The interaction between the two appears essential for PDAC cell proliferation, and could be a potential drug target.
The PILOT technology is now being widely adopted by researchers in MD Anderson’s “Moon Shots Program”, designed to speed up translation of scientific discoveries into new treatment, diagnosis and, prevention efforts.
- A Carugo et al., “In vivo functional platform targeting patient-derived xenografts identifies WDR5-Myc association as a critical determinant of pancreatic cancer”, Cell Reports (2016). PMID: 27320920
“As Editor of The Translational Scientist, I’m working closely with our audience to create vibrant, engaging content that reflects the hard work and passion that goes into bringing new medicines to market. I got my start in biomedical publishing as a commissioning editor for healthcare journals and have spent my career covering everything from early-stage research to clinical medicine, so I know my way around. And I can’t think of a more interesting, challenging or important area to be working in.”