Timeframe: 2022 – 2023
Goal: Knock-out gene targets in a mouse model of FLC to identify potentially effective drug combinations for patients with advanced FLC
Principal Investigator: Sean Ronnekleiv-Kelly, MD, Surgical Oncology
This study will apply an innovative gene-editing based technology (genome-wide CRISPR knockout screen) on a mouse cellular model to screen all possible cancer targets (i.e., all genes) coupled with promising drugs to precisely identify the most lethal drug combinations in FLC. This knowledge will enable discovery of new and effective combined drug treatments for FLC that can overcome the cancer cell adaptive mechanism, and work cooperatively to maximize the tumor-killing effect.
The rationale is threefold. First, combination drug therapy is requisite for treatment resistant cancers like FLC, yet identifying optimal therapeutic combinations has been exceedingly difficult with existing methods. Second, genome-wide CRISPR screens knockout each of the ~20,600 protein coding genes in the genome (one gene per cancer cell) to identify specific genes associated with cancer cell lethality. Remarkably, this unique approach can couple each possible target (i.e. entire genome) with concurrent promising drug treatment (i.e. a core ‘backbone’ drug) to precisely reveal clinically relevant multi-drug therapy for FLC. Third, this innovative approach could identify and exploit the essential pathways by which the DNAJB1-PRKACA driver gene mutation promotes FLC aggressiveness and treatment resistance.
In future studies, any novel drug treatments identified will be tested in pre-clinical animal models meant to closely mimic human FLC, followed by evaluation in patients with this deadly cancer.