Elucidating the genetic causes of variation in chemotherapeutic cytotoxicity

Elucidating the genetic causes of variation in chemotherapeutic cytotoxicity ! Structural technical abstract:! ! Background:! Patients vary in cancer treatment efficacy when exposed to identical chemotherapy delivery regimes. This variability comes from both genetic and environmental factors. To maximize efficacy, we need to know which genetic variants alter susceptibility to these drugs. The field of pharmacogenomics seeks that connection, but few variants have been identified. Currently, there are two approaches to identify drug susceptibility variants: (1) genome-wide association studies of patient responses, and (2) genome-wide association studies of immortalized lymphoblastic cell lines. To reach statistical significance, studies require large cohorts of patients and controls. In addition to the drug responses, the genotypes of each individual must be determined. For these reasons, such studies are expensive and time-consuming. We require a method to rapidly identify variant genes and pathways in a tissue and organism context.! ! Objective: We propose to use the nematode Caenorhabditis elegans to identify genes that affect human chemotherapeutic cytotoxicity. Most model organism research is based on a single strain with little connection to genetic variation in the population, which is like studying a single person to make conclusions about all humans. Although many discoveries came from research using the laboratory strain, we need to understand genetic variation in populations if we are to learn about pathways that vary to cause disease. C. elegans has genetic variation comparable to that of humans, providing the unique opportunity to identify the genes and the molecular mechanisms for how individuals differentially respond to chemotherapy. ! Specific aims: (1) To expand on our preliminary results and map cytotoxic responses to a larger set of chemotherapeutic drugs. (2) To narrow genetic mappings to candidate genes and test causality in chemotherapeutic cytotoxicity variation using the CRISPR/cas system. (3) To compare our cytotoxicity results with mappings performed on human cell lines and clinical populations along with comparisons to variation in The Cancer Genome Atlas. ! Study design: We will use the power of C. elegans quantitative genetics to address the fundamental mechanisms of cytotoxicity in the tissues and organism context. This study will combine highthroughput phenotyping, molecular genetics, and computational modeling to make better predictions about variants that affect human chemotherapeutic responses. ! Cancer relevance: Historically, C. elegans research has been crucial to our understanding of fundamental cellular steps often mis-regulated in cancer. This proposal will continue to make use of an excellent model organism to understand the basic principles of how individuals and populations vary in responses to chemotherapeutic drugs. Our results will provide key predictive genetic information for patient responsiveness to such drugs, increasing drug efficacy and decreasing treatment time.