This application addresses broad Challenge Area (15) Translational Science, and specific Challenge Topic, 15- CA-104: Use of novel mouse genetic resources to elucidate determinants of drug toxicities. Variation in the efficacy and toxicity of chemotherapeutic agents is consistently observed across human populations with severe systemic toxicity and unpredictable efficacy being hallmarks of cancer therapies. Adverse drug reactions can be difficult to study in humans due to issues such as environmental variability and the availability of relevant populations. Consequently, animal model systems are needed to fully understand the genetic basis of drug response. Genetically defined mouse models offer a tractable experimental system for mapping susceptibility genes and for examining their function in the context of a complex, living organism. The Jackson Laboratory is developing a new variety of mice that are designed to maximize allelic diversity (Diversity Outbred Mice). Each individual animal within this population will be genetically unique and, as a whole, the population approximates the genetic diversity observed in human populations. Diversity Outbred Mice can be subjected to sophisticated physiological and molecular phenotyping beyond what is possible in human subjects. Their population structure will allow high resolution genetic mapping analogous to human genome-wide association studies. We propose to use the Diversity Outbred Mice in a proof of concept study to establish their utility in rapidly identifying the genetic contribution to drug toxicity. This study can be executed quickly and will provide the most information possible while containing cost. We propose to identify genes responsible for the myelosuppressive effects of three cancer chemotherapeutic drugs, doxorubicin, cyclophosphamide, and docetaxel. We have chosen myelosuppression as the physiological response because this adverse effect is a major contributor to morbidity, mortality and costs associated with cancer treatment;mice are known to respond to these agents in a manner similar to humans;and the response can be measured using standard clinical hematological methods.
Adverse drug reactions are one of the leading causes of death and morbidity in cancer treatment. This study will develop and test a novel animal model for the identification of genetic factors that can predict the likelihood of adverse reactions in humans.
| Didion, John P; Morgan, Andrew P; Clayshulte, Amelia M-F et al. (2015) A multi-megabase copy number gain causes maternal transmission ratio distortion on mouse chromosome 2. PLoS Genet 11:e1004850 |
