Identification of Paralog Dependencies and Resistance Mechanisms in Melanoma
Abstract
Principal Investigator: My research interest is identifying links between genetic alterations and dependencies for targeted cancer treatments. The Horizon Award will help advance the development of novel functional genomic technologies to profile potential drug targets for given genetic alterations in cancer. For my postdoctoral training, I sought an institute with a demonstrated history of answering bold questions through a multidisciplinary approach to science. Furthermore, I wanted to work in a laboratory that was committed to the development of new technologies, dedicated to the mentorship and professional development of junior scientists, and actively disseminated data and resources. The laboratory of Dr. William Sellers at The Broad Institute of MIT and Harvard provides an unparalleled environment and culture for me to realize my goal of developing breakthrough technologies for the identification of novel cancer therapies. In this era of multifaceted biomedical challenges, the key word is integration: a research model characterized by deep and collaborative relationships with exceptional scientists across diverse areas of expertise. The Horizon Award will foster essential, multidisciplinary collaborations, ensuring an innovative integrative approach to my research. I will be able to continue to work closely with computer scientists to analyze large datasets, the Genetic Perturbation Platform to develop new technologies, and Dr. Sellers who has pioneered the use of cutting-edge genetic and functional genomic approaches to discover seminal therapeutics in cancer. These opportunities will expand my scientific skill set and perspective. Research Plan: Cancer cells harbor a multitude of genetic alterations, from single mutations to whole chromosome duplications, some of which contribute to the uncontrolled growth and survival of these cells. Precision medicine and functional genomics leverage these genetic alterations to identify potential dependencies that can serve as therapeutic vulnerabilities to selectively target cancer cells while having minimal effects on "normal" cells. In the past decade, researchers examined the effects of individual genes in hundreds of cancer types with the advent of technologies like RNAi and CRISPR pooled screens, which silence every gene in the genome. These data revealed striking patterns in single genes and pathways cancer cells require for survival, identifying novel targets for cancer therapeutics. Understandably, however, redundant functions of paralogous genes present a caveat to the current screening technologies. Paralogs are gene-families that have originated by gene duplication during evolution and may provide redundancy in protein functionality. While approved cancer therapeutics often inhibit multiple paralogs, single-gene perturbation screens are unable to identify novel drug targets that require the inhibition of paralogous genes with redundant functions. Importantly, to date, no comprehensive search has identified paralogs that have retained either full or partial functional redundancy or have diverged in function. To improve upon the single-gene perturbation screens, I have developed a novel CRISPR screen to simultaneously perturb paralogs to identify novel paralog dependencies. Specifically, for this project, I will identify paralog vulnerabilities in NRAS-mutant melanoma and identify paralogs that confer resistance to current therapeutics in BRAF-mutant melanomas. Just as CRISPR and RNAi technology have revolutionized the speed and scale of targeted discovery efforts in oncology research, we envision that this novel technology will be utilized by many research groups around the world to discover new therapeutics not limited to only cancer research. Contributions to Service members, Veterans, and families: I am investigating in the fiscal year 2018 Peer Reviewed Cancer Research Program topic area of cutaneous melanoma, representing one of the most aggress
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910271
Entities
People
- Takahiro Ito
Organizations
- Broad Institute
- United States Army