Development of Deep Mutational Scanning with Duplex Sequencing (DMS-DS) for anti-cancer drug evaluation and administration

Cancer remains a leading cause of death worldwide. Targeted agents have dramatically improved the prognosis of over 30 cancer types, but are fundamentally limited by the evolution of resistance. Currently, next generation targeted therapies are retrospectively designed to cover the liabilities of clinically available targeted therapies. Unfortunately, every investigational compound will have resistance mutations that prevent complete and durable response. Deep mutational scanning (DMS) has emerged as a powerful tool for evaluating the mutational landscape of target proteins. DMS screens have recently been used by academic labs to characterize the resistance landscape of targeted anticancer compounds, but employ standard next generation sequencing (NGS) techniques to measure a highly complex mutant pool. NGS has a high error rate that prohibits accurate measurements of complex mutational pools. Duplex Sequencing (DS) is an error correction method that enables the precise measurement of mutations down to a frequency of 1 in 300,000 in a pooled cell-based library. The Pritchard lab has developed Deep Mutational Scanning with Duplex Sequencing (DMS-DS) and propose to refine this technology into a commercially viable service for anticancer pharmaceutical development. In Phase I of this Small Business Transition Grant, we will harden and scale our DMS-DS technology into an industry- viable screening platform. In Phase II we will screen all approved BCR-ABL inhibitors, design and build DMS-DS screens for two lung cancer drug targets, and harden our BCR-ABL DMS-DS platform into a commercialized end-to-end service. The final product of this SBTG project will be a robust, powerful, and marketable new research tool ready for use by anticancer pharmaceutical developers. Our company will leverage this tool (DMS-DS) to expedite lead candidate prioritization and optimize next generation drug design. Targeted therapies have revolutionized clinical outcomes for numerous cancers, but acquired resistance critically limits their long-term utility. Having a commercially available screening platform that can accurately predict the mutational landscape of next generation therapies will lead to more successful clinical trials, better targeted therapies, and more effective treatment plans for cancer patients. We firmly believe our technology will accelerate effective anticancer drug development and that our team is an unparalleled position to succeed at the commercialization of this product.