Abstract 4367: Accelerating prediction of tumor vulnerabilities using next-generation cancer models

The mapping of cancer genomes is rapidly approaching completion. The genomic information encoded by individual patients’ tumors should, in principle, provide a guide for predicting dependencies, but our ability to do so is suboptimal. The challenge stems from the absence of clinical data relating genotypes with dependencies since most cancer mutations are rare and our arsenal of cancer drugs is incomplete. If it was possible to build a preclinical ‘cancer dependency map’ at a scale that captured the genomic diversity of cancer (for instance, models of all genotypes tested for genetic and small-molecule dependencies), it should be feasible to improve dependency predictions. New technologies (e.g. CRISPR/Cas9 libraries) make such an effort now feasible. However, we lack a sufficient diversity of cancer models derived directly from patient samples to reflect the genetic diversity of cancer and the ability to systematically create functional data for each cancer patient to expand the map. In an attempt to overcome these obstacles, we have established an industry-scale pipeline to generate new cancer models directly from patient samples, a “Cancer Cell Line Factory”. We have processed over 620 samples from 400 patients across 16 cancer types through this pipeline with a 25% success rate overall. To optimize conditions for each tumor type, we have systematically compared published cell line generation methods with standard approaches and captured all information with a data management system that will enhance the ability to predict optimal ex vivo propagation conditions for future samples. In all, we report the successful derivation of over 100 new genomically confirmed cancer and normal cell lines, including a series of unique pediatric cancer models derived from rare tumors. We hypothesized that novel patient-derived cultures could be used to enhance dependency predictions. To test this hypothesis, we tested dependencies of 65 of these novel cultures against an identical set of 440 small molecules that were previously tested against 860 existing cancer cell lines. Our results suggest that dependency data generated with novel cell cultures is potentially backwards-compatible with existing small molecule dependency datasets. Finally, we demonstrate proof-of-concept that such new models can successfully used in CRISPR-Cas9 screens and integrate results with small molecule sensitivities to uncover CDK4 and XPO1 dependencies in a rare pediatric undifferentiated sarcoma. In aggregate, these proof-of-concept studies demarcate a path by which pre-clinical dependency maps may enhance clinical dependency predictions from genomic data alone. Citation Format: Yuen-Yi Tseng, Andrew Hong, Paula Keskula, Shubhroz Gill, Jaime Cheah, Grigoriy Kryukov, Aviad Tsherniak, Francisca Vazquez, Glenn Cowley, Coyin Oh, Anson Peng, Abeer Sayeed, Rebecca Deasy, Peter Ronning, Philip Kantoff, Levi Garraway, Mark Rubin, Calvin Kuo, Sidharth Puram, Adi Gazdar, Filemon Dela Cruz, Adam Bass, Nikhil Wagle, Keith Ligon, Katherine Janeway, David Root, Stuart Schreiber, Paul Clemons, Aly Shamji, William Hahn, Todd Golub, Jesse S. Boehm. Accelerating prediction of tumor vulnerabilities using next-generation cancer models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4367.