Ongoing pre-clinical efforts aim to deploy genome-scale CRISPR/Cas9 technology and large collections of small molecules to catalog maps of cancer vulnerabilities at scale. However, such efforts in pediatric and rare cancers have lagged behind comparable efforts in more common cancer types due to the dearth of cell models. Here, we present an update from our “Cancer Cell Line Factory” project on efforts to overcome key laboratory and biologistics challenges precluding progress in pediatric and rare cancers. This effort, now in it’s 3rd year, represents an industry scale pipeline aiming to generate, characterize and share novel cancer models of many tumor types with the scientific community. Overall, we have processed 1153 samples from 818 patients across over 16 cancer types through this pipeline with a 28% success rate overall, including over 350 patient samples from rare and pediatric cancers. To optimize conditions for each tumor type, we have systematically compared published methods including (1) next-generation 2-dimension, (2) organoid and (3) standard approaches and have captured all information with a data management system that should enhance the ability to predict optimal ex vivo propagation conditions for future samples. Among the successful cell models verified already as part of this effort, we have generated a series of over 30 unique pediatric and rare cancer models, many of which represent the first of their kind. We screened these and other models against a library of highly annotated 440 small molecules that were previously tested against 860 existing cancer cell lines. Our results suggest that dependency data generated with novel next-generation cell cultures is potentially backwards-compatible with existing small molecule dependency datasets. Furthermore, we tested the novel Broad Institute Drug Repurposing library consisting of 4100 approved therapeutics, or those under investigation for any disease, against the first cell line models of several of these rare next generation models including angioimmunoblastic T-cell lymphoma and renal medullary carcinoma, leading to several novel drug repurposing hypotheses for rare cancers. Given these proof-of-concept studies, in partnership with the Rare Cancer Research Foundation, we launched an online matchmaking platform to connect patients with rare cancers to available research studies, facilitate online consent and provide biologistics support to enable fresh tissue donation to support cancer model generation from any clinical site in the United States. We will present results from this novel direct-to-patient approach to facilitate the generation of even larger numbers of next generation models from rare and pediatric cancers, propelling the generation of pre-clinical dependency maps of these tumors for the scientific community.

Citation Format: Yuen-Yi Tseng, Andrew Hong, Paula Keskula, Shubhroz Gill, Jaime Cheah, Grigoriy Kryukov, Aviad Tsherniak, Francisca Vazquez, Glenn Cowley, Sahar Alkhairy, Coyin Oh, Anson Peng, Rebecca Deasy, Abeer Sayeed, Peter Ronning, Samuel Ng, Steven Corsello, Corrie Painter, David Sandak, Levi Garraway, Mark Rubin, Calvin Kuo, Sidharth Puram, David Weinstock, Adam Bass, Nikhil Wagle, Keith Ligon, Katherine Janeway, David Root, Stuart Schreiber, Paul Clemons, Aly Shamji, Aly Shamji, William Hahn, Todd Golub, Jesse Boehm. Accelerating prediction of pediatric and rare cancer vulnerabilities using next-generation cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1953. doi:10.1158/1538-7445.AM2017-1953