1. Developing pipelines for personalized testing of tumor vulnerabilities. Despite decades of work, generating new cancer cell lines has been extremely challenging. However, recent work now suggests that matched tumor and normal cultures can be rapidly generated from nearly any primary or tumor culture. We’ve recently developed a pipeline to isolate and sequence circulating tumor cells from prostate and other cancers and are now utilizing new cell line creation protocols as part of the Broad’s Cell Line Factory Initiative to develop and characterize hundreds of new cancer cell lines for the community. We are also developing approaches to build new methods to isolate and preserve heterogeneous subclones present in primary tumors. Importantly, these models are being comprehensively characterized (both in terms of their molecular features and their drug vulnerabilities). If successful, a path to clinical chemosensitivity testing might one day be possible.
2. Quantitative assessment of oncogenic potential via next generation tumorigenesis assays. Distinguishing which of the hundreds of mutant alleles within a given tumor enhances tumor fitness and which are merely passenger alterations is a major challenge. Such information could rapidly focus therapeutic interventions. However, the existing pre-cancer models suitable for such experiments have been limited by throughput and cost. Together with colleagues at the Broad Institute, we’ve built a pipeline to create thousands of mutant cancer alleles with molecular barcodes, beginning with our high quality collection of wild type cDNAs. We’re also developing a suite of robust, high-throughput tumorigenesis assays suitable for multiplexed assays in vivo. These technologies should make it possible to assess the tumorigenic potential of thousands of mutant clones in a massively parallel scale.
3. Mapping cancer variant function at scale via integrated computational and experimental approaches.
With the comprehensive analysis of cancer genomes approaching completion, the research community stands poised to rapidly advance genome-guided therapeutic hypotheses into clinical settings. However, for the vast majority of cancer patients, existing knowledge of the function(s) of the newly discovered mutant genes harbored by their tumor is incomplete or non-existent since most cancer mutations are exceedingly rare. As a result, we now have long lists of candidate alleles but a paucity of targets whose biology is sufficiently well understood to guide therapeutics.With collaborators at the Broad, we have launched a pilot effort aiming to create a generalizable framework to systematically map the molecular consequences of cancer variants at scale. We call this approach the "Target Accelerator."