Most human tumors, particularly those derived from epithelial cancers, exhibit global genomic alterations that make it difficult to identify mutations critical for cell transformation and to define the consequences of specific cancer associated mutations. Recent advances in sequencing technologies and comprehensive methods to map cancer-associated amplicons and deletions now make it possible to identify all of the genetic alterations harbored by a particular tumor, and large-scale efforts such as TCGA to apply these technologies have already begun to provide comprehensive views of cancer genomes. Despite these important advances, a critical bottleneck in translating these discoveries into therapies that will enter the clinic remais the functional characterization of genes as potential therapeutic targets. Specifically, although the identification of genes that are mutated in a substantial fraction of particular cancer types is an essential first step, the parallel development of efficient methods to annotate the function of cancer-associated genes is necessary to distill promising candidate cancer targets from this structural description of cancer genomes. Thus, functional annotation of cancer genes will identify those genes whose protein products are essential for tumor initiation or maintenance and will provide critical insights into the biochemical pathways that ar dysregulated in these same cancers. This information will accelerate the development of new molecularly targeted therapeutics. In this application, we propose use these studies as a foundation to establish the Dana- Farber Cancer Institute Cancer Target Discovery and Development Center. This Center will focus on the use of high throughput genetic and bioinformatic approaches to identify and credential oncogenes and co-dependencies in three cancers (GBM, ovarian, and colon) in vitro and in vivo. We will make the outputs of these studies (data and methodologies) freely available to the scientific community and intend to participate in CTDD Network projects throughout the time frame of this project. We anticipate that this Center will provide the cancer research community with information tht will facilitate the prioritization of targets based on both genomic and functional evidence, inform the most appropriate genetic context for downstream mechanistic and validation studies and facilitate the translation of this information into therapeutics and diagnostis.
The overarching goals of these studies are the implementation of high throughput technologies that will provide functional information for genes identified as mutated or amplified in glioblastoma, ovarian, colon and pancreatic cancers and the dissemination of this information and validated reagents to the cancer research community. The cancer genes identified using these approaches represent prioritized candidates for investigator-initiated research programs and targets of particular promise for future therapeutic efforts. These studies will leverage prior investments in cancer genome characterization and provide outputs that will facilitate investigator-initiated baic and translational studies and accelerate the development of new therapeutic approaches.
|Kryukov, Gregory V; Wilson, Frederick H; Ruth, Jason R et al. (2016) MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351:1214-8|
|Hong, Andrew L; Tseng, Yuen-Yi; Cowley, Glenn S et al. (2016) Integrated genetic and pharmacologic interrogation of rare cancers. Nat Commun 7:11987|
|Choudhury, Atish D; Schinzel, Anna C; Cotter, Maura B et al. (2016) Castration resistance in prostate cancer is mediated by the kinase NEK6. Cancer Res :|
|Gannon, Hugh S; Kaplan, Nathan; Tsherniak, Aviad et al. (2016) Identification of an "Exceptional Responder" Cell Line to MEK1 Inhibition: Clinical Implications for MEK-Targeted Therapy. Mol Cancer Res 14:207-15|
|Rosenbluh, Joseph; Mercer, Johnathan; Shrestha, Yashaswi et al. (2016) Genetic and Proteomic Interrogation of Lower Confidence Candidate Genes Reveals Signaling Networks in Î²-Catenin-Active Cancers. Cell Syst 3:302-316.e4|
|Cancer Target Discovery and Development Network (2016) Transforming Big Data into Cancer-Relevant Insight: An Initial, Multi-Tier Approach to Assess Reproducibility and Relevance. Mol Cancer Res 14:675-82|
|Kim, Eejung; Ilic, Nina; Shrestha, Yashaswi et al. (2016) Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles. Cancer Discov 6:714-26|
|Aguirre, Andrew J; Meyers, Robin M; Weir, Barbara A et al. (2016) Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting. Cancer Discov 6:914-29|
|Kim, Jong Wook; Botvinnik, Olga B; Abudayyeh, Omar et al. (2016) Characterizing genomic alterations in cancer by complementary functional associations. Nat Biotechnol 34:539-46|
|Luo, Leo Y; Hahn, William C (2015) Oncogenic Signaling Adaptor Proteins. J Genet Genomics 42:521-9|
Showing the most recent 10 out of 29 publications