The Dana-Farber Cancer Institute Cancer Target Discovery and Development Center

丹娜—法伯癌症研究所癌症靶标发现和开发中心

• 批准号: 10190844
• 负责人: WILLIAM C HAHN
• 金额: $ 100.79万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10190844
• 关键词: Bioinformatics; Biological; CRISPR/Cas technology; CRKL gene; Cancer Model; Cancer cell line; Carcinoma; Clinical; Clinical Trials; Colon Carcinoma; Combination immunotherapy; Combined Modality Therapy; Communities; Credentialing; Dana-Farber Cancer Institute; Data; Dependence; Development; Diagnostic; FRS2 gene; Foundations; Future; GAB2 gene; Gene Combinations; Gene Targeting; Genes; Genetic; Genetic Screening; Genomic Instability; Genomics; Goals; Human; Immune; Immune Evasion; Immune Response Genes; Immune system; Immunotherapeutic agent; Immunotherapy; In Vitro; Infrastructure; International; Investigator-Initiated Research; Investments; Knowledge; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Mammalian Cell; Maps; Methodology; Methods; Modeling; Mus; Mutation; Oncogenes; Oncogenic; Open Reading Frames; Output; Pathway interactions; Patients; RNA Interference; Resistance; SMARCA2 gene; System; TBK1 gene; Techniques; Testing; Therapeutic; Translations; Tumor Suppressor Genes; anticancer research; base; cancer cell; cancer classification; cancer genome; cancer heterogeneity; cancer transplantation; drug discovery; effective therapy; experimental study; gain of function; gene discovery; genetic technology; genome-wide; immune checkpoint blockade; improved; in vivo; insight; loss of function; member; molecular targeted therapies; neoplastic cell; novel; novel therapeutic intervention; pressure; programs; response; success; therapeutic candidate; therapeutic target; tool; translational study; tumor; tumor heterogeneity

Abstract International efforts to characterize cancer genomes now provide us with an initial view of the mutations and copy number alterations that occur in human cancers. These efforts have expanded our knowledge of known oncogenic pathways and have identified new classes of oncogenes and tumor suppressor genes. However, it is now also clear that most epithelial cancers harbor hundreds of genetic alterations as a consequence of genomic instability, which complicates efforts to identify mutations critical for tumor maintenance and drives tumor heterogeneity. Moreover, it remains unclear which of these alterations confers on the tumor cell the ability to evade the immune system. The emerging clinical success of checkpoint blockade is tempered by the observation that most patients do not respond to immunotherapy. New immunotherapy targets are needed to improve tumor responses and guide rational combination immunotherapy to overcome resistance. Identifying genes that are essential for tumor survival and immune evasion will accelerate the development of new molecularly targeted therapeutics. Over the past several years, we have developed and deployed high throughput genetic and bioinformatics approaches to identify and credential cancer targets. Specifically, we have performed genome scale loss of function and gain of function screens in large sets of human cancer cell lines and patient-derived models and have identified new oncogenes and synthetic lethal interactions. The scale of these experiments has allowed us to overcome the inherent heterogeneity of cancers and to classify cancer dependencies and their context, which is essential for the initiation of drug discovery efforts. In this application, we propose to use these studies as a foundation for a new Dana-Farber Cancer Institute CTD2 Center. This Center will focus on the identification of and credentialing cancer targets, developing the means to rationally define combination therapies, and the identification of genes that modulate the response to immunotherapeutics, all through the use of novel in vitro and in vivo HT genetic and bioinformatic approaches. We will continue to make the outputs of these studies readily available to the scientific community and to participate in CTD2 Network activities. We anticipate that this Center will provide the cancer research community with information that will facilitate the prioritization of targets based on both genomic and functional evidence, inform the most appropriate genetic context for downstream mechanistic studies and facilitate the translation of this information into therapeutics and diagnostics.

摘要

项目成果

Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6.

• DOI: 10.1158/0008-5472.can-16-0455
• 发表时间: 2017-02-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Choudhury AD;Schinzel AC;Cotter MB;Lis RT;Labella K;Lock YJ;Izzo F;Guney I;Bowden M;Li YY;Patel J;Hartman E;Carr SA;Schenone M;Jaffe JD;Kantoff PW;Hammerman PS;Hahn WC
• 通讯作者: Hahn WC

PRMT1-Mediated Translation Regulation Is a Crucial Vulnerability of Cancer.

• DOI: 10.1158/0008-5472.can-17-0216
• 发表时间: 2017-09-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Hsu JH;Hubbell-Engler B;Adelmant G;Huang J;Joyce CE;Vazquez F;Weir BA;Montgomery P;Tsherniak A;Giacomelli AO;Perry JA;Trowbridge J;Fujiwara Y;Cowley GS;Xie H;Kim W;Novina CD;Hahn WC;Marto JA;Orkin SH
• 通讯作者: Orkin SH

Defining a Cancer Dependency Map.

• DOI: 10.1016/j.cell.2017.06.010
• 发表时间: 2017-07-27
• 期刊: Cell
• 影响因子: 64.5
• 作者: Tsherniak A;Vazquez F;Montgomery PG;Weir BA;Kryukov G;Cowley GS;Gill S;Harrington WF;Pantel S;Krill-Burger JM;Meyers RM;Ali L;Goodale A;Lee Y;Jiang G;Hsiao J;Gerath WFJ;Howell S;Merkel E;Ghandi M;Garraway LA;Root DE;Golub TR;Boehm JS;Hahn WC
• 通讯作者: Hahn WC

A Community Challenge for Inferring Genetic Predictors of Gene Essentialities through Analysis of a Functional Screen of Cancer Cell Lines.

• DOI: 10.1016/j.cels.2017.09.004
• 发表时间: 2017-11-22
• 期刊: Cell systems
• 影响因子: 9.3
• 作者: Gönen M;Weir BA;Cowley GS;Vazquez F;Guan Y;Jaiswal A;Karasuyama M;Uzunangelov V;Wang T;Tsherniak A;Howell S;Marbach D;Hoff B;Norman TC;Airola A;Bivol A;Bunte K;Carlin D;Chopra S;Deran A;Ellrott K;Gopalacharyulu P;Graim K;Kaski S;Khan SA;Newton Y;Ng S;Pahikkala T;Paull E;Sokolov A;Tang H;Tang J;Wennerberg K;Xie Y;Zhan X;Zhu F;Broad-DREAM Community;Aittokallio T;Mamitsuka H;Stuart JM;Boehm JS;Root DE;Xiao G;Stolovitzky G;Hahn WC;Margolin AA
• 通讯作者: Margolin AA

An alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer.

• DOI: 10.7554/elife.37184
• 发表时间: 2018-07-30
• 期刊: eLife
• 影响因子: 7.7
• 作者: Li J;Choi PS;Chaffer CL;Labella K;Hwang JH;Giacomelli AO;Kim JW;Ilic N;Doench JG;Ly SH;Dai C;Hagel K;Hong AL;Gjoerup O;Goel S;Ge JY;Root DE;Zhao JJ;Brooks AN;Weinberg RA;Hahn WC
• 通讯作者: Hahn WC