Genomic instability and DNA repair in a distinct molecular class of prostate canc

描述(由申请者提供)：克里斯托弗·巴比耶里博士的这份为期五年的K08职业发展奖提案描述了一项职业发展计划，旨在成为一名泌尿外科肿瘤学的独立研究员。巴比耶里博士是威尔·康奈尔医学院的一名泌尿科医生，致力于从事前列腺癌分子特征研究的外科科学家职业生涯。这项职业发展奖将使Barbieri博士成为前列腺癌分子特征方面的专家，并将这项研究转化为前列腺癌患者的临床护理。Barbieri博士将得到马克·鲁宾博士的指导，他是前列腺癌基因组学和前列腺癌分子分类领域的领先者。鲁宾博士是威尔康奈尔医学院实验病理学副主席兼精密医学研究所所长，并监督了许多年轻研究人员的职业发展。研究培训将由一支优秀的合作者团队加强，以发展基因组学、老鼠建模和计算生物学方面的技能。最后，由临床医生、科学家和机构领导人等公认的个人组成的咨询委员会将进一步指导职业发展。该研究计划的重点是基因组重排，这在前列腺癌的发病机制中发挥着关键作用。最近描述的SPOP的反复突变定义了前列腺癌的一个新的分子亚类，其特征是与其他亚型相比，总基因组重排显著增加。这一建议的中心假设是，SPOP突变前列腺癌具有不同的DNA断裂形成和修复管理，导致对基因组重排的影响，改变对治疗药物的敏感性，并潜在地影响患者的预后。具体目的包括：1)阐明SPOP突变在前列腺细胞DNA断裂的形成和修复中的作用。2)检测SPOP突变对前列腺癌细胞对影响DNA损伤和修复的治疗药物敏感性的影响。3)确定SPOP突变与患者预后的关系，以及在一大群有良好注解的根治性前列腺癌标本中放松对DNA损伤途径的调控。总之，这些研究将确定SPOP突变在基因组不稳定中的作用，提名SPOP突变前列腺癌的潜在抑制剂，并确定SPOP突变对前列腺癌患者预后的影响。

DESCRIPTION (provided by applicant): This five year K08 Career Development Award proposal for Dr. Christopher Barbieri describes a career development program designed to culminate in a career as an independent investigator in Urologic Oncology. Dr. Barbieri is an urologist at Weill Cornell Medical College, committed to a career as a surgeon-scientist focused on the molecular characterization of prostate cancer. This Career Development Award will allow Dr. Barbieri to become an expert in the molecular characterization of prostate cancer, and translate this research into the clinical care of prostate cancer patients. Dr. Barbieri will be mentored by Dr. Mark Rubin, a leader in the field of prostate cancer genomics and molecular classification of the disease. Dr. Rubin is Vice Chair for Experimental Pathology and Director of the Institute for Precision Medicine at Weill Cornell Medical College, and has overseen the career development of numerous young investigators. Research training will be enhanced by an outstanding team of collaborators to allow development of skills in genomics, mouse modeling, and computational biology. Finally, an advisory committee composed of well-recognized individuals serving roles as clinicians, scientists, and institutional leaders will further guide career development. The research proposal focuses on genomic rearrangements, which play a critical role in the pathogenesis of prostate cancer. Recently described recurrent mutations in SPOP define a novel molecular subclass of prostate cancer characterized by striking increases in total genomic rearrangements compared to other subtypes. The central hypothesis of this proposal is that SPOP mutant prostate cancers have distinct management of DNA break formation and repair, leading to effects on genomic rearrangements, altered sensitivity to therapeutic agents, and potentially effects on patient prognosis. Specific Aims include: 1) To elucidate the role of SPOP mutation in the formation and repair of DNA breaks in prostate cells. 2) To determine the effect of SPOP mutation on the sensitivity of prostate cancer cells to therapeutic agents affecting DNA damage and repair. 3) To define the association of SPOP mutations with patient outcomes and deregulation of DNA damage pathways in a large, well annotated cohort of radical prostatectomy specimens. Together, these studies will define the role of SPOP mutations in genomic instability, nominate potential inhibitors of SPOP mutant prostate cancer, and define the effect of SPOP mutation on the outcomes of patients with prostate cancer.