AP4 Center for Studies on Hereditary Colorectal Cancer

描述（由申请人提供） 我们的AP 4中心将专注于遗传性结直肠癌（HCC），因为：I）HCC，包括遗传性非息肉病性结肠癌（HNPCC）和家族性腺瘤性息肉病（FAP）是结直肠癌（CRC）的子集（约3%，约1%），携带HCC性状（生殖系MMR或APC突变）的个体患CRC的风险极高。2)我们的主任，布鲁斯博曼，医学博士，博士，非常熟悉基本和临床HCC问题，是一个HCC专门的学术研究组织-美洲遗传性结直肠癌合作组（CGA-ICC）的主席。3)我们的团队在癌症研究中与生物技术和工业合作方面有着良好的记录。4)遗传学定义的CRC亚群具有不同的病因机制、突变模式、生物学行为和对治疗的反应。定义CRC的遗传子集以开发更有效的抗癌药物的策略适用于HNPCC和FAP携带者和患者，因为这些是遗传上明确定义的队列。5)我们的团队准备通过有前途的研究项目来解决HCC领域的迫切需求：P1- A需要在发展CRC之前识别所有性状携带者。我们的解决方案是一种基于血清的免疫测定法，可定量淋巴细胞中的野生型MMR或APC蛋白; P2/P3-性状携带者需要化学预防药物。我们将针对FAP开发15-LOX-1的模拟物和β-连环蛋白/TCF-4/Survivin信号传导的抑制剂。P4 - A需要在晚期疾病发生之前早期发现HCC。我们将开发用于早期HCC检测的血清标志物。P5/P6 -需要治疗患有晚期疾病的性状携带者。我们将开发原型新的代理商的基础上（a）的抗增殖作用的uroguanylin和（B）GC-C蛋白为基础的疫苗，激发免疫反应，攻击微转移，但不是结肠。该中心还将开发资源，促进中心合作伙伴之间的协作，多学科HCC研究项目（例如，HCC患者和研究人员的数据库;组织库）。规划年的预期成果：i）确定学术和工业合作伙伴和初步项目，并在这些合作伙伴之间建立协作和多学科的工作关系;（二）策划并成功举办合作伙伴会议（其中将包括讨论AP 4计划，我们的中心研究重点和管理，研究项目，合作伙伴承诺和中心资金，知识产权，战略规划，5年申请）; iii）制定详细的战略计划; iv）合作伙伴的财务和其他承诺; v）提交未完成的和可资助的5年AP 4赠款申请。

DESCRIPTION (provided by applicant) Our AP4 center will focus on hereditary colorectal cancer (HCC) because: I) HCC, including Hereditary Non-polyposis Colon Cancer (HNPCC) and Familial Adenomatous Polyposis (FAP) are subsets (approximately 3%, approximately 1%) of colorectal cancer (CRC) and individuals carrying an HCC trait (a germline MMR or APC mutation) are at extremely high risk for CRC. 2) Our Director, Bruce Boman, MD, PhD, has great familiarity with basic and clinical HCC issues and is President of an HCC-dedicated organization of academic investigators - the Collaborative Group of the Americas for Inherited Colorectal Cancer (CGA-ICC). 3) Our team has an established track record of working with biotechnology and industry in cancer research. 4) Genetically defined subsets of CRC have tumors with different etiotogic mechanisms, patterns of mutations, biological behaviors and responses to treatments. The strategy of defining genetic subsets of CRC to develop more effective anti-cancer drugs is applicable to HNPCC and FAP carriers and patients because these are genetically well-defined cohorts. 5) Our team is poised to address pressing needs in the HCC field with promising research projects: P1- A need to identify all trait carriers before they develop CRC. Our solution is a serum-based immunoassay that quantifies wild type MMR or APC proteins in lymphocytes; P2/P3- A need for chemopreventives for trait carriers. We will develop, for FAP, mimetics of 15-LOX-1 & inhibitors of Beta-catenin/TCF-4/Survivin signaling. P4 - A need to detect HCC early, before advanced disease occurs. We will develop serum markers for early HCC detection. P5/P6 - A need for treatments for trait carriers with advanced disease. We will develop prototype new agents based on (a) the anti-proliferative effects of uroguanylin and (b) a GC-C Protein-based vaccine that elicits an immune response that attacks micrometastases but not the colon. The Center will also develop resources that promote collaborative, multidisciplinary HCC research projects among Center partners (e.g., database of HCC patients and researchers; tissue bank). Anticipated Outcomes of the planning year: i) identification of academic and industry partners and initial projects and establishment of collaborative, multidisciplinary working relationships among these partners; ii) planning and holding a successful Partners meeting (which will include discussions of the AP4 program, our Center research focus and administration, research projects, partner commitment and Center funding, intellectual property rights, strategic planning, 5 y application); iii) development of a detailed Strategic Plan; iv) financial and other commitments of partners; v) submission of an outstanding and fundable 5 y AP4 grant application.