Proteolytically Cleaved Receptors as Oncogenes and Therapeutic Targets

描述（由申请人提供）：我的长期职业目标是成为一名独立的学术研究者，研究参与上皮肿瘤发生的分子信号及其作为癌症治疗靶点的潜力。K99/R00独立之路奖和在这个申请中提出的研究将有助于我作为一名科学家的专业发展和向教师职位的过渡。环境。在该奖项的指导K99阶段，我将在加州大学洛杉矶分校（UCLA）的Witte博士的直接指导下进行拟议的研究。维特博士是世界著名的癌症研究领域的领导者。Witte博士将进一步对我进行癌症生物学方面的培训，因为他的实验室开发了一套独特的方法来研究前列腺细胞生物学和癌症发病机制。我还组建了一个顾问委员会，由一位共同导师和几位顾问/合作者组成，其中包括：加州大学洛杉矶分校生物化学系教授Kurdistani博士，他是功能基因组学方面的专家；黄博士是加州大学洛杉矶分校病理学和检验医学教授、泌尿病理学主任，是前列腺临床病理学专家；Pienta博士是约翰霍普金斯大学肿瘤学、药理学和分子科学教授，是开发前列腺癌新治疗方案的领导者；鲁宾博士是威尔康奈尔医学院病理学、实验室医学和肿瘤学教授，是国际公认的病理学家和前列腺癌基因组学的领导者。Horvath博士是加州大学洛杉矶分校生物统计学和人类遗传学教授，也是阵列数据分析小组的负责人，是开发生物信息学方法的领导者。在该奖项的K99阶段，我将获得功能基因组学领域的培训，以及将分子信号转化为治疗方法的策略。这次培训将成为我作为癌症生物学家独立职业生涯的垫脚石。研究。我之前已经描述了I型跨膜蛋白Trop2在前列腺肿瘤发生中的致癌作用。我之前的研究表明，Trop2是通过调节的膜内蛋白水解激活的，导致Trop2在两个不同的位点上断裂。在裂解后，Trop2的胞内结构域易位到细胞核中，并启动下游信号级联，驱动细胞增殖和肿瘤发生。我最近的研究发现Notch1是另一种通过蛋白水解裂解调节的I型跨膜蛋白，在前列腺肿瘤发生中起关键作用。我的初步结果表明，Trop2和Notch1受体之间存在串扰。在Aim 1中，我将利用最近建立的原发性人组织重组试验，研究Trop2和Notch1受体在体内前列腺肿瘤发生和发展中的功能合作。在Aim 2中，我将定义新的Trop2下游靶点，并确定Trop2与Notch1信号传导之间的生化关系。在Aim 3中，我将测试联合抑制Trop2和Notch1信号作为一种新的癌症治疗策略。

DESCRIPTION (provided by applicant): My long term career objective is to be an independent investigator in an academic setting studying molecular signaling involved in epithelial tumorigenesis and their potential to be targeted for cancer therapy. The K99/R00 Pathway to Independence Award and the research proposed in this application will be instrumental in my professional development as a scientist and in transitioning to a Faculty Position. ENVIRONMENT. During the mentored K99 phase of the award I will perform the proposed research under the direct guidance of Dr. Witte at the University of California at Los Angeles (UCLA). Dr. Witte is a world- renowned leader in the field of cancer research. Dr. Witte will further my training in cancer biology since his laboratory has developed a unique set of approaches to study prostate cell biology and cancer pathogenesis. I have also assembled an advisory board with a co-mentor and several consultants/collaborators including: Dr. Kurdistani, Professor in the Department of Biological Chemistry at UCLA, is an expert in functional genomics; Dr. Huang, Professor of Pathology and Laboratory Medicine and Director of Urologic Pathology at UCLA, is an expert in prostate clinical-pathology; Dr. Pienta, Professor of Oncology and Pharmacology and Molecular Sciences at Johns Hopkins University, is a leader in the developing of new therapeutic programs for prostate cancer; Dr. Rubin, Professor of Pathology and Laboratory Medicine and Oncology at Weill Cornell Medical College, is an internationally recognized pathologist and a leader in prostate cancer genomics. Dr. Horvath, Professor of Biostatistics and Human Genetics and Head of the Array Data Analysis Group at UCLA, is a leader in developing bioinformatics methods. During the K99 phase of the Award, I will gain training in the areas of functional genomics, and strategies to translate molecular signaling into therapeutics. This training will be a stepping stone for my independent career as a cancer biologist. RESEARCH. I have previously characterized the oncogenic role of the type I transmembrane protein Trop2 in prostate tumorigenesis. My previous studies demonstrated that Trop2 is activated through regulated intramembrane proteolysis resulting in cleavage of Trop2 at two distinct sites. Upon cleavage, the intracellular domain of Trop2 translocates into the nucleus and initiates a downstream signaling cascade driving cellular proliferation and tumor initiation. My recent studies identified Notch1, another type I transmembrane protein regulated through proteolytic cleavages, as a key player in prostate tumorigenesis. My preliminary results point to an existing cross-talk between Trop2 and Notch1 receptors. In Aim 1, I will investigate the functional cooperation between Trop2 and Notch1 receptors in prostate tumor initiation and progression in vivo utilizing the recently established primary human tissue recombination assay. In Aim 2, I will define new downstream targets of Trop2 and identify the biochemical relationship between Trop2 and Notch1 signaling. In Aim 3, I will test combined inhibition of Trop2 and Notch1 signaling as a new therapeutic strategy in cancer.