Proteolytically Cleaved Receptors as Oncogenes and Therapeutic Targets

作为癌基因和治疗靶点的蛋白水解受体

• 批准号: 9243998
• 负责人: Tanya I Stoyanova
• 金额: $ 24.3万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243998
• 关键词: Adenocarcinoma Cell; Antibodies; Area; Automobile Driving; Award; Benign; Biochemical; Biochemistry; Bioinformatics; Biological Assay; Biometry; Blocking Antibodies; California; Cancer Biology; Carcinoma; Cause of Death; Cell Nucleus; Cell Proliferation; Cell surface; Cells; Cellular biology; ChIP-seq; Cleaved cell; Clinical Pathology; Colorectal Cancer; DNA-Protein Interaction; Data Analyses; Development; Down-Regulation; ERBB2 gene; Epithelial; Epithelium; Exhibits; Extracellular Domain; Faculty; Gene Targeting; Genomic approach; Goals; Growth; Head; High-Throughput Nucleotide Sequencing; Human; Human Genetics; Integral Membrane Protein; International; Laboratories; Los Angeles; MS4A1 gene; Malignant Neoplasms; Malignant neoplasm of prostate; Medicine; Membrane; Mentors; Methods; Modeling; Molecular; Non-Hodgkin' s Lymphoma; Nuclear; Oncogenes; Oncogenic; Pathogenesis; Pathologist; Pathology; Pathway interactions; Pharmacology; Phase; Positioning Attribute; Prostate; Prostatic Neoplasms; Proteolysis; Proto-Oncogene Proteins c-akt; Public Health; Receptor Protein-Tyrosine Kinases; Research; Research Personnel; Role; Sampling; Science; Scientist; Signal Transduction; Site; Surface; Testing; Therapeutic; Tissue Recombination; Tissues; Training; Transcriptional Regulation; Translating; Trastuzumab; United States; Universities; Vascular Endothelial Growth Factors; anticancer research; beta catenin; bevacizumab; cancer genomics; cancer initiation; cancer therapy; cancer type; career; castration resistant prostate cancer; chromatin immunoprecipitation; cohort; experimental study; functional genomics; gamma secretase; genome-wide; genome-wide analysis; human tissue; improved; in vivo; inhibitor/antagonist; insight; malignant breast neoplasm; medical schools; metaplastic cell transformation; mortality; new combination therapies; new therapeutic target; novel therapeutic intervention; novel therapeutics; oncology; professor; programs; prostate carcinogenesis; public health relevance; receptor; rituximab; small molecule inhibitor; success; targeted cancer therapy; therapeutic target; transcriptome; transcriptome sequencing; tumor initiation; tumor progression; tumorigenesis; urologic

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.

描述（由申请人提供）：我的长期职业目标是成为学术环境中的独立研究者，研究参与上皮肿瘤发生的分子信号传导及其作为癌症治疗目标的潜力。 K99/R00 独立之路奖和本申请中提出的研究将有助于我作为科学家的专业发展和向教职人员的过渡。环境。在该奖项的 K99 指导阶段，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。 Witte 博士是癌症研究领域世界知名的领导者。 Witte 博士将进一步加强我在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。我还组建了一个咨询委员会，其中包括一位共同导师和几位顾问/合作者，其中包括：Kurdistani 博士，加州大学洛杉矶分校生物化学系教授，功能基因组学专家；黄博士，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，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； Rubin 博士是威尔康奈尔医学院病理学、实验医学和肿瘤学教授，是国际公认的病理学家和前列腺癌基因组学领域的领导者。 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兼阵列数据分析小组负责人，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传导转化为治疗学的策略。这次培训将成为我作为癌症生物学家的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 通过受调节的膜内蛋白水解作用被激活，导致 Trop2 在两个不同的位点裂解。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（另一种通过蛋白水解裂解调节的 I 型跨膜蛋白）是前列腺肿瘤发生的关键因素。我的初步结果表明 Trop2 和 Notch1 受体之间存在串扰。在目标 1 中，我将利用最近建立的原代人体组织重组测定来研究 Trop2 和 Notch1 受体在体内前列腺肿瘤发生和进展中的功能合作。在目标 2 中，我将定义 Trop2 的新下游靶标，并确定 Trop2 和 Notch1 信号传导之间的生化关系。在目标 3 中，我将测试 Trop2 和 Notch1 信号传导的联合抑制作为癌症的新治疗策略。