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Defining SPINK1 as a tumor driver and therapeutic target in ovarian cancer

将 SPINK1 定义为卵巢癌的肿瘤驱动因素和治疗靶点

基本信息

批准号：
8685917
负责人：
Evette S Radisky
金额：
$ 16.57万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8685917
关键词：
Affect Animal Cancer Model Apoptosis Binding Biochemical Biological Markers Biometry Breast Cancer Cell Cancer Biology Cancer Cell Growth Cancer Patient Cancer cell line Carboplatin Cell Culture Techniques Cell Line Cell Proliferation Cells Cisplatin Clinic Clinical Clinical Research Clinical Trials Cohort Analysis Data Development Diagnosis Disease Disease Resistance Drug resistance EGF gene Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Epithelial ovarian cancer Feeds Future Gene Silencing Growth Growth Factor Intervention Kazal Pancreatic Trypsin Secretory Inhibitor Learning Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of ovary Malignant neoplasm of pancreas Measurement Mediating Methods Modeling Molecular Molecular Target Oncogenic Operative Surgical Procedures Outcome Ovarian Surface Epithelial-Stromal Tumor Ovarian Tissue Paclitaxel Pathway interactions Patients Peptide Hydrolases Peptides Pharmaceutical Preparations Platinum Compounds Process Protease Inhibitor Proteins Qualifying Receptor Signaling Recombinants Recurrence Reporting Research Resources Role SPINK1 gene Serine Proteinase Inhibitors Serum Signal Pathway Signal Transduction Staging Staining method Stains Structure Subgroup Survival Rate Taxane Compound Testing Tissues Translating Translations Treatment Protocols Trypsin Trypsin Inhibitors Tumor Subtype Woman Women&apos s Group Work X-Ray Crystallography base cancer cell chemotherapeutic agent chemotherapy clinically significant design drug development improved inhibitor/antagonist insight killings mortality neutralizing antibody new therapeutic target novel ovarian neoplasm overexpression pre-clinical prognostic promoter prostate cancer cell protein protein interaction protein structure function public health relevance repository response standard care taxane therapeutic target treatment trial tumor

项目摘要

DESCRIPTION (provided by applicant): Ovarian cancer encompasses many molecularly and etiologically distinct diseases, but patients have not yet benefitted from our evolving understanding through the development and translation of subtype-specific molecularly targeted therapies. We hypothesize that, for a small molecularly-defined subset of ovarian cancer patients, the secreted protein protease inhibitor SPINK1 may represent a key oncogenic driver of tumor proliferation, invasion, and chemoresistance, and that SPINK1 may offer a novel therapeutic target for this group of women. We further hypothesize that these activities of SPINK1 are mediated not through protease inhibition, but through a newly discovered activity of SPINK1 as a growth factor capable of activating the epidermal growth factor receptor (EGFR). Here, we propose three specific aims designed to test these hypotheses. (1) We will define how SPINK1 affects ovarian cancer cell growth, invasion, and drug resistance, using cell culture models of ovarian cancer in combination with SPINK1 gene silencing and recombinant SPINK1 treatment. We will also test the ability of SPINK1 neutralizing antibodies to inhibit the growth an invasion of SPINK1-positive ovarian cancer cells, and to sensitize cells to chemotherapy. (2) We will define the molecular interaction between SPINK1 and EGFR, using quantitative binding measurements and X-ray crystallography. We will also determine the role of EGFR signaling in the cancer-promoting activities of SPINK1 in ovarian cancer cells. (3) We will evaluate expression of SPINK1 in a large set of invasive epithelial ovarian cancer biospecimens, testing the association with EGFR signaling pathway activation and with survival. In aggregate, this work has the potential to define SPINK1 signaling as a key driver of malignancy for a previously unrecognized subset of ovarian cancer patients, and as a molecular target for novel drug development.

描述（由申请人提供）：卵巢癌包括许多分子和病因学上不同的疾病，但患者尚未受益于我们通过开发和翻译亚型特异性分子靶向治疗而不断发展的理解。我们假设，对于一个小分子定义的卵巢癌患者子集，分泌的蛋白酶抑制剂SPINK1可能是肿瘤增殖，侵袭和化疗耐药的关键致癌驱动因素，SPINK1可能为这组女性提供一个新的治疗靶点。我们进一步假设SPINK1的这些活性不是通过蛋白酶抑制介导的，而是通过新发现的SPINK1作为能够激活表皮生长因子受体（EGFR）的生长因子的活性介导的。在这里，我们提出了三个具体的目标，旨在测试这些假设。(1)我们将使用卵巢癌细胞培养模型结合SPINK1基因沉默和重组SPINK1治疗来确定SPINK1如何影响卵巢癌细胞生长、侵袭和耐药性。我们还将测试SPINK1中和抗体抑制SPINK1阳性卵巢癌细胞生长和侵袭以及使细胞对化疗敏感的能力。(2)我们将使用定量结合测量和X射线晶体学来定义SPINK1和EGFR之间的分子相互作用。我们还将确定EGFR信号在卵巢癌细胞中SPINK1促癌活性中的作用。(3)我们将评估SPINK1在大量浸润性上皮性卵巢癌生物标本中的表达，检测其与EGFR信号通路激活和生存率的相关性。总的来说，这项工作有可能将SPINK1信号传导定义为以前未被识别的卵巢癌患者子集的恶性肿瘤的关键驱动因素，并作为新药开发的分子靶点。