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

• 批准号: 8563720
• 负责人: Evette S Radisky
• 金额: $ 21.9万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 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/8563720
• 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' 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

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上不同的疾病，但患者尚未通过通过亚型特异性分子靶向疗法的开发和翻译而受益于我们不断发展的理解。我们假设，对于卵巢癌患者的一个小分子亚群，分泌的蛋白质蛋白酶抑制剂Spink1可能代表了肿瘤增殖，侵袭和化学抗性的关键致癌驱动力，而Spink1可能为这群女性提供新的疗法。我们进一步假设，Spink1的这些活性不是通过蛋白酶抑制来介导的，而是通过Spink1的新活性作为能够激活表皮生长因子受体（EGFR）的生长因子的新活性。在这里，我们提出了三个旨在检验这些假设的特定目标。 （1）我们将使用卵巢癌的细胞培养模型与Spink1基因沉默和重组Spink1治疗结合使用卵巢癌的细胞培养模型来定义Spink1如何影响卵巢癌细胞的生长，侵袭和耐药性。我们还将测试Spink1中和抗体抑制Spink1阳性卵巢癌细胞侵袭的能力，并使细胞对化学疗法敏感。 （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促进癌症活性中的作用。 （3）我们将评估Spink1在大量浸润性上皮卵巢癌生物测量中的表达，从而测试与EGFR信号通路激活和生存的关联。总体而言，这项工作有可能将Spink1信号定义为先前未识别的卵巢癌患者子集的恶性肿瘤的关键驱动力，并且是新型药物发育的分子靶标。