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:
  • 金额:
    $ 16.57万
  • 依托单位:
  • 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

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)我们将评估大量侵袭性上皮性卵巢癌生物标本中SPINK 1的表达,测试其与EGFR信号通路激活和生存的相关性。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。

项目成果

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Evette S Radisky其他文献

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{{ truncateString('Evette S Radisky', 18)}}的其他基金

Exploiting new approaches for selective inhibition of trypsins
开发选择性抑制胰蛋白酶的新方法
  • 批准号:
    10338695
  • 财政年份:
    2022
  • 资助金额:
    $ 16.57万
  • 项目类别:
Exploiting new approaches for selective inhibition of trypsins
开发选择性抑制胰蛋白酶的新方法
  • 批准号:
    10542402
  • 财政年份:
    2022
  • 资助金额:
    $ 16.57万
  • 项目类别:
Engineering tissue inhibitor of metalloproteinases-2 (TIMP-2) for triple negative breast cancer therapy
用于三阴性乳腺癌治疗的工程组织金属蛋白酶-2 (TIMP-2) 抑制剂
  • 批准号:
    10177669
  • 财政年份:
    2021
  • 资助金额:
    $ 16.57万
  • 项目类别:
Engineering tissue inhibitor of metalloproteinases-2 (TIMP-2) for triple negative breast cancer therapy
用于三阴性乳腺癌治疗的工程组织金属蛋白酶-2 (TIMP-2) 抑制剂
  • 批准号:
    10559719
  • 财政年份:
    2021
  • 资助金额:
    $ 16.57万
  • 项目类别:
Engineering tissue inhibitor of metalloproteinases-2 (TIMP-2) for triple negative breast cancer therapy
用于三阴性乳腺癌治疗的工程组织金属蛋白酶-2 (TIMP-2) 抑制剂
  • 批准号:
    10357957
  • 财政年份:
    2021
  • 资助金额:
    $ 16.57万
  • 项目类别:
Engineering selective inhibition of metalloproteinases by tissue inhibitors of metalloproteinases (R01 GM132100 RESUB - *TIMPs)
通过金属蛋白酶组织抑制剂对金属蛋白酶进行工程选择性抑制(R01 GM132100 RESUB - *TIMP)
  • 批准号:
    10545017
  • 财政年份:
    2020
  • 资助金额:
    $ 16.57万
  • 项目类别:
Engineering selective inhibition of metalloproteinases by tissue inhibitors of metalloproteinases (R01 GM132100 RESUB - *TIMPs)
通过金属蛋白酶组织抑制剂对金属蛋白酶进行工程选择性抑制(R01 GM132100 RESUB - *TIMP)
  • 批准号:
    10319170
  • 财政年份:
    2020
  • 资助金额:
    $ 16.57万
  • 项目类别:
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
  • 财政年份:
    2013
  • 资助金额:
    $ 16.57万
  • 项目类别:
Inhibiting serine protease-induced prostate cancer progression
抑制丝氨酸蛋白酶诱导的前列腺癌进展
  • 批准号:
    8634737
  • 财政年份:
    2013
  • 资助金额:
    $ 16.57万
  • 项目类别:
Inhibiting serine protease-induced prostate cancer progression
抑制丝氨酸蛋白酶诱导的前列腺癌进展
  • 批准号:
    8498656
  • 财政年份:
    2013
  • 资助金额:
    $ 16.57万
  • 项目类别:
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