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Targeting Protein Kinase D in Triple Negative Breast Cancers

靶向蛋白激酶 D 在三阴性乳腺癌中的作用

基本信息

批准号：
9130798
负责人：
Peter Storz
金额：
$ 20.42万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-21 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130798
关键词：
Animal Model Breast Breast Cancer Cell Breast Cancer cell line Cell Proliferation Cells Chemicals Clinic Combined Modality Therapy Core Facility Cytotoxic Chemotherapy Data Development Distant Drug Targeting Family Goals Growth Health Histopathology Human In Vitro Letters Malignant Neoplasms Mammary Neoplasms Molecular Target Multi-Drug Resistance Neoadjuvant Therapy Neoplasm Metastasis Oncogenic Organ PKD2 protein Pathologist Patients Pattern Phenotype Primary Neoplasm Protein Isoforms Protein Kinase Protein-Serine-Threonine Kinases Research Sampling Signal Transduction Testing Therapeutic Therapeutic Uses Tissues Woman base cancer cell cell type chemotherapy cytotoxic ductal breast carcinoma effective therapy efficacy testing hormone therapy in vivo inhibitor/antagonist malignant breast neoplasm member novel patient subsets protein kinase D small hairpin RNA treatment effect triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): A difficulty in targeting triple-negative (TN) breast cancer is that neoadjuvant therapies are not very effective. Therefore, it is important to identify new potential targets for this subtype of breast cancer. Protein Kinase D3 (PKD3) in TN breast cancer cells regulates proliferation, invasion and multidrug resistance. This predicts that targeting PKD3 with a chemical inhibitor either alone, or in combination with current chemotherapy could be a successful strategy to target this subtype of breast cancer. It is our hypothesis that triple negative breast cancers underwent an isoform switch from expression of PKD1 to expression of PKD3. We further hypothesize that PKD3 drives the oncogenic phenotype of these cancers and that a pan PKD inhibitor will be effective for treatment alone or in combination with currently-used therapeutics. To test this we will: Examine if triple-negative Breast Cancers show an isoform switch in PKD expression to the oncogenic subtype PKD3 (Specific Aim 1); evaluate combinations of CRT0066101 with standard cytotoxic chemotherapy in triple-negative breast cancer cells (Specific Aim 2); and target PKD3 in triple negative cancers and evaluate effects on primary tumor growth and metastasis (Specific Aim 3). Successful completion of our project will identify PKD3 as new molecular target for triple-negative cancers. This is important since this subtype of breast cancer is aggressive and difficult to treat. Overall our results will provide the basis for the development of novel and more potent therapeutic strategies for patients with triple-negative Breast Cancer.

描述（由申请人提供）：靶向三阴性（TN）乳腺癌的困难在于新辅助治疗不是很有效。因此，识别乳腺癌的新的潜在靶点。TN乳腺癌细胞中的蛋白激酶D3（PKD 3）调节增殖、侵袭和多药耐药。这预示着单独使用化学抑制剂或与当前化疗联合使用靶向PKD 3可能是靶向这种亚型乳腺癌的成功策略。我们假设三阴性乳腺癌经历了从PKD 1表达到PKD 3表达的亚型转换。我们进一步假设PKD 3驱动这些癌症的致癌表型，并且pan PKD抑制剂将单独或与当前使用的治疗剂组合用于治疗。为了测试这一点，我们将：检查三阴性乳腺癌是否显示PKD表达亚型转换为致癌亚型PKD 3（特定目标1）;在三阴性乳腺癌细胞中评价CRT 0066101与标准细胞毒性化疗的联合治疗（特定目标2）;在三阴性癌症中靶向PKD 3 并评估对原发性肿瘤生长和转移的影响（具体目标3）。我们的项目的成功完成将确定PKD 3作为三阴性癌症的新分子靶点。这一点很重要，因为这种乳腺癌亚型具有侵袭性，难以治疗。我们的研究结果将为三阴性乳腺癌患者开发新的和更有效的治疗策略提供基础。