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：
8810789
负责人：
Peter Storz
金额：
$ 17.02万
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/8810789
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 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 protein kinase D public health relevance 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（由应用提供）：靶向三阴性（TN）乳腺癌的困难是，新辅助疗法不是很有效。因此，重要的是要识别这种乳腺癌亚型的新潜在靶标。 TN乳腺癌细胞中的蛋白激酶D3（PKD3）调节增殖，侵袭和多药耐药性。这预测，仅用化学抑制剂靶向PKD3或与当前的化学疗法结合使用可能是针对这种乳腺癌亚型的成功策略。我们的假设是，三重负乳腺癌从PKD1的表达转换为PKD3的表达。我们进一步假设PKD3驱动了这些癌症的致癌表型，并且PAN PKD抑制剂将有效单独治疗或与当前使用的治疗结合使用。为了测试这一点，我们将：检查三阴性乳腺癌是否显示出PKD表达中的同工型开关对致癌亚型PKD3（特定AIM 1）；在三阴性乳腺癌细胞中评估CRT0066101与标准细胞毒性化疗的组合（特定的目标2）；和三重负癌中的靶PKD3 并评估对原发性肿瘤生长和转移的影响（特定目标3）。成功完成我们的项目将确定PKD3是三阴性癌的新分子靶标。这很重要，因为这种乳腺癌的亚型具有侵略性且难以治疗。全面的我们的结果将为三阴性乳腺癌患者开发新的和更多潜在的治疗策略的基础。