Evaluation of TNBC treatment strategy utilizing novel signaling pathways

利用新型信号通路评估 TNBC 治疗策略

基本信息

批准号：
8616363
负责人：
IGOR GARKAVTSEV
金额：
$ 18.04万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2013-02-07 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616363
关键词：
Actins Affect Animals Biological Assay Breast Cancer Cell Breast Cancer Model Breast Cancer Treatment Cancer Patient Catabolism Cells Characteristics Chemical Agents Cytoskeleton Data Development Dioxygenases Disease Dissection Enzymes Epidermal Growth Factor Receptor Estrogen receptor negative Evaluation Genes Goals Growth Image Immune Immune response Immunization Immunosuppressive Agents Implant In Vitro Inbred BALB C Mice Left Lung Malignant Neoplasms Metastatic Lesion Migration Assay Modeling Molecular Molecular Target Mus Neoplasm Metastasis Normal tissue morphology PTK2 gene Pathway interactions Patients Pharmaceutical Preparations Phase Plants Pre-Clinical Model Prevention strategy Primary Neoplasm Regulatory T-Lymphocyte Research Resistance Role SCID Mice Signal Pathway Site T-Lymphocyte Testing Therapeutic Toxic effect Tryptophan Tumor Antigens Tumor Immunity alpha-lapachone base cancer cell cell motility high throughput screening human FRAP1 protein improved in vitro Model in vivo in vivo Model indoleamine malignant breast neoplasm metastasis prevention molecular marker mouse model neoplastic cell new therapeutic target novel outcome forecast prevent progesterone receptor negative public health relevance research study response rho GTP-Binding Proteins small molecule treatment strategy triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to investigate whether dehydro-alpha-lapachone (DAL) represses cancer cell motility, inhibits of primary tumor growth and reduces of metastatic burden in preclinical models of triple negative breast cancer. Our preliminary data indicate that DAL is a chemical agent with prominent anti-tumor effect and low toxicity toward normal tissues. Through the dissection of underlying molecular mechanisms, we have shown that DAL 1) represses the Rho-GTPase Rac1, which increases cancer cell motility through remodeling of the actin cytoskeleton, and 2) allosterically inhibits indoleamine-2,3-dioxygenase (IDO), which may confer immunosuppressive characteristics in tumors. We will study DAL's effects on cancer cell motility and invasion (Aim 1), DAL's influence on anti-tumor immunity (Aim 2) and DAL anti-metastatic efficacy (Aim 3). The experiments proposed will enable that DAL represses metastasis and invasion of the most aggressive subtype of breast cancer. To test this hypothesis we will utilize mouse models of spontaneous metastasis and in vitro models evaluating the effects of DAL on motility of cancer cells. The proposed research will clarify the role of cancer-host interaction in metastasis formation and contribute to the development of breast cancer metastasis prevention strategies based on potential novel therapeutic targets Rac1 and IDO.

描述（由申请人提供）：该项目的总体目标是研究脱氢-α-拉帕酮（DAL）是否能抑制三阴性乳腺癌临床前模型中的癌细胞运动、抑制原发性肿瘤生长并减少转移负担。我们的初步数据表明，DAL是一种具有显着抗肿瘤作用且对正常组织毒性低的化学制剂。通过对潜在分子机制的剖析，我们发现 DAL 1) 抑制 Rho-GTPase Rac1，从而通过重塑肌动蛋白细胞骨架来增加癌细胞的运动性，2) 以变构方式抑制吲哚胺-2,3-双加氧酶 (IDO)，这可能赋予肿瘤免疫抑制特征。我们将研究DAL对癌细胞运动和侵袭的影响（目标1）、DAL对抗肿瘤免疫的影响（目标2）和DAL抗转移功效（目标3）。所提出的实验将使 DAL 能够抑制最具侵袭性的乳腺癌亚型的转移和侵袭。为了检验这一假设，我们将利用自发转移的小鼠模型和体外模型来评估 DAL 对癌细胞运动的影响。拟议的研究将阐明癌症-宿主相互作用在转移形成中的作用，并有助于开发基于潜在新治疗靶点 Rac1 和 IDO 的乳腺癌转移预防策略。