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Novel c-Abl-directed Therapies to Alleviate Metastatic Breast Cancer

缓解转移性乳腺癌的新型 c-Abl 定向疗法

基本信息

批准号：
8916387
负责人：
Chevaun Danielle Morrison-Smith
金额：
$ 3.49万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
2013-09-12 至 2016-09-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8916387
关键词：
ABL1 gene Address Benign Biological Factors Biological Markers Breast Cancer Patient Breast Cancer cell line Chemotherapy-Oncologic Procedure Chinese Herbs Clinical Trials Clinical Trials Design Coupled Cytotoxic Chemotherapy Data Development Disease Disease Progression Effectiveness Epithelial Estrogen Receptors Estrogens Event Exhibits Experimental Models FDA approved Family member Fatty acid glycerol esters Gleevec Goals Health Human Implant In Vitro In complete remission Large Intestine Carcinoma Lead Left Lesion Malignant Epithelial Cell Malignant Neoplasms Mammary gland Measures Mediating Mesenchymal Metastatic breast cancer Modeling Molecular Monitor Mus Neoplasm Metastasis Pathologic Patients Phase III Clinical Trials Phenotype Progesterone Receptors Randomized Recurrence Staging Tumor Suppressor Proteins Tumorigenicity anticancer activity base c-abl Proto-Oncogenes chemotherapy cohort cytotoxic docetaxel in vivo innovation killings malignant breast neoplasm mouse model mutant novel overexpression pre-clinical response standard of care targeted treatment therapeutic effectiveness translational study triple-negative invasive breast carcinoma tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Triple-negative breast cancer (TNBC) is the most aggressive BC subtype and exhibits enhanced rates of metastasis, recurrence, and poor overall survival as compared to their non-TNBC counterparts. Due to the lack of estrogen and progesterone receptors, as well as that of Her2 overexpression, no FDA approved targeted therapies that are effective against TNBCs. As such, this aggressive BC subtype is typically treated with systemic chemotherapies as the standard of care for TNBCs. We previously established c-Abl as a novel suppressor of TNBC tumorigenesis through its inhibition of EMT, invasive, and metastatic phenotypes. Mechanistically, these c-Abl-mediated events transpired through its reactivation of p53 and p21 expression, thereby alleviating TNBC tumor development in mice. Recently, I have associated c-Abl expression with the response of TNBCs to docetaxel, as well as identified the ancient Chinese herb Securinine to mediate anticancer activities against dormant and metastatic TNBCs via a p73- and c-Abl-dependent mechanism. Therefore, I hypothesize that measures capable of activating c-Abl will alleviate TNBC development and metastatic progression. My innovative and translational studies will address the aforementioned hypothesis by determining (i) whether chemotherapeutic activation of c-Abl inhibits TNBC tumorigenicity; (ii) the value of c-Abl to predict for TNBC response to docetaxel; and (iii) the therapeutic effectiveness of Securinine to eradicate TNBCs. Collectively, my application will elucidate major translational advancements for TNBCs through administration of the allosteric c-Abl activator, DPH, together with Securinine to eradicate TNBCs. Finally, c-Abl is will be established as the first predictive biomarker capable of stratifying TNBC patients into docetaxel responders and nonresponders.

描述（由申请人提供）：三阴性乳腺癌 (TNBC) 是最具侵袭性的 BC 亚型，与非 TNBC 癌症亚型相比，其转移率、复发率更高，总体生存率较差。由于缺乏雌激素和孕激素受体，以及 Her2 过度表达，FDA 尚未批准对 TNBC 有效的靶向疗法。因此，这种侵袭性 BC 亚型通常采用全身化疗作为 TNBC 的标准治疗方法。我们之前通过抑制 EMT、侵袭性和转移表型将 c-Abl 确定为 TNBC 肿瘤发生的新型抑制剂。从机制上讲，这些 c-Abl 介导的事件是通过重新激活 p53 和 p21 表达而发生的，从而减轻了小鼠 TNBC 肿瘤的发展。最近，我将 c-Abl 表达与 TNBC 对多西紫杉醇的反应联系起来，并鉴定出古老的中药叶秋碱通过 p73 和 c-Abl 依赖性机制介导针对休眠和转移性 TNBC 的抗癌活性。因此，我假设能够激活 c-Abl 的措施将减轻 TNBC 的发展和转移进展。我的创新和转化研究将通过确定（i）c-Abl 的化疗激活是否抑制 TNBC 致瘤性来解决上述假设； (ii) c-Abl 预测 TNBC 对多西紫杉醇反应的价值； (iii) Securinine 根除 TNBC 的治疗效果。总的来说，我的申请将通过使用变构 c-Abl 激活剂 DPH 和 Securinine 来阐明 TNBC 的主要转化进展，以根除 TNBC。最后，c-Abl 是将被确立为第一个能够将 TNBC 患者分为多西紫杉醇应答者和无应答者的预测生物标志物。