Targeting SHP2 as a precision medicine for the treatment of HER2-positive breast cancer

以SHP2为靶点作为治疗HER2阳性乳腺癌的精准药物

基本信息

批准号：
10334496
负责人：
Yehenew M Agazie
金额：
$ 33.63万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-05 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10334496
关键词：
Aftercare Antibodies Antineoplastic Agents Biological Biological Availability Brain Breast Cancer Cell Breast Cancer Patient Breast Cancer Treatment Cancerous Cell Proliferation Cells Clinical Complication Data Development Disease Disease remission Dose Drug Targeting Drug resistance Drug usage EGFR Protein Overexpression Epidermal Growth Factor Receptor Future Gene Expression Profile Goals Half-Life Human Immunocompetent Institutes Investigation Lead Letters Malignant Neoplasms Mediator of activation protein Metastatic malignant neoplasm to brain Modeling Mus NOD/SCID mouse Names Neoplasm Metastasis Oncogenes Oncologist Operative Surgical Procedures Outcome Patient Care Patients Pertuzumab Pharmaceutical Preparations Pharmacology Phosphoric Monoester Hydrolases Plasma Process Progression-Free Survivals Property Protein Tyrosine Phosphatase Proteins Quality of life Receptor Protein-Tyrosine Kinases Recurrence Recurrent disease Reporting Resistance Resistance development Signal Pathway Signal Transduction Site Spontaneous Remission Testing Therapeutic Time Tissues Toxic effect Trastuzumab Treatment Cost Tyrosine Kinase Inhibitor Xenograft Model anti-cancer anticancer activity base blood-brain barrier permeabilization cancer stem cell cell transformation chemotherapy clinically significant dosage efficacy evaluation efficacy testing exhaustion experimental study genetic signature improved in vivo lapatinib malignant breast neoplasm meetings new therapeutic target novel therapeutic intervention overexpression patient derived xenograft model precision medicine protein phosphatase inhibitor-2 small molecule standard of care targeted treatment transcriptome tumor tumor growth tumor xenograft

项目摘要

PROJECT SUMMARY Approximately 20% of breast cancer (BC) is caused by overexpression of the human epidermal growth factor receptor 2 (HER2), on the basis of which anti-HER2 therapies have been developed. Although these drugs have benefited BC patients, development of resistance and disease recurrence continue to be the major clinical challenges. These clinical problems warrant studies on alternative therapeutic strategies to treat HER2-positive BC. In this application, we propose to develop a new targeted therapy through pharmacological inhibition of the Src homology phosphotyrosyl phosphatase 2 (SHP2), which acts by blocking HER2 and switch oncogene overexpression. As opposed to the existing anti-HER2 drugs that act by inactivating the already expressed protein, targeting SHP2 has the potential to block the process of overexpression. We predict that targeting SHP2 that controls multiple signaling pathways is more effective and at the same time eliminates the need for developing drugs against multiple targets. In addition, targeting SHP2 can reduce toxicities associated with the use of drug cocktails and enormously cuts the cost of treatment. In line with this concept, we have invented a specific small molecule SHP2 inhibitor (WGMDY) that shows promising anti-cancer effects in naïve and anti-HER2 drug resistant cells in culture and in vivo. In this study, we will investigate the potential of SHP2 as a drug target and WGMDY as an anti-cancer agent. The overall hypothesis is that pharmacological targeting of SHP2 induces remission of both treatment-naïve and anti-HER2 drug resistant cells and tumors. To attain these goals, three specific aims have been proposed. First (Specific aim #1), we will determine the effect of pharmacological targeting of SHP2 on oncogene expression, cell proliferation, transformation, and cancer stem cell properties. Second (Specific aim #2), we will determine maximum tolerable dose, toxicity, bioavailability, and stability of WGMDY in vivo. And third (Specific aim #3), we will determine the anti-cancer activity of SHP2 targeting with WGMDY in primary spontaneous and xenograft models and in brain metastatic models. The outcome of the proposed study can show the potential of SHP2 as a drug target and the viability of the anti-SHP2 compound as a lead molecule for future development of anti-SHP2 drugs.

项目摘要大约20％的乳腺癌（BC）是由人表皮生长过度表达引起的因子受体2（HER2），基于哪种抗HER2疗法。虽然这些药物使卑诗省患者受益，抗药性和疾病复发的发展继续是主要的临床挑战。这些临床问题保证有关替代治疗策略的研究治疗her2阳性卑诗省。在此应用中，我们建议通过 SRC同源性磷酸酪糖基磷酸酶2（SHP2）的药理抑制作用，该磷酸酪糖基磷酸酶2（SHP2）由阻止HER2并切换致癌基因过表达。与现有的抗HER2药物相反通过灭活已经表达的蛋白质，靶向SHP2具有阻止该过程的潜力过表达。我们预测，针对控制多个信号通路的SHP2更有效同时，消除了针对多个靶标开发药物的需求。另外，定位 SHP2可以减少与使用毒品鸡尾酒有关的毒性，并削减成本治疗。根据这个概念，我们发明了特定的小分子SHP2抑制剂（WGMDY）这显示了在培养和体内幼稚和抗HER2耐药细胞中有希望的抗癌作用。在这项研究中，我们将研究SHP2作为药物靶标的潜力和WGMDY作为抗癌者代理人。总体假设是SHP2的药理学靶向诱导两者的缓解不接受治疗和抗HER2耐药细胞和肿瘤。为了实现这些目标，三个特定的已经提出了目标。首先（特定目标＃1），我们将确定药物靶向的效果 SHP2在癌基因表达，细胞增殖，转化和癌细胞特性上的of of of shp2。第二（特定目标＃2），我们将确定最大的耐受剂量，毒性，生物利用度和稳定性 wgmdy in Vivo。和第三（特定目标＃3），我们将确定SHP2靶向的抗癌活性在原代赞助商和异种移植模型以及脑转移模型中具有WGMDY。结果在拟议的研究中，可以表明SHP2作为药物靶标的潜力和抗SHP2的生存能力作为抗SHP2药物未来开发的铅分子的化合物。