The treatment of PI3KCA-mutant breast cancer brain metastasis with a selective PI3K/mTOR-inhibitor: a preclinical study to evaluate the response to treatment

用选择性 PI3K/mTOR 抑制剂治疗 PI3KCA 突变乳腺癌脑转移：一项评估治疗反应的临床前研究

• 批准号: 325246018
• 负责人: Dr. Franziska Maria Ippen
• 金额: --
• 依托单位: Department of Neurology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/325246018?language=en
• 关键词: treatment; PI3KCA; mutant; breast; cancer

One of the most common mutations in breast cancer brain metastases is the Phosphatidylinositol-4,5-Bisphosphate 3-Kinase (PIK3CA) mutation, leading to an enhanced activation of the Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/ mammalian target of rapamycin (mTOR) pathway, which has been shown to be involved in the development, progression, and treatment resistance of this kind of cancer. These results indicate that the PIK3CA mutation could also be a potential therapeutic target for cerebral metastasis. Despite the development of numerous inhibitors targeting this pathway, there are no approved systemic therapies for the treatment of breast cancer brain metastases at present. Furthermore, the efficacy of some targeted therapies used for the treatment of systemic disease is largely unclear in patients with breast cancer brain metastasis. Thus, there is still an urgent unmet need for new targeted therapies, which are able to inhibit the PI3K/AKT/mTOR pathway in breast cancer brain metastasis in order to successfully treat affected patients. The goal of this research project is to evaluate the therapeutic efficacy of the new PI3K/mTOR-inhibitor GDC-0084 in PIK3CA-mutant breast cancer brain metastasis in a xenograft-mouse model in regards to progression-free survival and overall survival by using bioluminescence imaging (BLI).

乳腺癌脑转移中最常见的突变之一是磷脂酰肌醇-4，5-二磷酸3-激酶（PIK 3CA）突变，导致磷脂酰肌醇3-激酶（PI 3 K）/蛋白激酶B（AKT）/哺乳动物雷帕霉素靶点（mTOR）通路的活化增强，已显示其参与此类癌症的发生、进展和治疗抗性。这些结果表明PIK 3CA突变也可能是脑转移的潜在治疗靶点。尽管开发了许多针对该途径的抑制剂，但目前还没有批准用于治疗乳腺癌脑转移的全身疗法。此外，一些用于治疗全身性疾病的靶向治疗在乳腺癌脑转移患者中的疗效在很大程度上尚不清楚。因此，仍然迫切需要新的靶向疗法，其能够抑制乳腺癌脑转移中的PI 3 K/AKT/mTOR通路，以成功治疗受影响的患者。本研究项目的目的是通过使用生物发光成像（BLI），在异种移植物-小鼠模型中评价新型PI 3 K/mTOR抑制剂GDC-0084在PIK 3CA突变型乳腺癌脑转移中的无进展生存期和总生存期方面的治疗疗效。

项目成果

The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in PIK3CA-Mutant Breast Cancer Brain Metastases

• DOI: 10.1158/1078-0432.ccr-18-3049
• 发表时间: 2019-06-01
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Ippen, Franziska M.;Alvarez-Breckenridge, Christopher A.;Brastianos, Priscilla K.
• 通讯作者: Brastianos, Priscilla K.

Precision Medicine for Primary Central Nervous System Tumors: Are We There Yet?

原发性中枢神经系统肿瘤的精准医学：我们到了吗？

• DOI: 10.1200/edbk_199247
• 发表时间: 2018
• 期刊: American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting
• 作者: Ippen FM;Colman H;van den Bent MJ;Brastianos PK
• 通讯作者: Brastianos PK