Relevance of Rac1-regulated mechanisms for adverse tissue damage caused by conventional anticancer drugs and radiotherapy

Rac1调节机制与传统抗癌药物和放射治疗引起的不良组织损伤的相关性

• 批准号: 432471479
• 负责人: Professor Dr. Gerhard Fritz
• 金额: --
• 依托单位: Institut für Toxikologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/432471479?language=en
• 关键词: Relevance; Rac1; regulated; mechanisms; adverse

Conventional (i.e. genotoxic) anticancer drugs cause numerous side effects on normal tissue. These adverse effects are dose-limiting and severely impact the quality of life of cancer patients. Pharmacological inhibition of adverse tissue damage would be preferential in order to widen the therapeutic window of combined radio-chemotherapy and, in consequence, enable more efficient and better tolerable therapy of malignant diseases. Own preliminary data demonstrate that HMG-CoA reductase inhibitors (i.e. statins), which are believed to have pleiotropic cholesterol-independent effects by targeting Rac/Rho-signaling, mitigate adverse cytotoxic and genotoxic as well as inflammatory and pro-fibrotic responses of non-malignant cells in vitro and selected tissues in preclinical in vivo models following treatment with widely used anticancer drugs (e.g. doxorubicin, cisplatin) and irradiation (IR). Bearing in mind the multiple protective effects of statins and Rac-specific small-molecule inhibitors against different types of genotoxic drugs and towards different types of tissues/cell types, we hypothesize that these drugs interfere with superior molecular mechanisms involved in the pathophysiology of acute and chronic normal tissue damage resulting from anticancer therapeutics. The results of additional pharmacological studies provide cumulative evidence that the Ras-homologous GTPase Rac1 might be of particular relevance in this context. However, genetic evidence for this hypothesis is still missing. Yet, genetic data are essentially required to motivate novel clinical drug development. Therefore, the submitted proposal aims to verify Rac1 as promising target for the prevention of anticancer therapy-induced adverse tissue responses by employing a genetic rac1 knock-out mouse model. To this end, we intend to accomplish an inducible genetic deletion of the rac1 gene using the Rac1flox/flox/Mx1-Cre mouse model, which is already available to the applicant. Employing this poly-I:C inducible model system, rac1 can be extensively deleted in multiple cell types. Afterwards, comparative analyses using Rac1 proficient and Rac1 deficient animals will be performed to elucidate the impact of Rac1 on (i) the toxic effects of doxorubicin on the heart, (ii) the nephrotoxic effects of cisplatin and (iii) the toxic effects caused by fractionated irradiation of the lung. The working hypothesis is that Rac1-regulated signaling pathways are required for both acute and chronic normal tissue damage induced by anticancer therapeutics. In other words, we speculate that Rac1 deficiency is organoprotective in the context of anticancer therapy employing conventional drugs and irradiation. The project aims to validate Rac1 as therapeutic target for a tissue-overspanning prevention of multiple adverse effects of radio-chemotherapy.

常规（即遗传毒性）抗癌药对正常组织产生了许多副作用。这些不良反应是限制剂量的，严重影响了癌症患者的生活质量。为了扩大放射化学化学疗法的治疗窗口，对不良组织损伤的药理抑制作用将是优先的，因此，对恶性疾病的效率更高且可耐受地耐受治疗。自己的初步数据表明，HMG-COA还原酶抑制剂（即汀类药物）通过靶向RAC/Rho信号，减轻不良细胞毒素和基因毒性，以及与非炎症性和纤维化的细胞，以及在不纤维化的反应中，并在不良基因毒性中，并在不融合的组织中靶向RAC/Rho-SynaLSINAL，并在不良基因毒性和基因上选择性地进行了对Vito型细胞，并在维护中，并将其靶向不良，并在促炎性毒性和基因上，这些抑制剂（即汀类药物）具有与多毒素胆固醇无关的作用。广泛使用的抗癌药（例如阿霉素，顺铂）和辐照（IR）。考虑到他汀类药物和RAC特异性小分子抑制剂对不同类型的遗传毒性药物以及针对不同类型的组织/细胞类型的多种保护作用，我们假设这些药物会干扰参与急性和慢性正常组织病理生理学的卓越分子机制，从而损害了抗癌药物治疗抗癌。其他药理学研究的结果提供了累积证据，表明在这种情况下，RAS同源GTPase Rac1可能特别相关。但是，这一假设的遗传证据仍然缺失。然而，基本上需要遗传数据来激发新的临床药物发展。因此，提交的建议旨在通过采用遗传Rac1敲除小鼠模型来验证Rac1作为预防抗癌诱导的不良组织反应的有希望的目标。为此，我们打算使用Rac1Flox/Flox/MX1-CRE小鼠模型来完成RAC1基因的诱导遗传缺失，该模型已经可用于申请人。使用此Poly-I：C诱导模型系统，Rac1可以在多种细胞类型中广泛删除。之后，将进行使用RAC1熟练和Rac1缺乏动物的比较分析，以阐明Rac1对（i）阿霉素对心脏的毒性作用，（ii）顺铂和（iii）肾脏毒性作用是由肺部受分数递增引起的毒性作用。工作假设是抗癌治疗引起的急性和慢性正常组织损伤都需要Rac1调节的信号通路。换句话说，我们推测Rac1缺乏在采用常规药物和辐照的抗癌治疗的背景下是有机保护的。该项目旨在验证RAC1作为预防无线电疗法多种不良反应的组织范围范围的治疗靶标。