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）抗癌药物对正常组织造成许多副作用。这些不良反应是剂量限制性的，严重影响癌症患者的生活质量。对不良组织损伤的药理学抑制将是优选的，以便拓宽组合的放射-化学疗法的治疗窗，并且因此能够更有效和更好地耐受恶性疾病的治疗。初步数据表明，HMG-CoA还原酶抑制剂他汀类药物（即他汀类药物）被认为通过靶向Rac/Rho信号传导具有多效胆固醇非依赖性作用，在用广泛使用的抗癌药物治疗后，减轻体外非恶性细胞和临床前体内模型中选定组织的不良细胞毒性和遗传毒性以及炎症和促纤维化反应（例如多柔比星、顺铂）和照射（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和不同类型的组织/细胞类型的多重保护作用，我们假设这些药物干扰抗癌治疗引起的急性和慢性正常组织损伤的病理生理学中涉及的上级分子机制。额外的药理学研究的结果提供了累积的证据表明，Ras同源GTdR Rac 1可能在这种情况下特别相关。然而，这一假设的遗传学证据仍然缺失。然而，基因数据基本上需要激励新的临床药物开发。因此，提交的提案旨在通过采用基因rac 1敲除小鼠模型来验证Rac 1作为预防抗癌治疗诱导的不良组织反应的有希望的靶点。为此，我们打算使用Rac 1flox/flox/Mx 1-Cre小鼠模型完成rac 1基因的诱导型遗传缺失，该模型已提供给申请人。采用这种poly-I：C诱导模型系统，rac 1可以在多种细胞类型中广泛缺失。之后，将使用Rac 1熟练和Rac 1缺陷动物进行比较分析，以阐明Rac 1对（i）多柔比星对心脏的毒性作用，（ii）顺铂的肾毒性作用和（iii）肺分次照射引起的毒性作用的影响。工作假设是Rac 1调节的信号通路是由抗癌疗法诱导的急性和慢性正常组织损伤所必需的。换句话说，我们推测，Rac 1缺陷是有机保护的背景下，采用传统的药物和辐射的抗癌治疗。该项目旨在验证Rac 1作为治疗靶点，用于组织超范围预防放化疗的多种不良反应。