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.

传统（即基因毒性）抗癌药物会对正常组织造成许多副作用。这些副作用是剂量限制性的，严重影响癌症患者的生活质量。为了扩大放化疗联合治疗的治疗窗口，从而使恶性疾病的治疗更加有效和更好的耐受性，应优先采用药物抑制不良组织损伤。自己的初步数据表明，HMG-CoA 还原酶抑制剂（即他汀类药物）被认为通过靶向 Rac/Rho 信号传导而具有多效性胆固醇独立作用，可减轻不良细胞毒性和基因毒性以及非炎症和促纤维化反应。使用广泛使用的抗癌药物（例如阿霉素、顺铂）治疗后的体外恶性细胞和临床前体内模型中的选定组织和辐照（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基因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了急性和慢性疾病病理生理学中涉及的高级分子机制。抗癌治疗造成的慢性正常组织损伤。其他药理学研究的结果提供了累积的证据，表明 Ras 同源 GTPase Rac1 可能在这种情况下特别相关。然而，这一假设的遗传证据仍然缺失。然而，基因数据对于推动新型临床药物的开发至关重要。因此，提交的提案旨在通过采用基因 rac1 敲除小鼠模型来验证 Rac1 作为预防抗癌治疗引起的不良组织反应的有希望的靶点。为此，我们打算使用申请人已经可用的 Rac1flox/flox/Mx1-Cre 小鼠模型来完成 rac1 基因的诱导性遗传删除。利用这种多聚 I:C 诱导模型系统，rac1 可以在多种细胞类型中被广泛删除。随后，将使用 Rac1 精通和 Rac1 缺陷的动物进行比较分析，以阐明 Rac1 对以下方面的影响：(i) 阿霉素对心脏的毒性作用，(ii) 顺铂的肾毒性作用，以及 (iii) 顺铂引起的毒性作用肺部分段照射。目前的假设是，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 缺陷在使用常规药物和放射的抗癌治疗中具有器官保护作用。该项目旨在验证 Rac1 作为跨组织预防放化疗多种不良反应的治疗靶点。