Rho GTPases and Neuroprotection Model in Cancer Therapy

描述（由申请人提供）：广泛使用的化疗药物，如铂，表现出高水平的治疗相关毒性，包括神经毒性，这通常是剂量限制的，并且在治疗结束后很长一段时间内可能对患者的生活质量造成破坏性影响。我们已经发现p160ROCK/Rho激酶抑制剂Y-27632抑制RhoA信号，抑制癌细胞的运动和侵袭，可以逆转抗癌药物诱导的顺铂诱导的周围神经病变（CIPN）小鼠模型。很少有分子途径显示出这种独特的抑制癌细胞扩张的能力，同时表现出神经保护作用。由于铂和Y-27632已被证明是临床安全的，并且可以扩展到许多抗癌药物的应用，因此建立这一途径的机制以提高抗癌疗效将具有重大影响。在这个R15 AREA项目中，我们建议使用正常小鼠和荷瘤小鼠来验证化疗药物联合抑制Rho GTPase信号是一种有效的攻击癌症同时保护神经元的策略。特异性目的1将研究两个潜在的分子机制（ERM蛋白激活和重新分配到肌动蛋白以激活Fas受体/CD95和srf依赖性基因转录），通过抑制Rho GTPase信号通路保护神经元免受顺铂诱导的神经毒性。特异性目标2将应用创新的小分子Rac1/Cdc42激活剂/抑制剂库来研究Rho gtpase亚类之间的串扰是否会增强RhoA抑制介导的CIPN抑制。特异性目的3将研究顺铂抗癌治疗原发性和转移性肺癌小鼠模型中的RhoA通路抑制和神经保护作用。我们将确定顺铂和Y-27632（或RhoA/ srf依赖性转录抑制剂CCG-1423）联合使用是否能增强抗癌疗效，同时降低免疫功能小鼠的CIPN（通过改善腓肠神经传导和触觉来测量）。这些研究，结合本实验室研究生和本科生的持续研究，将在临床癌症治疗中确立Rho GTPase信号作为神经保护和肿瘤抑制联合治疗的创新药物靶点。

DESCRIPTION (provided by applicant): Widely-used chemotherapy drugs, such as platinum, exhibit a high level of treatment-associated toxicity including neurotoxicity which is often dose limiting and can be devastating to a patient's quality of life long after the therapy ends. We have identified that suppression of RhoA signaling by p160ROCK/Rho kinase inhibitor Y-27632, which inhibits cancer cell motility and invasion, can reverse anti-cancer drug-induced neurodegeneration in the novel cisplatin-induced peripheral neuropathy (CIPN) mouse model developed in this laboratory. Few molecular pathways demonstrate this unique capacity of inhibiting cancer cell expansion while exhibiting neuroprotective effects. Establishing the mechanisms underlying this pathway to increase cancer-attacking efficacy will have significant impact since both platinum and Y-27632 have proven to be clinically safe and can expand to many anti-cancer drug applications. In this R15 AREA project, we propose to use both normal and tumor-bearing mice to test the hypothesis that suppression of Rho GTPase signaling coupled with chemotherapy drugs provides an effective strategy for attacking cancer while protecting neurons. Specific aim 1 will investigate two potential molecular mechanisms (ERM protein activation and redistribution to actin to activate Fas receptor/CD95 and SRF-dependent gene transcription) by which suppression of Rho GTPase signaling pathway protects neurons from cisplatin-induced neurotoxicity. Specific aim 2 will apply innovative small molecule Rac1/Cdc42 activator/inhibitor reservoirs to investigate whether crosstalks among the subclasses of Rho GTPases enhance the RhoA suppression-mediated inhibition of CIPN. Specific aim 3 will investigate RhoA pathway inhibition and neuroprotection in cisplatin anti-cancer therapy in murine models of primary and metastatic lung carcinoma. We will determine whether cisplatin and Y-27632 (or RhoA/SRF-dependent transcription inhibitor CCG-1423) combinations enhance anti-cancer efficacy while reducing CIPN (measured by improving sural nerve conduction and touch sensation) in immunocompetent mice inoculated with syngeneic Lewis Lung carcinoma cells. These studies, engaging the continuous graduate and undergraduate student research in this laboratory, will establish Rho GTPase signaling as an innovative drug target for combined neuroprotection and cancer inhibition in clinical cancer therapy. PUBLIC HEALTH RELEVANCE: Widely-used chemotherapy drugs, such as platinum, exhibit a high level of treatment-associated toxicity including neurotoxicity which is often dose limiting and can be devastating to a patient's quality of life long after the therapy ends. This project is a preclinical study to determine whether suppression of Rho GTPase signaling coupled with chemotherapy drugs provides an effective strategy for attacking cancer while protecting neurons.