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，其通常是剂量限制性的，并且在治疗结束后很长时间内可能对患者的生活质量造成破坏。 我们已经确定，抑制RhoA信号的p160 ROCK/Rho激酶抑制剂Y-27632，抑制癌细胞的运动和侵袭，可以逆转抗癌药物诱导的神经退行性疾病的新的顺铂诱导的周围神经病变（CIPN）在本实验室开发的小鼠模型。很少有分子途径证明这种独特的抑制癌细胞扩增的能力，同时表现出神经保护作用。建立这一途径的机制以提高癌症攻击功效将产生重大影响，因为铂和Y-27632已被证明在临床上是安全的，并且可以扩展到许多抗癌药物的应用。 在这个R15 AREA项目中，我们建议使用正常和荷瘤小鼠来测试这一假设，即抑制Rho GT3信号传导与化疗药物结合提供了一种有效的攻击癌症的策略，同时保护神经元。具体目标1将研究两种潜在的分子机制（ERM蛋白激活和再分布到肌动蛋白以激活Fas受体/CD 95和SRF依赖的基因转录），通过抑制Rho GT3信号通路保护神经元免受顺铂诱导的神经毒性。具体目标2将应用创新的小分子Rac 1/Cdc 42激活剂/抑制剂储库来研究Rho GTP酶亚类之间的串扰是否增强RhoA抑制介导的CIPN抑制。具体目标3将在原发性和转移性肺癌的鼠模型中研究顺铂抗癌疗法中的RhoA通路抑制和神经保护。我们将确定顺铂和Y-27632（或RhoA/SRF依赖性转录抑制剂CCG-1423）组合是否在接种同系刘易斯肺癌细胞的免疫活性小鼠中增强抗癌疗效，同时降低CIPN（通过改善腓肠神经传导和触觉测量）。 这些研究，从事连续的研究生和本科生在这个实验室的研究，将建立Rho GTdR信号作为一个创新的药物靶点，在临床癌症治疗中联合神经保护和癌症抑制。 公共卫生相关性：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，其通常是剂量限制性的，并且在治疗结束后很长时间内可能对患者的生活质量造成破坏。该项目是一项临床前研究，旨在确定Rho GT3信号转导抑制与化疗药物结合是否为攻击癌症同时保护神经元提供了有效的策略。

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.