Rho GTPases and Neuroprotection Model in Cancer Therapy

Rho GTPases 和癌症治疗中的神经保护模型

• 批准号: 8769217
• 负责人: QUN LU
• 金额: $ 7.84万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769217
• 关键词: Actins; Activation Analysis; Antineoplastic Agents; CD95 Antigens; CREB1 gene; Cisplatin; Clinical; Coupled; Cytoskeleton; Dose-Limiting; Drug Targeting; Exhibits; FOS gene; Family; Gene Expression; Genetic Transcription; Immunocompetent; Immunohistochemistry; In Vitro; Laboratories; Lewis Lung Carcinoma; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Measures; Mediating; Modeling; Molecular; Mus; Nerve Degeneration; Neural Conduction; Neurons; Pathway interactions; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Physiological; Platinum; Protein Family; Quality of life; Recovery; Regimen; Research; Rho-associated kinase; Sensory; Serum Response Factor; Signal Pathway; Signal Transduction; Small Interfering RNA; TNFRSF6 gene; Testing; Therapeutic; Touch sensation; Toxic effect; Universities; base; cancer cell; cancer therapy; cell motility; chemotherapy; cytotoxicity; ezrin; graduate student; improved; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; lung Carcinoma; moesin; mouse model; neuroprotection; neurotoxicity; novel; preclinical study; protein activation; public health relevance; radixin protein; relating to nervous system; response; rho; rho GTP-Binding Proteins; small molecule; sural nerve; tumor; undergraduate student; Actins; Activation Analysis; Antineoplastic Agents; CD95 Antigens; CREB1 gene; Cisplatin; Clinical; Coupled; Cytoskeleton; Dose-Limiting; Drug Targeting; Exhibits; FOS gene; Family; Gene Expression; Genetic Transcription; Immunocompetent; Immunohistochemistry; In Vitro; Laboratories; Lewis Lung Carcinoma; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Measurement; Measures; Mediating; Modeling; Molecular; Mus; Nerve Degeneration; Neural Conduction; Neurons; Pathway interactions; Patients; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Physiological; Platinum; Protein Family; Quality of life; Recovery; Regimen; Research; Rho-associated kinase; Sensory; Serum Response Factor; Signal Pathway; Signal Transduction; Small Interfering RNA; TNFRSF6 gene; Testing; Therapeutic; Touch sensation; Toxic effect; Universities; base; cancer cell; cancer therapy; cell motility; chemotherapy; cytotoxicity; ezrin; graduate student; improved; in vivo; inhibitor/antagonist; innovation; kinase inhibitor; lung Carcinoma; moesin; mouse model; neuroprotection; neurotoxicity; novel; preclinical study; protein activation; public health relevance; radixin protein; relating to nervous system; response; rho; rho GTP-Binding Proteins; small molecule; sural nerve; tumor; undergraduate student

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.

描述（由申请人提供）：广泛使用的化学疗法药物（例如铂）表现出高水平的治疗相关毒性，包括神经毒性，通常是剂量限制的，并且在治疗结束后很长一段时间都会毁灭患者的生活质量。 我们已经确定，P160ROCK/RHO激酶抑制剂Y-27632抑制RhoA信号传导，抑制了癌细胞的运动性和侵袭性，可以逆转抗癌药物诱导的神经变性，在新颖的顺铂诱导的周围神经性神经疗法（CIPN）小鼠模型中。很少有分子途径表现出在表现出神经保护作用时抑制癌细胞扩张的独特能力。建立这种提高癌症攻击疗效的途径的基础机制将产生重大影响，因为铂和Y-27632均已证明在临床上是安全的，并且可以扩展到许多抗癌药物应用。 在这个R15区域项目中，我们建议同时使用正常和肿瘤的小鼠来测试以下假设：Rho GTPase信号抑制与化学疗法药物相结合，为攻击癌症提供了一种有效的策略，同时保护神经元。特定目标1将研究两种潜在的分子机制（ERM蛋白激活和肌动蛋白的再分配，以激活Fas受体/CD95和SRF依赖性基因转录），通过抑制Rho GTPase信号途径可保护神经元免受顺铂诱导的神经毒素的能力。具体的目标2将应用创新的小分子Rac1/cdc42激活剂/抑制剂储存库来研究Rho GTPases的亚类中的串扰是否增强了RhoA抑制介导的CIPN抑制作用。具体目标3将研究在原发性和转移性肺癌的鼠模型中，在顺铂抗癌疗法中，RHOA途径抑制和神经保护作用。 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. 这些研究与该实验室的持续研究生和本科生研究相关，将建立Rho GTPase信号传导，作为临床癌症治疗中神经保护和癌症抑制的创新药物靶标。 公共卫生相关性：广泛使用的化学疗法药物（例如铂）表现出高度与治疗相关的毒性，包括神经毒性，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会破坏患者的生活质量。该项目是一项临床前研究，旨在确定Rho GTPase信号的抑制是否与化学疗法药物相结合，在保护神经元的同时为攻击癌症提供了有效的策略。