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

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）：广泛使用的化疗药物，例如铂，表现出高水平的治疗相关毒性，包括神经毒性，这种毒性通常是剂量限制的，并且在治疗结束后很长时间内可能会严重损害患者的生活质量。 我们发现，在本实验室开发的新型顺铂诱导的周围神经病变（CIPN）小鼠模型中，p160ROCK/Rho激酶抑制剂Y-27632抑制RhoA信号传导（抑制癌细胞运动和侵袭）可以逆转抗癌药物诱导的神经变性。很少有分子途径证明这种抑制癌细胞扩张同时表现出神经保护作用的独特能力。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应用，因此建立该途径的潜在机制以提高抗癌功效将产生重大影响。 在这个 R15 AREA 项目中，我们建议使用正常小鼠和荷瘤小鼠来测试以下假设：抑制 Rho GTPase 信号传导与化疗药物相结合，可提供一种在保护神经元的同时攻击癌症的有效策略。具体目标 1 将研究两种潜在的分子机制（ERM 蛋白激活和重新分配至肌动蛋白以激活 Fas 受体/CD95 和 SRF 依赖性基因转录），通过抑制 Rho GTPase 信号通路可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 Rac1/Cdc42 激活剂/抑制剂库来研究 Rho GTPases 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小鼠模型中研究顺铂抗癌治疗中的 RhoA 通路抑制和神经保护作用。我们将确定在接种同基因 Lewis 肺癌细胞的免疫活性小鼠中，顺铂和 Y-27632（或 RhoA/SRF 依赖性转录抑制剂 CCG-1423）组合是否可以增强抗癌功​​效，同时降低 CIPN（通过改善腓肠神经传导和触觉来测量）。 这些研究吸引了该实验室的研究生和本科生的持续研究，将确立 Rho GTPase 信号传导作为临床癌症治疗中联合神经保护和癌症抑制的创新药物靶点。 公共卫生相关性：广泛使用的化疗药物（例如铂）表现出高水平的治疗相关毒性，包括神经毒性，这种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严重影响患者的生活质量。该项目是一项临床前研究，旨在确定抑制 Rho GTPase 信号传导与化疗药物相结合是否可以提供一种在保护神经元的同时攻击癌症的有效策略。

项目成果

Pharmacological Modulators of Small GTPases of Rho Family in Neurodegenerative Diseases.

神经退行性疾病中Rho家族小的GTPases的药理学调节剂。

• DOI: 10.3389/fncel.2021.661612
• 发表时间: 2021
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Guiler W;Koehler A;Boykin C;Lu Q
• 通讯作者: Lu Q

C-Src-mediated phosphorylation of δ-catenin increases its protein stability and the ability of inducing nuclear distribution of β-catenin.

• DOI: 10.1016/j.bbamcr.2013.12.021
• 发表时间: 2014-04
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
• 影响因子: 5.1
• 作者: He, Yongfeng;Kim, Hangun;Ryu, Taeyong;Lee, Kwang-Youl;Choi, Won-Seok;Kim, Kyeong-Man;Zheng, Mei;Joh, Yechan;Lee, Jae-Hyuk;Kwon, Dong-Deuk;Lu, Qun;Kim, Kwonseop
• 通讯作者: Kim, Kwonseop

Rho GTPases as therapeutic targets in Alzheimer's disease.

• DOI: 10.1186/s13195-017-0320-4
• 发表时间: 2017-12-15
• 期刊: Alzheimer's research & therapy
• 作者: Aguilar BJ;Zhu Y;Lu Q
• 通讯作者: Lu Q

Amelioration of cisplatin-induced experimental peripheral neuropathy by a small molecule targeting p75 NTR.

• DOI: 10.1016/j.neuro.2014.09.005
• 发表时间: 2014-12
• 期刊: NEUROTOXICOLOGY
• 影响因子: 3.4
• 作者: Friesland, Amy;Weng, Zhiying;Duenas, Maria;Massa, Stephen M.;Longo, Frank M.;Lu, Qun
• 通讯作者: Lu, Qun