Targeting p38/JNK MAPK to ameliorate cisplatin-induced adverse sequelae on the nervous system

靶向 p38/JNK MAPK 改善顺铂引起的神经系统不良后遗症

• 批准号: 10437925
• 负责人: Daniela Annenelie Bota
• 金额: $ 61.67万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10437925
• 关键词: Adverse effects; Affect; Aftercare; Alzheimer' s Disease; Antineoplastic Agents; Apoptosis; Attention; Attenuated; Axon; Behavioral; Bioenergetics; Blood - brain barrier anatomy; Brain; Breast; Breast Cancer Model; C57BL/6 Mouse; Cancer Model; Cancer Patient; Cell Line; Chemotherapy-induced peripheral neuropathy; Cisplatin; Clinical; Clinical Trials; Cognitive; Cognitive deficits; DNA Damage; Data; Dendritic Spines; Development; Diagnosis; Disease Progression; Dose; Electrophysiology (science); Epithelial ovarian cancer; Excitatory Synapse; FDA approved; Female; Fracture; Gait; Hippocampus (Brain); Impaired cognition; Impairment; In Vitro; Individual; Inflammation; Intervention; Kidney; Length; MAPK8 gene; Malignant Neoplasms; Malignant neoplasm of ovary; Memory; Mitochondria; Mitochondrial DNA; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Mitogens; Molecular; Morphology; Motor; Mus; N-terminal; Nerve; Nerve Fibers; Nervous system structure; Neurologic; Neurons; Neuropathy; Nuclear; Numbness; Ovarian; Oxidative Stress; Oxygen; Painful Paresthesias; Pathway interactions; Patients; Performance; Peripheral; Peripheral Nervous System; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacology; Phosphotransferases; Platinum Compounds; Play; Preventive treatment; Process; Protein Kinase; Protein Kinase C; Quality of life; Rattus; Reporting; Rodent Model; Role; SP600125; Sensory; Signal Pathway; Signal Transduction; Skin; Small Interfering RNA; Spinal Ganglia; Spinal Injuries; Symptoms; Testing; Time; Toxic effect; Transgenic Organisms; United States; Vinca Alkaloids; Woman; anticancer activity; attenuation; axon injury; base; cancer pain; cancer therapy; chemobrain; chemotherapeutic agent; chemotherapy; cognitive testing; density; disability; druggable target; executive function; experience; falls; health disparity; improved; in vivo; information processing; inhibitor; kinase inhibitor; male; malignant breast neoplasm; men; multidisciplinary; neuron apoptosis; neurotoxic; neurotoxicity; neurotransmission; novel; novel strategies; novel therapeutics; ototoxicity; p38 Mitogen Activated Protein Kinase; painful neuropathy; patient mobility; peripheral nerve damage; prevent; processing speed; relating to nervous system; side effect; small molecule inhibitor; stem; stem cells; taxane; translational potential

Chemotherapy-related cognitive impairment (CRCI, chemobrain), chemotherapy-induced peripheral neuropathy (CIPN) and gait changes are debilitating side-effects of cancer treatment with platinum agents (e.g., cisplatin), taxanes, and vinca alkaloids. Cisplatin is widely used as a chemotherapeutic agent to treat ovarian malignancies. Over 70% of women report experiencing CRCI, CIPN and/or falls during treatment or after completion, impairing their quality of life. These neurotoxic impairments can also compromise treatment with cisplatin, influencing disease progression. Currently, there are no FDA-approved clinical interventions for the treatment of CRCI and CIPN. Mechanistically, cisplatin-induced neuronal toxicity derives from nuclear and mitochondrial DNA damage, and oxidative stress, which induce the activation of the mitogen-activated protein kinases (MAPK), p38MAPK and c-Jun N-terminal kinase (JNK), leading to neuronal apoptosis. Our preliminary data show that in vitro pharmacological inhibition with small molecule inhibitors, i.e., neflamapimod for p38MAPK and SP600125 for JNK, prevents cisplatin-induced reduction in dendritic spine branching and density. Based on these data, we hypothesize that inhibition of the p38MAPK/JNK pathways will prevent cisplatin-induced neuronal apoptosis and damage, leading to attenuation of cognitive impairments, gait changes, and neuropathic pain associated with CRCI and CIPN. In this project, we propose to determine if: (1) cisplatin-induced p38 MAPK/JNK signaling underlies structural and functional neuronal damage, using in vitro pharmacological inhibition and siRNA silencing; (2) neflamapimod and SP600125 prevent cisplatin-induced neuropathy and gait alterations in the ID8 syngeneic epithelial ovarian cancer in C57BL/6 mice and the transgenic breast cancer model C3TAg in FVBN mice; and (3) cisplatin-induced neurotoxicity is attenuated by p38MAPK/JNK inhibition without compromising its anti-cancer activity. Our Approach includes in vitro analysis of 2 separate neuronal cell lines, behavioral analysis using sensory testing for CIPN, testing of cognitive impairment, and novel MouseWalker for gait changes in female mice using the two mouse cancer models. The proposed studies will demonstrate the role of the p38MAPK and JNK in cisplatin induced CRCI/CIPN, and translational potential for novel strategies to treat CRCI and CIPN. Due to health disparities, women suffer more disproportionately from cancer and pain-related treatment than men. Therefore, testing our hypothesis in female mice is expected to significantly advance the understanding and treatment of cisplatin-induced neurotoxic side effects and improve the quality of life for women with cancer. Nevertheless, we expect that these findings may also apply to cisplatin- induced neurotoxicity in males and to other cancers than ovarian and breast cancers.

化疗相关认知障碍（CRCI、chemobrain）、化疗引起的周围神经病变 (CIPN) 和步态改变是铂类药物（例如顺铂）癌症治疗的令人衰弱的副作用， 紫杉烷类和长春花生物碱。顺铂广泛用作治疗卵巢恶性肿瘤的化疗剂。 超过 70% 的女性表示在治疗期间或完成后经历过 CRCI、CIPN 和/或跌倒，从而损害 他们的生活质量。这些神经毒性损伤也会影响顺铂的治疗，影响 疾病进展。目前，尚无 FDA 批准的用于治疗 CRCI 的临床干预措施 CIPN。从机制上讲，顺铂诱导的神经元毒性源自核和线粒体 DNA 损伤， 和氧化应激，诱导丝裂原激活蛋白激酶 (MAPK)、p38MAPK 的激活 和 c-Jun N 末端激酶 (JNK)，导致神经元凋亡。我们的初步数据表明，在体外 小分子抑制剂的药理抑制作用，即 p38MAPK 的奈夫拉马莫德和 p38MAPK 的 SP600125 JNK 可防止顺铂引起的树突棘分支和密度减少。根据这些数据，我们 假设抑制 p38MAPK/JNK 通路将阻止顺铂诱导的神经元 细胞凋亡和损伤，导致认知障碍、步态改变和神经病变的减轻 与 CRCI 和 CIPN 相关的疼痛。在这个项目中，我们建议确定：(1) 顺铂诱导的 p38 MAPK/JNK 信号传导是结构和功能性神经元损伤的基础，使用体外药理学 抑制和 siRNA 沉默； (2)奈弗拉马莫德和SP600125预防顺铂引起的神经病变和步态 C57BL/6 小鼠 ID8 同基因上皮性卵巢癌和转基因乳腺癌的变化 FVBN 小鼠模型 C3TAg； (3) p38MAPK/JNK 抑制可减弱顺铂诱导的神经毒性 而不影响其抗癌活性。我们的方法包括对 2 个独立神经元细胞的体外分析 线、使用 CIPN 感官测试的行为分析、认知障碍测试以及新颖的 MouseWalker 使用两种小鼠癌症模型来改变雌性小鼠的步态。拟议的研究将 证明 p38MAPK 和 JNK 在顺铂诱导的 CRCI/CIPN 中的作用，以及转化潜力 治疗 CRCI 和 CIPN 的新策略。由于健康差异，女性更容易遭受以下疾病的困扰 癌症和疼痛相关的治疗高于男性。因此，在雌性小鼠中检验我们的假设预计会 显着促进对顺铂引起的神经毒性副作用的理解和治疗，并改善 患有癌症的女性的生活质量。尽管如此，我们预计这些发现也可能适用于顺铂 对男性以及卵巢癌和乳腺癌以外的其他癌症产生神经毒性。