CNS vulnerability to systemic chemotherapy: Causes and prevention

中枢神经系统对全身化疗的脆弱性：原因和预防

• 批准号: 7533303
• 负责人: MARK D NOBLE
• 金额: $ 31.96万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7533303
• 关键词: Acute; Adult; Adverse effects; Adverse event; Aftercare; Animal Model; Biological; Cancer cell line; Cell Death; Cell division; Cells; Cerebral Infarction; Childhood; Erythropoietin; Event; Foundations; Frequencies; Generations; Hippocampus (Brain); Impaired cognition; In Vitro; Individual; Leukoencephalopathy; Mainstreaming; Malignant Neoplasms; Mus; Myelin; Neurologic; Neurons; Normal Cell; Numbers; Oligodendroglia; Oxidation-Reduction; Pathway interactions; Prevention; Public Health; Receptor Protein-Tyrosine Kinases; Regulatory Pathway; Research; Research Design; Risk; Seizures; Signaling Molecule; Stem cells; Survivors; Testing; Therapeutic Agents; Time; base; brain tract; cancer cell; cancer stem cell; cancer therapy; chemotherapeutic agent; chemotherapy; clinically relevant; in vivo; prevent; transcription factor; white matter

DESCRIPTION (provided by applicant): One of the disturbing findings to emerge from studies on survivors of both childhood and adult cancers is the frequency with which systemic chemotherapy is associated with adverse neurological sequelae, including leukoencephalopathy, seizures, cerebral infarctions, and cognitive impairment. In our studies designed to understand the biological foundations for these effects, we have discovered that multiple mainstream chemotherapeutic agents applied at clinically relevant exposure levels are more toxic for the progenitor cells of the CNS and for non-dividing oligodendrocytes than they are for multiple cancer cell lines. Enhancement of cell death and suppression of cell division were seen in vitro and in vivo. When administered systemically in mice, these diverse chemotherapeutic agents caused increased cell death and decreased cell division in multiple regions of the CNS, with a high degree of correlation between in vitro observations and in vivo effects. Our current efforts are focused on three questions central to increasing our understanding of the biological underpinnings of the adverse neurological effects of cancer treatment and to developing means of preventing these effects. In this proposal, Aim 1 provides the first animal model of delayed CNS damage associated with chemotherapy and tests the hypotheses that (i) transient systemic administration of chemotherapy causes delayed damage to the CNS that is more severe than damage observed at short times after treatment; (ii) a particular target of damage is the myelinated white matter tracts of the brain; (iii) early indicators of delayed damage are dysregulation of transcription factor expression in myelin-forming oligodendrocytes, followed by marked reductions in oligodendrocyte numbers and an absence of oligodendrocyte replacement; and, (iv) delayed damage is also associated with reductions in the generation of new hippocampal neurons. Aim 2 provides the first paradigm for reducing or preventing such damage, and is focused on analysis of the hypothesis that co-treatment with erythropoietin (EPO) reduces CNS damage caused by chemotherapy. Aim 3 focuses on mechanism-based discovery of protective strategies for acute and delayed adverse effects of chemotherapy, and tests the hypotheses that (i) chemically diverse chemotherapeutic agents disrupt the function of primary cells -but not cancer cells - by convergence on a newly discovered regulatory pathway (the redox/Fyn/c-Cbl pathway) that converts small increases in oxidative state into enhanced degradation of a subset of receptor tyrosine kinases important in cell division and survival, with consequent reductions in activity of signaling molecules vital in cell division and survival; and, (ii) this prevention of activation of the redox/Fyn/c-Cbl pathway provides a mechanistic strategy for protecting primary cells from the adverse effects of chemotherapy without also rescuing cancer cells in bulk or cancer stem cells in particular. PUBLIC HEALTH RELEVANCE One of the disturbing findings to emerge from studies on survivors of both childhood and adult cancers is the frequency with which systemic chemotherapy is associated with adverse neurological sequelae, including leukoencephalopathy, seizures, cerebral infarctions, and cognitive impairment. The concern of our research is to understand the biological and mechanistic foundations for these adverse effects, both to discover means of protecting against such events and to develop means of identifying individuals at increased risk for adverse events. Such protection can be achieved both by increasing the vulnerability of cancer cells to chemotherapy and by selectively protecting normal cells from the adverse effects of these therapeutic agents.

描述（由申请人提供）：对儿童和成人癌症幸存者的研究中出现的令人不安的发现之一是，全身化疗与不良神经系统后遗症相关的频率，包括脑白质病、癫痫、脑梗死和认知障碍。在我们旨在了解这些效应的生物学基础的研究中，我们发现，在临床相关暴露水平下应用的多种主流化疗药物对中枢神经系统祖细胞和非分裂少突胶质细胞的毒性大于对多种癌细胞系的毒性。在体外和体内观察到细胞死亡增强和细胞分裂抑制。在小鼠体内系统给药时，这些不同的化疗药物在中枢神经系统的多个区域引起细胞死亡增加和细胞分裂减少，在体外观察和体内效果之间具有高度相关性。我们目前的工作集中在三个问题上，这三个问题对提高我们对癌症治疗对神经系统不良影响的生物学基础的理解以及开发预防这些影响的方法至关重要。在该提案中，Aim 1提供了与化疗相关的延迟性中枢神经系统损伤的第一个动物模型，并验证了以下假设：(i)短暂的全身化疗引起的延迟性中枢神经系统损伤比治疗后短时间内观察到的损伤更严重；（ii）损伤的特定目标是大脑的髓质束；（iii）迟发性损伤的早期指标是髓磷脂形成少突胶质细胞中转录因子表达失调，随后是少突胶质细胞数量显著减少和少突胶质细胞替代缺失；（iv）迟发性损伤也与新海马神经元生成的减少有关。目的2提供了减少或预防这种损伤的第一个范例，并重点分析了与促红细胞生成素（EPO）联合治疗可减少化疗引起的中枢神经系统损伤的假设。目的3侧重于基于机制的发现化疗急性和延迟不良反应的保护策略。并测试了以下假设：(i)化学上不同的化疗药物通过聚合新发现的调节途径（氧化还原/Fyn/c-Cbl途径）破坏原代细胞（但不是癌细胞）的功能，该途径将氧化状态的少量增加转化为对细胞分裂和存活重要的受体酪氨酸激酶亚群的增强降解，从而降低对细胞分裂和存活至关重要的信号分子的活性；（ii）防止氧化还原/Fyn/c-Cbl通路的激活提供了一种机制策略，可以保护原代细胞免受化疗的不良影响，同时又不挽救大量癌细胞，特别是癌症干细胞。对儿童和成人癌症幸存者的研究中出现的令人不安的发现之一是，全身化疗与不良神经系统后遗症（包括脑白质病、癫痫发作、脑梗死和认知障碍）相关的频率。我们研究的重点是了解这些不良反应的生物学和机制基础，既要发现预防这些事件的方法，又要找到识别不良事件风险增加的个体的方法。这种保护可以通过增加癌细胞对化疗的脆弱性和选择性地保护正常细胞免受这些治疗剂的不利影响来实现。