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得出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，包括白质脑病、癫痫发作、脑梗塞和认知障碍。在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比对多种癌细胞的毒性更大线。在体外和体内均观察到细胞死亡的增强和细胞分裂的抑制。当对小鼠全身给药时，这些不同的化疗药物导致中枢神经系统多个区域的细胞死亡增加和细胞分裂减少，体外观察结果与体内效果之间具有高度相关性。我们目前的努力集中在三个问题上，这些问题对于增进我们对癌症治疗不良神经系统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，目标 1 提供了第一个与化疗相关的延迟性中枢神经系统损伤的动物模型，并测试了以下假设：(i) 短暂全身性化疗导致中枢神经系统延迟性损伤，比治疗后短时间内观察到的损伤更为严重； (ii) 特定的损伤目标是大脑的有髓鞘白质束； (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，随后少突胶质细胞数量显着减少且缺乏少突胶质细胞替代； (iv) 延迟损伤也与新海马神经元生成的减少有关。目标 2 提供了减少或预防此类损伤的第一个范例，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。目标 3 侧重于基于机制的发现化疗急性和迟发不良反应的保护策略，并测试以下假设：(i) 化学上多样化的化疗药物会破坏原代细胞（而不是癌细胞）的功能，方法是汇聚到新发现的调节途径（氧化还原/Fyn/c-Cbl 途径），将氧化状态的小幅增加转化为对细胞分裂和存活很重要的受体酪氨酸激酶子集的增强降解，从而降低信号分子的活性对细胞分裂和生存至关重要； (ii)这种对氧化还原/Fyn/c-Cbl途径激活的预防提供了一种机制策略，用于保护原代细胞免受化疗的不利影响，而不同时拯救大量癌细胞或特别是癌症干细胞。公共健康相关性 对儿童和成人癌症幸存者的研究得出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，包括白质脑病、癫痫发作、脑梗死和认知障碍。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，既发现预防此类事件的方法，又开发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保护正常细胞免受这些治疗剂的不利影响来实现。