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; 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）：从童年和成人癌症的幸存者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有关的频率，包括白细胞症，癫痫发作，癫痫发作，脑梗塞和认知障碍。在我们旨在了解这些作用的生物基础的研究中，我们发现，在临床相关的暴露水平上应用的多种主流化学治疗剂对中枢神经系统的祖细胞和非分裂的少突胶质细胞的毒性比对多个癌细胞系更具毒性。在体外和体内可见细胞死亡和细胞分裂的抑制。当在小鼠中全身施用时，这些多样化的化学治疗剂导致CNS多个区域的细胞死亡增加和细胞分裂减少，并且体外观察和体内效应之间的相关程度很高。我们目前的努力集中在三个问题上，这是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作用的方法的核心。在此提案中，AIM 1提供了与化学疗法相关的延迟中枢神经系统损伤的第一个动物模型，并检验了（i）（i）（i）化学疗法的瞬时全身给药会导致对中枢神经系统的损害延迟损害，而CNS比在治疗后短时间内观察到的损害更为严重； （ii）损害的一个特殊目标是大脑的髓白质。 （iii）延迟损伤的早期指标是在形成髓磷脂形成的少突胶质细胞中转录因子表达的失调，然后在少突胶质细胞数量和缺乏少突胶质细胞替换的情况下明显减少； （iv）延迟损伤也与新的海马神经元的减少有关。 AIM 2提供了第一个减少或防止这种损害的范式，并专注于分析与红细胞生成素（EPO）共同治疗可减少化学疗法造成的中枢神经系统损害的假设。 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受体酪氨酸激酶在细胞分裂和存活中很重要的受体酪氨酸激酶，从而降低了信号分子在细胞分裂和存活中至关重要的活性； （ii）预防氧化还原/Fyn/c-CBL途径的激活提供了一种机械策略，可保护原代细胞免受化学疗法的不良反应，而无需挽救大量或癌症干细胞中的癌细胞。公共卫生相关性来自关于儿童和成人癌症幸存者的研究的令人不安的发现之一是全身化学疗法与不良神经后遗症有关的频率，包括白血病，癫痫发作，癫痫发作，大脑培养和认知障碍。我们的研究的关注是了解这些不良影响的生物学和机械基础，既要发现保护此类事件的手段，又要开发识别患有不良事件风险增加的个体的方法。可以通过增加癌细胞对化学疗法的脆弱性以及选择性保护正常细胞免受这些治疗剂的不良影响来实现这种保护。