CNS vulnerability to systemic chemotherapy: Causes and prevention

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，包括白质脑病、癫痫发作、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，以临床相关暴露水平应用的多种主流化疗药物对CNS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的增强和细胞分裂的抑制。当在小鼠中全身给药时，这些不同的化疗剂引起CNS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应之间高度相关。我们目前的努力集中在三个问题的核心，以增加我们对癌症治疗的不良神经系统影响的生物学基础的理解，并制定预防这些影响的方法。在该提议中，目的1提供了与化疗相关的迟发性CNS损伤的第一个动物模型，并测试了以下假设：（i）化疗的短暂全身给药引起CNS的迟发性损伤，其比治疗后短时间内观察到的损伤更严重;（ii）损伤的特定靶点是脑的有髓鞘白色物质束;（iii）迟发性损伤的早期指标是髓鞘形成少突胶质细胞中转录因子表达的失调，随后是少突胶质细胞数量的显著减少和少突胶质细胞替代的缺乏;和（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害的第一个范例，并集中在与促红细胞生成素（EPO）共同治疗减少化疗引起的CNS损害的假设分析。目标3侧重于机制为基础的发现保护战略的急性和迟发性不良反应的化疗，并测试了以下假设：（i）化学上不同的化疗剂通过会聚在新发现的调节途径上而破坏原代细胞的功能，但不破坏癌细胞（氧化还原/Fyn/c-Cbl途径），其将氧化状态的小幅增加转化为对细胞分裂和存活重要的受体酪氨酸激酶亚组的增强降解，从而降低了在细胞分裂和存活中至关重要的信号分子的活性;和（ii）这种对氧化还原/Fyn/c-Cbl途径活化的预防提供了一种机制策略，用于保护原代细胞免受化学疗法的不利影响，而不拯救大量的癌细胞或特别是癌干细胞。对儿童和成人癌症幸存者的研究中出现的一个令人不安的发现是，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。我们的研究关注的是了解这些不良反应的生物学和机械学基础，既要发现防止此类事件的方法，又要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通过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。

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.