CNS vulnerability to systemic chemotherapy: Causes and prevention

描述(申请人提供)：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上应用多种主流化疗药物对中枢神经系统的祖细胞和未分裂的少突胶质细胞的毒性比对多种癌细胞系的毒性更大。在体外和体内均能促进细胞死亡，抑制细胞分裂。当在小鼠体内全身给药时，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，体外观察和体内效应之间具有高度的相关性。我们目前的努力集中在三个问题上，这三个问题对于增加我们对癌症治疗不利神经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。在这项建议中，Aim 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，并检验了假说：(1)短暂的全身给药对中枢神经系统造成延迟性损害，比治疗后短时间观察到的损害更严重；(2)损害的特定靶点是大脑的有髓白质束；(3)延迟性损害的早期指标是髓鞘形成的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著减少，缺乏少突胶质细胞替代；(4)延迟性损害也与新海马神经元的生成减少有关。目的2提供了减少或预防这种损伤的第一个范例，并专注于分析与促红细胞生成素(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着重于发现针对化疗的急性和延迟性不良反应的保护策略，并测试以下假设：(I)化学上不同的化疗药物通过聚集在新发现的调节途径(氧化还原/Fyn/c-Cbl途径)上，将氧化状态的微小增加转化为对细胞分裂和生存至关重要的一组受体酪氨酸激酶的加速降解，从而破坏原代细胞的功能，从而降低对细胞分裂和生存至关重要的信号分子的活性；而且，(Ii)这种对氧化还原/Fyn/c-Cbl途径的激活的预防提供了一种机械性的策略，可以保护原代细胞免受化疗的不利影响，同时也不会拯救大量的癌细胞或特别是癌症干细胞。公共卫生相关性从对儿童和成人癌症幸存者的研究中发现的一个令人不安的发现是，全身化疗与不良神经后遗症相关的频率，包括白质脑病、癫痫发作、脑梗塞和认知障碍。我们的研究关注的是了解这些不利影响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人的方法。这种保护既可以通过增加癌细胞对化疗的脆弱性来实现，也可以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.