(PQ12) Enhancement of DNA repair in neurons via a targeted APE1 small molecule modifier to decrease and reverse chemotherapy-induced peripheral neuropathy (CIPN)

项目摘要/摘要 化疗所致周围神经病变(CIPN)是许多有效抗癌药物的主要副作用。 包括铂类药物、紫杉烷类、蛋白酶体抑制剂、长春花碱、埃博西酮和免疫调节剂。 它们的神经毒性副作用可能会使人虚弱，可能需要减少或停止治疗。然而， 与化疗的其他主要副作用(如恶心、脱发、骨髓衰竭)不同，没有标准， 有有效的治疗方法可以预防或逆转CIPN。这很大程度上是因为CIPN的细胞机制 CIPN的症状包括麻木，流向四肢的血液减少， 本体感觉丧失、肌腱反射丧失、疼痛、超敏和/或对寒冷的敏感度增加在 病人。由于CIPN是衰弱的，可能是不可逆转的，因此确定关键目标以防止 在不损害抗癌药物杀瘤效果的情况下，神经毒性是开发一种第一代抗癌药物的关键 可直接影响患者接受最佳治疗的能力的等级治疗。我们之前的研究 检验感觉神经元DNA损伤有助于CIPN的假设为 拟议的工作，这是准备开发一种候选药物。我们证明了减少DNA碱基切除 通过减少脱嘌呤/脱嘧啶核酸内切酶/氧化还原因子(APE1)的表达来修复(BER)活性 增强抗癌治疗所产生的神经毒性，而补充APE1‘S修复活性 减轻了神经毒性。在像神经元这样的未分裂细胞中，DNA损伤很可能会改变 感觉神经元的功能，表现为在CIPN中观察到的症状。因此，DNA 修复对于正确表达正确类型和数量的蛋白质是至关重要的，蛋白质是一种关键元素 基因组的维护。对于拟议的研究，我们将检查是否增加APE1修复 体内活动将防止化疗引起的感觉神经元功能改变(表现为 作为CIPN)，而不会危及癌症治疗。使用荷瘤小鼠，我们将检查是否 增强神经元APE1‘S DNA修复功能的小分子(E3330)可以 预防(目标1)或逆转(目标2)感觉神经元的DNA损伤和功能改变 顺铂、奥沙利铂或卡铂。此外，我们将检查小分子(E3330) 将通过检测DNA损伤和肿瘤来影响铂类药物的抗癌效果 治疗后存活率(目标3)。因为E3330已被发现充当单一代理，并且在 与其他癌症治疗药物联合使用以减少肿瘤细胞生长，这种分子具有潜在的 提供一个“双赢”的方案；在阻止肿瘤细胞生长的同时，防止神经元功能障碍。另外， E3330将进入实体肿瘤的第一阶段临床试验，随后是各种适应症的1b阶段/第二阶段试验 这包括他们的SOC中的铂(例如，结肠、胰腺)。因此，它需要进一步的临床前研究使用 在神经元保护和CIPN模型的背景下展示有效性的体内范例。

PROJECT SUMMARY/ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of many efficacious anticancer drugs, including platinum drugs, taxanes, proteasome inhibitors, vinca alkaloids, epothilones, and immunomodulators. Their neurotoxic side effects can be so debilitating that treatment may need to be reduced or stopped. However, unlike other major side effects of chemotherapy (e.g. nausea, hair loss, bone marrow failure), no standard, effective treatments exist to prevent or reverse CIPN. This is largely because the cellular mechanisms for CIPN have not been identified and the symptoms of CIPN including numbness, decreased blood flow to extremities, loss of proprioception, loss of tendon reflexes, pain, allodynia, and/or increased sensitivity to cold vary greatly in patients. Because CIPN is debilitating and may be irreversible, identification of key targets to prevent neurotoxicity without compromising the tumor-killing effects of anticancer drugs is critical in developing a first-in- class therapeutic that can directly affect a patient's ability to receive optimal treatment. Our previous studies examining the hypothesis that DNA damage of sensory neurons contributes to CIPN laid the foundation for the proposed work, which is poised to develop a drug candidate. We demonstrated that reducing DNA base excision repair (BER) activity by reducing expression of the apurinic/apyrimidinic endonuclease/redox factor (APE1) augmented the neurotoxicity produced by anticancer treatment, whereas supplementing APE1's repair activity attenuated the neurotoxicity. It is likely that, in non-dividing cells like neurons, DNA damage could alter the function of sensory neurons in ways that manifest as the symptoms observed in CIPN. Consequently, DNA repair would be critical for proper genetic expression of the right types and amounts of proteins, a crucial element of genomic maintenance. For the proposed studies, we will examine whether augmenting APE1 repair activity in vivo will prevent chemotherapy-induced alterations in sensory neuronal function (manifested as CIPN) without jeopardizing the cancer treatment. Using tumor bearing mice, we will examine whether a small molecule (E3330) which was identified to enhance APE1's DNA repair function in neurons can prevent (aim 1) or reverse (aim 2) DNA damage and alterations in the function of sensory neurons caused by cisplatin, oxaliplatin or carboplatin. Furthermore, we will examine whether the small molecule (E3330) will compromise the anticancer efficacy of the platinum drugs by examining DNA damage and tumor survival following treatment (aim 3). Because E3330 has been found to act as a single agent and in combination with other cancer therapeutic drugs to decrease tumor cell growth, this molecule has the potential to offer a “win-win” scenario; block tumor cell growth while protecting against neuronal dysfunction. Additionally, E3330 will enter a phase 1 clinical trial for solid tumors followed by phase 1b/phase 2 trials for various indications that include platinums in their SOC (e.g. colon, pancreatic). Therefore, it requires further preclinical study using an in vivo paradigm to demonstrate effectiveness in the context of neuronal protection and CIPN models.