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

(PQ12) 通过靶向 APE1 小分子修饰剂增强神经元 DNA 修复，以减少和逆转化疗引起的周围神经病变 (CIPN)

• 批准号: 10241458
• 负责人: JILL C FEHRENBACHER
• 金额: $ 46.08万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241458
• 关键词: Address; Advanced Development; Affect; Afferent Neurons; Animal Model; Antineoplastic Agents; Apoptosis; Attenuated; Base Excision Repairs; Behavior; Blood flow; Bone Marrow Neoplasms; Bone Marrow Suppression; Carboplatin; Chemotherapy-induced peripheral neuropathy; Cisplatin; Clinical Trials; Colon; Coupled; DNA Damage; DNA Repair; DNA Repair Endonuclease; DNA Repair Enzymes; DNA Sequence Alteration; Data; Development; Dose; Effectiveness; Elements; Epothilones; Foundations; Future; Genetic; Genomics; Goals; Hair; Hepatitis C Therapy; Human; Immune; Immunomodulators; In Vitro; Interphase Cell; Japan; Knowledge; Limb structure; Liver Failure; Maintenance; Malignant Neoplasms; Measures; Mediating; Modeling; Morphology; Mus; Nausea; Nerve; Neuronal Dysfunction; Neurons; Neuropathy; Nociception; Numbness; Oxidation-Reduction; Pain; Pancreas; Pancytopenia; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase Ib/II Trial; Platinum; Platinum adduct; Prevention; Proprioception; Proteasome Inhibitor; Proteins; Quality of life; Safety; Sensory; Solid Neoplasm; Stress; Symptoms; Tendon Reflex; Testing; Therapeutic; Therapeutic Uses; Translating; Validation; Vinca Alkaloids; Work; allodynia; anti-cancer; anti-cancer therapeutic; anticancer activity; anticancer treatment; antitumor effect; base; cancer therapy; cell growth; chemotherapy; crosslink; drug candidate; effective therapy; efficacy testing; endonuclease; in vivo; in vivo Model; interest; mouse model; mutant; neoplastic cell; nephrotoxicity; nerve supply; neurotoxic; neurotoxicity; optimal treatments; oxaliplatin; oxidative DNA damage; phase 1 study; preclinical study; prevent; repair function; repaired; safety study; side effect; small molecule; taxane; treatment strategy; tumor

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.

项目摘要/摘要 化学疗法诱导的周围神经病（CIPN）是许多有效抗癌药物的主要副作用， 白金药物，紫杉虫，蛋白酶体抑制剂，文ca生物碱，雌激素和免疫调节剂。 它们的神经毒性副作用可能会使人衰弱，以至于可能需要减少或停止治疗。然而， 与化学疗法的其他主要副作用不同（例如恶心，脱发，骨髓衰竭），没有标准 存在有效的治疗方法来预防或反向CIPN。这主要是因为CIPN的细胞机制 尚未鉴定出CIPN的症状，包括麻木，血流降低到四肢， 本体感受的丧失，肌腱反射的丧失，疼痛，异常性和/或对感冒的敏感性差异很大 患者。因为CIPN令人衰弱，可能是不可逆的，所以确定了关键目标以防止 神经毒性而不损害抗癌药物的肿瘤杀伤作用，对于开发第一届 可以直接影响患者接受最佳治疗能力的类疗法。我们以前的研究 研究了感觉神经元的DNA损伤有助于CIPN奠定基础的假设 拟议的工作，被毒害以发展候选药物。我们证明了减少DNA基础惊喜 修复（BER）活性通过减少肾上腺素/哌啶核酸内切酶/氧化还原因子（APE1）的表达 增强了抗癌治疗产生的神经毒性，而补充APE1的维修活动 减弱神经毒性。在神经元等非分裂细胞中，DNA损伤可能会改变 感觉神经元的功能以表现为CIPN中观察到的症状的方式。因此，DNA 维修对于正确类型和数量的蛋白质的遗传表达至关重要，这是关键元素 基因组维护。对于拟议的研究，我们将检查是否增加APE1修复 体内活性将防止化疗引起的感觉神经元功能的改变（表现为 作为CIPN），而不会危害癌症治疗。使用肿瘤轴承小鼠，我们将检查是否 一个小分子（E3330），该分子被确定以增强APE1在神经元中的DNA修复功能可以 预防（AIM 1）或反向（AIM 2）DNA损伤和引起感觉神经元功能的改变 通过顺铂，奥沙利铂或卡铂。此外，我们将检查小分子是否（E3330） 通过检查DNA损伤和肿瘤，将损害白金药物的抗癌效率 治疗后的生存（AIM 3）。因为已发现E3330充当单个代理商 结合其他癌症治疗药物可降低肿瘤细胞的生长，该分子具有潜力 提供“双赢”场景；阻止肿瘤细胞生长，同时预防神经元功能障碍。此外， E3330将进入实体瘤的1阶段临床试验，然后进行1B/第2期试验的各种指示 其中包括其SOC中的铂（例如结肠，胰腺）。因此，它需要使用 在神经元保护和CIPN模型的背景下显示有效性的体内范式。