(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: 10463843
• 负责人: JILL C FEHRENBACHER
• 金额: $ 45.16万
• 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/10463843
• 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; Bone marrow failure; 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; 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.

项目总结/摘要 化疗诱导的周围神经病变（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、蛋白酶体抑制剂、长春花生物碱、埃博霉素和免疫调节剂。 它们的神经毒性副作用可能会使人衰弱，因此可能需要减少或停止治疗。然而，在这方面， 与化疗的其他主要副作用（例如恶心、脱发、骨髓衰竭）不同，没有标准， 存在预防或逆转CIPN的有效治疗。这主要是因为CIPN的细胞机制 CIPN的症状包括麻木，四肢血流减少， 本体感觉丧失、腱反射丧失、疼痛、异常性疼痛和/或对冷的敏感性增加在 患者由于CIPN是衰弱的，并且可能是不可逆的，因此确定预防的关键目标 在不损害抗癌药物的肿瘤杀伤作用的情况下，神经毒性是开发第一个 这类治疗可以直接影响患者接受最佳治疗的能力。我们以前的研究 检验感觉神经元的DNA损伤有助于CIPN的假设奠定了基础， 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（APE 1）的表达来修复（BER）活性 增强了抗癌治疗产生的神经毒性，同时补充了APE 1的修复活性 减轻神经毒性。很可能，在非分裂细胞如神经元中，DNA损伤可以改变细胞的结构。 感觉神经元的功能，表现为CIPN中观察到的症状。因此，DNA 修复对于正确的蛋白质类型和数量的正确基因表达至关重要， 基因组的维护。对于拟议的研究，我们将检查是否加强APE 1修复， 体内活性将防止化疗诱导的感觉神经元功能的改变（表现为 作为CIPN）而不危害癌症治疗。使用荷瘤小鼠，我们将检查是否 一种小分子（E3330）被鉴定为增强APE 1在神经元中的DNA修复功能， 预防（目的1）或逆转（目的2）DNA损伤和感觉神经元功能的改变 顺铂奥沙利铂或卡铂。此外，我们将研究小分子（E3330） 通过检测DNA损伤和肿瘤， 治疗后存活率（目标3）。由于E3330被发现作为单一药剂并在 与其他癌症治疗药物组合以减少肿瘤细胞生长，这种分子具有潜力 提供一个“双赢”的方案;阻止肿瘤细胞生长，同时防止神经元功能障碍。此外，本发明还 E3330将进入实体瘤的I期临床试验，随后进入各种适应症的Ib期/II期试验 在SOC中包含铂类（例如结肠、胰腺）。因此，它需要进一步的临床前研究， 一个体内范例，以证明在神经元保护和CIPN模型的背景下的有效性。