Targeting neuronal transport to ameliorate vincristine neurotoxicity

靶向神经元运输以改善长春新碱神经毒性

• 批准号: 10736789
• 负责人: Sharyn D Baker
• 金额: $ 64.59万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-11 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736789
• 关键词: 2-tyrosine; Acute; Acute leukemia; Adult; Affect; Antineoplastic Agents; Binding; Biological Markers; Cell Line; Childhood Leukemia; Chronic; Circulation; Clinical; Combined Modality Therapy; Data; Dependence; Disease; Dose; Dose Limiting; Drug Kinetics; Drug Prescriptions; Etiology; Event; Experimental Models; FDA approved; Future; Genetic; Goals; Human; Image; In Vitro; Incidence; Intervention; Investigation; Kyocristine; LYN gene; Lead; Leukemic Cell; Libraries; Link; Malignant - descriptor; Measures; Mediating; Microtubules; Modeling; Mus; Neurons; OATP Transporters; Oncology; Outcome; Pathway interactions; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Phosphotransferases; Phylogenetic Analysis; Plasma; Prevention strategy; Preventive treatment; Process; Property; Proteomics; Quality of life; Regimen; Rifampin; Safety; Sampling; Schedule; Severities; Solid Neoplasm; Specificity; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Spinal Ganglia; Testing; Therapeutic; Time; Toxicokinetics; Treatment Protocols; Tyrosine Kinase Inhibitor; Tyrosine Phosphorylation; Validation; Vinca Alkaloids; Vincristine; Vitamin E; Wild Type Mouse; Work; Xenobiotics; access restrictions; acute leukemia cell; alpha Tocopherol; anti-cancer; biomarker driven; biomarker performance; clinical implementation; combinatorial; companion diagnostics; cytotoxic; efficacy evaluation; future implementation; improved; in vivo; in vivo evaluation; inhibitor; insight; leukemia; metabolomics; mouse model; negative affect; neuronal transport; neuroprotection; neurotoxicity; novel; overexpression; pharmacologic; preservation; prevent; side effect; specific biomarkers; uptake; validation studies

Abstract Microtubule-binding chemotherapeutics such as vincristine are among the most widely used anticancer agents in oncology for the treatment of multiple solid tumors and leukemias in children and adults. The clinical use of vincristine is associated with a debilitating, dose-limiting peripheral neurotoxicity for which no effective preventative treatments are presently available. In addition, the mechanism by which vincristine accumulates into dorsal root ganglion (DRG) neurons remains unclear to this day. Using a transporter screen of xenobiotic uptake carriers in heterologous overexpressed models, we recently found that the organic anion transporting polypeptide OATP1B3 (in mice, OATP1B2; collective referred to as OATP1B2/3) is an efficient transporter of vincristine that is expressed in human and mouse DRG neurons. Functional validation studies in OATP1B2- deficient mice and secondary screens confirmed that vincristine is transported into DRG neurons by OATP1B2. Furthermore, deficiency of OATP1B2 protected mice from vincristine-related changes in various hallmarks of peripheral neurotoxicity without altering the plasma levels of vincristine. To provide proof-of-principle and demonstrate translational relevance of this transport mechanism, we found that several known pharmacological inhibitors of OATP1B, including rifampin and the tyrosine kinase inhibitor, nilotinib, can preserve DRG neuronal function following treatment with vincristine without affecting its plasma levels or its cytotoxic potential against multiple acute leukemia cell lines. Finally, we identified α-tocopherol (vintamin E) as a previously unrecognized biomarker of neuronal OATP1B2/3 function that can be measured in the systemic circulation, and we validated the translational utility of this biomarker in a mouse model receiving treatment with OATP1B inhibitors. Based on these preliminary findings, we now outline three sets of related studies that will further test and refine the validity of our central hypothesis that targeted modulation of OATP1B2/3 function with optimized doses and schedules of novel OATP1B2/3 inhibitors can specifically affect accumulation of vincristine in DRG neurons and affect downstream toxic events without negatively influencing its plasma pharmacokinetic profile or anti-leukemic properties: (i) mechanistic characterization of nilotinib as the proof-of - principle OATP1B inhibitor, and identification and validation of additional modulators derived from a library screen that includes FDA-approved agents; (ii) biomarker-driven optimization using α-tocopherol as a companion diagnostic to guide dose selection of OATP1B modulators for in vivo testing; and (iii) safety and efficacy analyses of optimized combinatorial regimens of OATP1B inhibitors with vincristine, including simultaneous assessment of neuroprotection and anti-leukemic properties in established experimental models of acute leukemia. It is expected that these collective studies will not only shed light on the etiology of vincristine-induced peripheral neurotoxicity, but will be of translational relevance and provide a rationale for the future implementation of novel targeted intervention strategies to prevent this debilitating side effect.

摘要 微管结合化疗药物如长春新碱是最广泛使用的抗癌药物之一 在肿瘤学中用于治疗儿童和成人的多种实体瘤和白血病。的临床使用 长春新碱与使人衰弱的、剂量限制性外周神经毒性相关， 预防性治疗目前是可用的。此外，长春新碱蓄积的机制 到背根神经节（DRG）神经元中的作用至今仍不清楚。使用异生物质的转运体筛选 在异源过度表达模型中，我们最近发现， 多肽OATP 1B 3（在小鼠中，OATP 1B 2;统称为OATP 1B 2/3）是一种有效的转运蛋白， 长春新碱在人和小鼠DRG神经元中表达。OATP 1B 2中的功能验证研究- 缺陷小鼠和二次筛选证实长春新碱通过OATP 1B 2转运到DRG神经元中。 此外，OATP 1B 2缺乏可保护小鼠免受长春新碱相关变化的影响， 外周神经毒性，而不改变长春新碱的血浆水平。提供原理证明并 证明翻译相关的这种运输机制，我们发现，几个已知的 OATP 1B的药理学抑制剂，包括利福平和酪氨酸激酶抑制剂尼洛替尼，可以 长春新碱治疗后保留DRG神经元功能，而不影响其血浆水平或 对多种急性白血病细胞系的细胞毒潜力。最后，我们确定α-生育酚（vintamin E）为 一种以前未被认识到的神经元OATP 1B 2/3功能的生物标志物，可在全身性 循环，我们验证了这种生物标志物在接受治疗的小鼠模型中的翻译效用 OATP 1B抑制剂基于这些初步发现，我们现在概述三组相关研究， 将进一步测试和完善我们的中心假设的有效性，即靶向调节OATP 1B 2/3功能 优化剂量和时间表的新型OATP 1B 2/3抑制剂可特异性影响 长春新碱在DRG神经元中的作用，并影响下游毒性事件，而不会对其血浆产生负面影响 药代动力学特征或抗白血病特性：（i）尼洛替尼作为 主要OATP 1B抑制剂，以及来源于文库的其他调节剂的鉴定和验证 筛选，包括FDA批准的药物;（ii）生物标志物驱动的优化，使用α-生育酚作为 指导用于体内测试的OATP 1B调节剂的剂量选择的伴随诊断;和（iii）安全性和 OATP 1B抑制剂与长春新碱优化组合方案的疗效分析，包括 在建立的实验模型中同时评估神经保护和抗白血病特性 急性白血病预计这些集体研究不仅将阐明 长春新碱诱导的外周神经毒性，但将具有翻译相关性，并为 未来实施新的有针对性的干预策略，以防止这种削弱副作用。