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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的微管结合化学治疗剂（例如长春新碱）是使用最广泛的抗癌药在肿瘤学治疗儿童和成人的多种实体瘤和白血病中。临床用途长春新碱与无效的衰弱，剂量限制的周围神经毒性有关提供了预防性治疗。另外，长春新碱积累的机制直到今天，进入背根神经节（DRG）神经元尚不清楚。使用异种生物的转运蛋白屏幕异源过表达模型中的吸收载体，我们最近发现有机阴离子运输多肽OATP1B3（在小鼠中，OATP1B2；集体称为OATP1B2/3）是有效的转运蛋白在人和小鼠DRG神经元中表达的长春新碱。 OATP1B2-的功能验证研究缺乏小鼠和二次筛选证实，长春新碱被OATP1B2转运到DRG神经元中。此外，OATP1B2受保护小鼠的缺乏免受长春克碱相关的变化的不同标志周围神经毒性，而不改变血浆的血浆水平。提供原理证明和证明了这种运输机制的翻译相关性，我们发现几个已知 OATP1B的药理抑制剂，包括利福平和酪氨酸激酶抑制剂尼洛替尼可以维护葡萄晶质治疗后的DRG神经元功能，而不会影响其血浆水平或ITS的血浆水平针对多个急性白血病细胞系的细胞毒性潜力。最后，我们确定α-生育酚（VINTAMIN E）为可以在全身性中测量的神经元OATP1B2/3功能的先前未识别的生物标志物循环，我们在接受处理的小鼠模型中验证了该生物标志物的翻译效用与OATP1B抑制剂。基于这些初步发现，我们现在概述了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，该假设是针对OATP1B2/3功能的调制的具有优化的OATP1B2/3抑制剂的优化剂量和时间表可以特别影响 DRG神经元中的vincristine，并影响下游有毒事件，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）尼洛替尼作为机械表征 - 原理OATP1B抑制剂，以及从库中得出的其他调节器的识别和验证包括FDA批准的代理的屏幕；（ii）使用α-生育酚作为A的生物标志物驱动优化伴侣诊断以指导OATP1B调节剂的剂量选择用于体内测试；（iii）安全和 OATP1B抑制剂的优化组合方案的功效分析，包括长春新碱，包括在既定的实验模型中对神经保护和抗白血病特性的简单评估急性白血病。预计这些集体研究不仅会阐明长春新碱引起的周围神经毒性，但将具有转化相关性，并为未来实施新颖的有针对性干预策略，以防止这种使人衰弱的副作用。