Opening of the Blood-Brain Barrier to Antitumor Agents

 描述(申请人提供)：化疗是许多脑恶性肿瘤的主要治疗方法，但由于血脑屏障(BBB)和血肿瘤屏障的低渗透性，其疗效受到限制。在过去的三十年里，指导OHSU血脑屏障计划的总体假设是，增加通过血脑屏障的化疗药物输送和癌细胞内的剂量强度将提高抗肿瘤效果。然而，除了对肿瘤细胞的毒性外，化疗药物还会在正常组织中诱导氧化应激，导致毒性副作用，如耳毒性和肾毒性，可导致剂量减少和生活质量下降。以铂为基础的化疗顺铂，常用于儿童脑肿瘤的治疗，导致80%以上的髓母细胞瘤患者进行性听力损失。我们已经研究了模拟内源性抗氧化剂谷胱甘肽活性的硫醇的使用，以防止氧化应激和减少化疗毒性。我们由美国国立卫生研究院资助的硫代硫酸钠(STS)化学保护的临床前和临床研究已经导致了两个第三阶段合作小组试验。儿童肿瘤学小组(COG)的试验ACCL0431清楚地表明，延迟STS对接受顺铂治疗的儿童听力损失具有保护作用，但也表明在听力保护方面需要进一步改进。在具体目标1中，我们将研究使用STS和N-乙酰半胱氨酸(NAC)改善化疗保护的策略，以对抗顺铂和其他烷基化化疗的毒性。COG试验和国际儿科肿瘤学会进行的一项试验都表明，延迟的STS对局部标准风险癌症患者的顺铂疗效没有影响；然而，COG试验的一项小型事后分析确实表明，在患有播散性疾病的患者中，肿瘤具有保护作用。我们推测，播散性髓母细胞瘤需要进一步的剂量增强，因此需要额外的化学保护策略。具体目标2将评估化学保护对播散性髓母细胞瘤大鼠模型化疗效果的影响，并探讨播散性疾病与局限性肿瘤的不同机制。我们将探索新的方法，通过剂量递增，通过破坏血脑屏障来加强给药，或通过耗尽谷胱甘肽浓度来增加化疗毒性。具体目标3将进一步将我们的化学保护策略翻译到临床上。我们将进行 一项I期剂量递增研究，旨在确定在接受以顺铂为基础的化疗的局部疾病儿童中，可以安全地结合STS给予的NAC剂量，以达到化疗保护所需的血浆水平。此外，我们将确定在OHSU接受顺铂治疗的儿童癌症幸存者中的一个独特的大队列(n=160)中听力和生活质量之间的关系。我们假设，通过调整化疗增强剂、化疗和化学保护的给药时间和途径，可以在保持或增加抗肿瘤疗效的同时降低毒性。

 DESCRIPTION (provided by applicant): Chemotherapy is a primary therapy in many brain malignancies, but efficacy is limited by the low permeability of the blood-brain barrier (BBB) and blood-tumor barrier. The overall hypothesis guiding the OHSU Blood-Brain Barrier Program for the past three decades has been that increasing chemotherapy delivery across the BBB and dose intensity within the cancer cells will improve anti-tumor efficacy. However, in addition to tumor cell toxicity, chemotherapy agents also induce oxidative stress in normal tissues causing toxic side effects such as ototoxicity and nephrotoxicity that can lead to dose reductions and decreased quality of life. The platinum-based chemotherapeutic cisplatin, commonly used for brain tumor therapy in pediatric patients, causes progressive hearing loss in over 80% of patients with medulloblastoma. We have investigated the use of thiols that mimic the activity of the endogenous antioxidant glutathione to protect against oxidative stress and to reduce chemotherapy toxicities. Our preclinical and clinical NIH-funded studies of chemoprotection with sodium thiosulfate (STS) have led to two Phase III cooperative group trials. The Children's Oncology Group (COG) trial ACCL0431 clearly showed that delayed STS protected against hearing loss in children receiving cisplatin, but also showed the need for further improvement in hearing protection. In Specific Aim 1 we will investigate strategies to improve chemoprotection using both STS and N-acetylcysteine (NAC) against the toxicities of cisplatin and other alkylating chemotherapy. The COG trial and a trial conducted by the International Society of Pediatric Oncology both showed no impact of delayed STS on cisplatin efficacy in localized standard risk cancers; however, a small post hoc analysis of the COG trial did show tumor protection in patients with disseminated disease. We hypothesize that disseminated medulloblastoma will require further dose intensification and therefore additional chemoprotection strategies. Specific Aim 2 will assess the impact of chemoprotection on chemotherapy efficacy in rat models of disseminated medulloblastoma and investigate mechanisms by which disseminated disease differs from localized tumors. We will investigate new approaches to improve chemotherapy efficacy by dose escalation, enhancing delivery with BBB disruption or increasing chemotherapy toxicity by depleting glutathione concentrations. Specific Aim 3 will further translate our chemoprotection strategies to the clinic. We will conduct a phase I dose escalation study to determine the NAC dose that can safely be given in combination with STS to achieve plasma levels needed for chemoprotection, in children with localized disease who undergo treatment with cisplatin-based chemotherapy. In addition, we will determine the association between hearing and quality of life in a unique large cohort (n = 160) of childhood cancer survivors who were treated at a young age with cisplatin at OHSU. We hypothesize that by modulating the timing and route of administration of chemo-enhancers, chemotherapy, and chemoprotection, toxicity can be decreased while maintaining or increasing anti-tumor efficacy.