Opening of the Blood-Brain Barrier to Antitumor Agents

抗肿瘤药物打开血脑屏障

• 批准号: 9899211
• 负责人: EDWARD A. NEUWELT
• 金额: $ 61.72万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-04 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899211
• 关键词: 5 year old; Acetaminophen; Acetylcysteine; Age; Alkylating Agents; Antioxidants; Blood - brain barrier anatomy; Bone Marrow; Brain; Brain Neoplasms; Buthionine Sulfoximine; Carboplatin; Cellular Stress; Central Nervous System Neoplasms; Cerebellum; Cerebrospinal Fluid; Chemoprotection; Chemoprotective Agent; Child; Childhood Brain Neoplasm; Childhood Central Nervous System Primitive Neuroectodermal Tumor; Cisplatin; Clinic; Clinical; Clinical Research; DNA Adduction; Development; Disease; Dose; Enhancers; Evaluation; Funding; Glutathione; Hearing; International; Lead; Localized Disease; Malignant Childhood Neoplasm; Malignant Neoplasms; Melphalan; Modeling; Normal tissue morphology; Oxidative Stress; Patient Self-Report; Patients; Pediatric Oncology; Pediatric Oncology Group; Phase; Plasma; Platinum; Quality of life; Rattus; Reactive Oxygen Species; Regimen; Route; Safety; Societies; Sulfhydryl Compounds; Survivors; Time; Tissues; Toxic effect; Toxicity due to chemotherapy; Translating; United States National Institutes of Health; Work; antitumor agent; base; blood-brain barrier disruption; blood-brain barrier permeabilization; blood-brain tumor barrier; cancer cell; cancer risk; chemotherapeutic agent; chemotherapy; childhood cancer survivor; cohort; hearing impairment; human model; improved; medulloblastoma; neoplastic; neoplastic cell; nephrotoxicity; novel strategies; older patient; ototoxicity; pediatric patients; phase III trial; pre-clinical; preclinical study; programs; progressive hearing loss; prospective; public health relevance; side effect; sodium thiosulfate; temozolomide; tumor

 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.

 描述（由申请人提供）：化疗是许多脑部恶性肿瘤的主要治疗方法，但疗效受到血脑屏障（BBB）和血肿瘤屏障的低渗透性的限制。指导 OHSU 血液-肿瘤屏障的总体假设。过去三十年的脑屏障计划一直认为，增加跨血脑屏障的化疗递送和癌细胞内的剂量强度将提高抗肿瘤疗效。然而，除了肿瘤细胞毒性之外，化疗药物还会诱导氧化应激。正常组织会引起耳毒性和肾毒性等毒副作用，从而导致剂量减少和生活质量下降。通常用于儿科患者脑肿瘤治疗的铂类化疗药物会导致 80% 以上的患者进行性听力损失。我们研究了使用硫醇来模拟内源性抗氧化剂谷胱甘肽的活性，以防止氧化应激并减少化疗毒性。 NIH 资助的硫代硫酸钠 (STS) 化学保护的临床前和临床研究已开展了两项 III 期合作小组试验，儿童肿瘤组 (COG) 试验 ACCL0431 清楚地表明，STS 可以保护接受顺铂的儿童免受听力损失。需要进一步改善听力保护。在具体目标 1 中，我们将研究使用 STS 和 N-乙酰半胱氨酸 (NAC) 改善化学保护的策略。 COG 试验和国际儿科肿瘤学会进行的一项试验均表明，延迟 STS 对顺铂对局部标准风险癌症的疗效没有影响；然而，对 COG 进行的一项小型事后分析试验确实显示了对播散性疾病患者的肿瘤保护作用，我们发现播散性髓母细胞瘤需要进一步加强剂量，因此将评估额外的化学保护策略。化学保护对播散性髓母细胞瘤大鼠模型化疗疗效的影响，并研究播散性疾病与局部肿瘤不同的机制。我们将通过剂量递增、通过破坏血脑屏障增强化疗效果或通过消耗谷胱甘肽增加化疗毒性来提高化疗疗效。具体目标 3 将进一步将我们的化学保护策略转化为临床。 一项 I 期剂量递增研究，以确定在接受基于顺铂化疗的患有局部疾病的儿童中，可以安全地与 STS 联合给药以达到化学保护所需的血浆水平的 NAC 剂量。此外，我们将确定这种关联。在 OHSU 年轻时接受顺铂治疗的一个独特的大型儿童癌症幸存者队列 (n = 160) 中，我们研究了听力和生活质量之间的关系。化学增强剂、化疗和化学保护可以降低毒性，同时保持或增加抗肿瘤功效。

项目成果

Long-Term Outcomes of Intra-Arterial Chemotherapy for Progressive or Unresectable Pilocytic Astrocytomas: Case Studies.

进行性或不可切除的毛细胞星形细胞瘤的动脉内化疗的长期结果：案例研究。

• 发表时间: 2021-03-15
• 影响因子: 4.8
• 作者: Uluc, Kutluay;Siler, Dominic A;Lopez, Ricardo;Varallyay, Csanad;Netto, Joao Prola;Firkins, Jenny;Lacy, Cindy;Huddleston, Amy;Ambady, Prakash;Neuwelt, Edward A
• 通讯作者: Neuwelt, Edward A