NOVEL APPROACAHES FOR IMPROVING PEDIATRIC BRAFV600E GLIOMA PATIENT OUTCOMES

改善儿科 BRAFV600E 胶质瘤患者预后的新方法

基本信息

批准号：
9134603
负责人：
Charles David James
金额：
$ 23.35万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9134603
关键词：
Address Affect Animals BRAF gene Brain Brain Neoplasms CDK4 gene CDKN2A gene Cancer Patient Child Childhood Childhood Brain Neoplasm Childhood Glioma Clinical Research Clinical Trials Cognitive Combination Drug Therapy Combined Modality Therapy Cytotoxic Chemotherapy Development Diagnosis Disease Effectiveness Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Excision FDA approved Failure Feedback Glioma Gliomagenesis Grant Life MEKs Malignant Childhood Neoplasm Malignant Neoplasms Mediator of activation protein Morbidity - disease rate Mutation Neurologic Oncogenes Operative Surgical Procedures Outcome Patient-Focused Outcomes Patients Phase Population Preclinical Testing Proto-Oncogene Proteins c-akt Radiation Radiation therapy Radiosurgery Recurrence Refractory Reproduction spores Research Resected Risk Safety Salvage Therapy Signal Transduction Specimen Testing Toxic effect antitumor effect base chemotherapy driving force drug efficacy effective therapy efficacy trial improved improved outcome in vivo inhibitor/antagonist melanoma mouse model novel patient population pediatric patients prevent research clinical testing response small molecule inhibitor standard of care targeted treatment therapeutic target tumor tumor growth

项目摘要

Gliomas are aggressive brain tumors that affect children. Current treatment of high-grade glioma, most often involving surgery, radiation, and cytotoxic chemotherapy, only extend median survival of affected children to14 months, and results in significant morbidity. Low-grade glioma, that cannot be completely resected aretreated with radiation, typically after failure of chemotherapy approaches, with significant resulting neuro-cognitive and developmental risks. This project addresses a specific oncogene alteration, BRAFV600E occurring in as many as 14% of pediatric high-grade glioma. For certain subtypes of pediatric glioma thefrequency of BRAFV600E is much higher (66% in pleomorphic xanthoastrocytoma). Inhibitors that specifically target BRAFV600E have been developed and have shown remarkable efficacy against melanomas that harborthis mutation. One such inhibitor, vemurafenib, has now been FDA-approved for melanoma, and is underinvestigation for treating a number of other BRAFV600E malignancies. We have shown that BRAFV600E inhibitor treatment significanfiy extends survival of intracranial BRAFV600E glioma-bearing animals. We have also noted the activation of tumor feedback mechanisms may limit drug efficacy, suggesting that combination therapies targeting these mechanisms may further improve the response of BRAFV600E glioma to BRAF inhibitor therapy. Our preliminary studies have highlighted three specific and targetable activities that might be exploitable for this purpose. First, we have observed that CDKN2A inactivation and resultant increased CDK4/6 signaling occurs in the majority of BRAFV600E high grade glioma, and that concurrent treatment with CDK4/6 and BRAFV600E inhibitors provides additional survival benefit to animals bearing BRAFV600E and CDKN2A deficient tumors. Second, we observed that the reactivation of ERK signaling following BRAF inhibitor monotherapy is prevented by addition of a MEK inhibitor, which also increases anti-proliferative effect and survival for animais with intracranial BRAFV600E glioma. Finally, we have observed that BRAF-targeted treatment of BRAFV600E glioma results in EGFR feedback activation, suggesting that BRAF + EGFR combination therapy may augment the anti-tumor effect of BRAF monotherapy. Although these combination strategies appear to enhance BRAF inhibitor efficacy we do not fully understand the mechanistic basis for their actions, which of these combination approaches may be the most effective alone or combined with radiotherapy, or if BRAF inhibitors alone or in combination are safe in the pediatric population. These issues will be addressed in association with the proposed research that follows.

神经胶质瘤是影响儿童的侵略性脑肿瘤。当前的高级神经胶质瘤治疗（通常涉及手术，放射线和细胞毒性化学疗法）仅将受影响儿童的中位生存期扩展到14个月，并导致显着发病。低度神经胶质瘤，通常在化学疗法方法失败之后，无法完全通过辐射进行完全切除，并产生了显着的神经认知和发育风险。该项目解决了特定的癌基因改变，BRAFV600E发生在多达14％的小儿高级神经胶质瘤中。对于某些小儿神经胶质瘤的亚型，BRAFV600E的频率要高得多（多态Xanthotocytocytomay）。已经开发出了专门针对BRAFV600E的抑制剂，并显示出针对携带突变的黑色素瘤的显着疗效。一种这样的抑制剂Vemurafenib现在已被FDA批准用于黑色素瘤，并且不足以治疗许多其他BRAFV600E恶性肿瘤。我们已经表明，BRAFV600E抑制剂处理显着扩展了颅内BRAFV600E的存活率含有神经胶质瘤的动物。我们还注意到肿瘤反馈机制的激活可能会限制药物功效，表明针对这些机制的组合疗法可能会进一步改善 BRAFV600E神经胶质瘤对BRAF抑制剂治疗的反应。我们的初步研究突出了三个可能为此目的利用的特定和目标活动。首先，我们观察到 CDKN2A灭活和最终增加的CDK4/6信号在大多数BRAFV600E中发生等级神经胶质瘤，以及与CDK4/6和BRAFV600E抑制剂的同时治疗可提供额外带有BRAFV600E和CDKN2A缺乏肿瘤的动物的生存益处。其次，我们观察到通过添加MEK，可以预防BRAF抑制剂单一疗法后ERK信号传导的重新激活抑制剂，还增加了具有颅内BRAFV600E的动物的抗增殖作用和生存神经胶质瘤。最后，我们观察到BRAF靶向BRAFV600E神经胶质瘤的治疗导致EGFR 反馈激活，表明BRAF + EGFR组合疗法可能会增强抗肿瘤效应 Braf单一疗法。尽管这些组合策略似乎增强了BRAF抑制剂功效我们不完全理解其行为的机理基础，这些组合方法中的哪种可能是最有效的，或与放射疗法结合，或者单独使用BRAF抑制剂或组合在儿科人群中是安全的。这些问题将与拟议的随后的研究。