Enhancing MAPK-targeted Therapy in PDX Models of BRAF-Mutant Pediatric Brain Tumors

增强 BRAF 突变儿童脑肿瘤 PDX 模型中的 MAPK 靶向治疗

• 批准号: 10175336
• 负责人: Sandeep Burma
• 金额: $ 55.41万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-08 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10175336
• 关键词: Address; Astrocytoma; BRAF gene; Brain Neoplasms; Cause of Death; Cell Death; Central Nervous System Neoplasms; Child; Childhood; Childhood Brain Neoplasm; Childhood Central Nervous System Neoplasm; Childhood Glioblastoma; Childhood Glioma; Childhood Pilocytic Astrocytoma; Clinical; Clinical Trials; Complex; Cytotoxic agent; DNA Damage; Data; Databases; Diagnosis; Diffuse astrocytoma; Disease; Disease Progression; Dose; Drug Combinations; Drug resistance; Ganglioglioma; Glioblastoma; Glioma; Goals; Laboratories; Lead; Low Dose Radiation; MAP2K1 gene; MAPK Signaling Pathway Pathway; MEKs; Malignant Neoplasms; Mediating; Mitogen-Activated Protein Kinase Inhibitor; Mitogen-Activated Protein Kinases; Modeling; Mutation; NF1 gene; Outcome; Pathway interactions; Patients; Pediatric Brain Tumor Consortium; Pediatric Neoplasm; Pediatric Oncology Group; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phase; Phase I/II Trial; Phosphorylation; Point Mutation; Quality of life; Radiation Physics; Radiation therapy; Regimen; Relapse; Reporting; Research Personnel; Resistance; Resistance development; Signal Pathway; Signal Transduction; Sirolimus; TSC2 gene; Testing; Therapeutic; Therapeutic Studies; Toxic effect; Translating; Translational Research; Tuberous sclerosis protein complex; base; cell killing; chemoradiation; cytotoxicity; driver mutation; drug development; improved; inhibitor/antagonist; mouse model; multidisciplinary; mutant; neoplastic cell; next generation; novel; patient derived xenograft model; pediatric patients; phase II trial; pre-clinical; preclinical study; prevent; radiation resistance; resistance mechanism; response; targeted treatment; tumor; tumor progression

Pediatric glioma is characterized by activation of the MAPK pathway, either through a tandem duplication of the BRAFA locus, or through point mutations (most frequently the V600E mutation). Approximately 1400 new cases of BRAF-activated childhood brain tumors are diagnosed annually in the US. Recent phase I/II trials have confirmed the efficacy of MEK inhibitors ((MEKi) for teatment of these cancers. However, for tumors driven by the BRAF(V600E) mutant patients may progress on selumetinib treatment (i.e. become resistant), or rapidly progress if drug dose is reduced or treatment stopped (at 2 years as in the recent phase II trial). Thus, while MEKi is effective in causing tumor regression, it is not curative. Clinical results suggest that selumetinib is equally as effective as conventional chemo-radiation therapy, but without toxicities associated with intensive chemo- radiation treatment. Hence, MEK inhibitors usher in a new era in treatment for these patients. Our studies were some of the only PDX preclinical data that lead to testing of selumetinib (MEK inhibitor) in the Pediatric Brain Tumor Consortium trial (PBTC029), with efficacy confirmed in the subsequent phase II trial (NCT01089101). Here we propose preclinical studies that could lead to the next generation of clinical trials building on the results from current MEKi trials. The studies proposed in this application will use a unique panel of BRAF(V600E) pediatric brain tumor PDX models to focus on two critical issues: 1) to develop MAPK inhibitor combinations that selectively enhance tumor cell kill in combination with radiation therapy (RT), and 2) to develop therapeutic approaches to prevent development of drug resistance. The central hypothesis is that sensitivity to MAPKi is a consequence of dual MAPK/TORC1 inhibition, and low-dose intermittent rapamycin can prevent emergence of resistance to MEKi, and also to radiation therapy. These studies will also explore mechanisms of resistance to MAPK inhibitor combinations and radiation treatment (RT), alone or in combination, and characterize the mechanism/s by which rapamycin prevents emergence of resistance. Our overall goal is to identify optimal MAPK/TORC1 inhibitor drug combinations that retard or prevent emergence of drug or RT resistance, determine the mechanism/s by which rapamycin retards/prevents emergence of MAPKi and RT resistance, and determine whether such combinations can maintain tumor control at lower doses of RT. Potentially, the proposed studies will identify novel regimens that will be more efficacious than selumetinib and ultimately result in the ability to reduce the RT dose in patients, thus improving long-term outcomes and quality of life.

小儿神经胶质瘤的特征是MAPK途径激活，要么通过串联重复 BRAFA基因座，或通过点突变（最常见的V600E突变）。大约1400个新 在美国，每年诊断为BRAF激活的儿童脑肿瘤病例。最近的I/II期试验有 确认了MEK抑制剂的功效（（Meki）这些癌症的触发。但是，对于由 BRAF（V600E）突变患者可能会在selumetinib治疗（即具有抗性）或迅速进行 如果降低药物剂量或停止治疗（如最近的II期试验，在2年时）进展。因此， Meki有效地导致肿瘤回归，这是无法治愈的。临床结果表明selumetinib同样是 与常规化学辐射疗法一样有效，但没有与密集化学的毒性相关的 辐射处理。因此，MEK抑制剂迎来了这些患者的新时代。 我们的研究是唯一导致selumetinib（MEK抑制剂）测试的PDX临床前数据 小儿脑肿瘤联盟试验（PBTC029），在随后的II期试验中证实了功效 （NCT01089101）。在这里，我们提出的临床前研究可能导致下一代临床试验 基于当前MEKI试验的结果。本应用程序中提出的研究将使用独特的面板 BRAF（V600E）小儿脑肿瘤PDX模型的重点是两个关键问题：1）开发MAPK抑制剂 选择性增强肿瘤细胞与放射治疗（RT）和2）的组合形成 防止耐药性发展的治疗方法。中心假设是灵敏度 MAPKI是双MAPK/TORC1抑制的结果，低剂量间歇性雷帕霉素可以预防 对Meki的抗性以及对放射疗法的抗性。这些研究还将探索 对MAPK抑制剂组合和辐射处理（RT）的抗性，单独或组合，以及 表征雷帕霉素阻止抗药性出现的机制。 我们的总体目标是确定最佳MAPK/TORC1抑制剂药物组合，以阻止或预防 药物或RT耐药性的出现，确定雷帕霉素追踪/阻止的机制 MAPKI和RT电阻的出现，并确定此类组合是否可以维持肿瘤控制 在较低剂量的RT处。可能的是，拟议的研究将确定新的方案，这些方案将更有效 比selumetinib并最终导致减少患者的RT剂量的能力，从而改善了长期 成果和生活质量。