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: 10553688
• 负责人: Sandeep Burma
• 金额: $ 55.31万
• 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/10553688
• 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; Clinical; Clinical Trials; Combined Modality Therapy; Complex; Cytotoxic agent; DNA Damage; Data; Databases; Diffuse astrocytoma; Disease; Disease Progression; Dose; Drug Combinations; Drug resistance; Ganglioglioma; Glioblastoma; Glioma; Goals; Juvenile Pilocytic Astrocytomas; Laboratories; 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; Research Personnel; Resistance; Resistance development; Signal Pathway; Signal Transduction; Sirolimus; TSC2 gene; Testing; Therapeutic; Toxic effect; Translating; Translational Research; Tuberous Sclerosis; cell killing; chemoradiation; cytotoxicity; driver mutation; drug resistance development; improved; inhibitor; inhibitor therapy; 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 diagnosis; 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.

儿童神经胶质瘤的特征是 MAPK 通路的激活，或者通过串联重复 BRAFA 基因座，或通过点突变（最常见的是 V600E 突变）。约1400新 在美国，每年都会诊断出 BRAF 激活的儿童脑肿瘤病例。最近的 I/II 期试验 证实了 MEK 抑制剂（（MEKi）治疗这些癌症的功效。然而，对于由 BRAF（V600E）突变患者可能在司美替尼治疗中进展（即产生耐药性），或迅速进展 如果减少药物剂量或停止治疗（最近的 II 期试验为 2 年），就会取得进展。因此，虽然 MEKi 可有效促使肿瘤消退，但不能治愈。临床结果表明司美替尼与 与传统化学放射治疗一样有效，但没有与强化化学放射治疗相关的毒性 放射治疗。因此，MEK 抑制剂开创了这些患者治疗的新时代。 我们的研究是唯一一些 PDX 临床前数据，可用于测试司美替尼（MEK 抑制剂） 小儿脑肿瘤联盟试验 (PBTC029)，其疗效在随后的 II 期试验中得到证实 （NCT01089101）。在这里，我们提出可能导致下一代临床试验的临床前研究 基于当前 MEKi 试验的结果。本申请中提出的研究将使用独特的面板 BRAF(V600E)儿童脑肿瘤PDX模型的研究重点关注两个关键问题：1）开发MAPK抑制剂 与放射治疗 (RT) 相结合选择性增强肿瘤细胞杀伤的组合，以及 2) 开发 预防耐药性发展的治疗方法。中心假设是敏感性 MAPKi 是 MAPK/TORC1 双重抑制的结果，低剂量间歇性雷帕霉素可以预防 出现对 MEKi 以及放射治疗的耐药性。这些研究还将探索机制 对单独或联合使用的 MAPK 抑制剂组合和放射治疗 (RT) 的耐药性，以及 描述雷帕霉素防止耐药性出现的机制。 我们的总体目标是确定最佳的 MAPK/TORC1 抑制剂药物组合，以延缓或预防 药物或 RT 耐药性的出现，确定雷帕霉素延迟/预防的机制 MAPKi 和 RT 耐药性的出现，并确定此类组合是否可以维持肿瘤控制 在较低剂量的 RT 下。拟议的研究有可能确定更有效的新疗法 优于司美替尼，最终能够减少患者的放疗剂量，从而改善长期疗效 结果和生活质量。