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

儿童胶质瘤的特征是MAPK通路的激活，或者是通过串联复制 BRAFA基因座，或通过点突变(最常见的V600E突变)。新增约1400个 在美国，每年都会诊断出BRAF激活的儿童脑瘤病例。最近的I/II期试验已经 证实了MEK抑制剂((Meki))对这些癌症的治疗效果。然而，对于由 BRAF(V600E)突变患者可能在赛鲁米替尼治疗方面取得进展(即变得耐药)，或迅速进步 如果药物剂量减少或治疗停止(在最近的第二阶段试验中为2年)，则进展。因此，虽然 Meki在导致肿瘤消退方面是有效的，但它不是治愈的。临床结果表明，赛鲁米替尼的疗效相同 与传统的放化疗一样有效，但没有与密集化疗相关的毒性。 放射治疗。因此，MEK抑制剂开启了这些患者治疗的新纪元。 我们的研究是导致赛鲁米替尼(MEK抑制剂)试验的仅有的PDX临床前数据之一。 儿童脑肿瘤联合试验(PBTC029)，疗效在随后的II期试验中得到证实 (NCT01089101)。在这里，我们提出了可能导致下一代临床试验的临床前研究 建立在目前Meki试验结果的基础上。本申请中提出的研究将使用一个独特的小组 对BRAF(V600E)儿童脑肿瘤PDX模型的研究主要集中在两个关键问题上：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 预防抗药性发展的治疗方法。中心假设是敏感度 MAPKI是MAPK/TORC1双重抑制的结果，小剂量间歇雷帕霉素可预防 出现对Meki的抗药性，也对放射治疗产生抗药性。这些研究还将探索 对MAPK抑制剂组合和放射治疗(RT)的耐药性，单独或联合使用，以及 描述雷帕霉素防止耐药性出现的机制/S。 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 耐药或RT耐药的出现，确定雷帕霉素延缓/预防的机制/S MAPKi和RT耐药的出现，并确定这种组合是否可以维持肿瘤控制 在较低剂量的RT下。潜在地，拟议的研究将确定更有效的新疗法。 与赛鲁米替尼相比，最终能够减少患者的RT剂量，从而改善长期 结果和生活质量。

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.