Project 1--Targeted therapies for pediatric low-grade astrocytoma (Eck/Wright/Haas)

项目1——儿童低级别星形细胞瘤的靶向治疗（Eck/Wright/Haas）

• 批准号: 10696099
• 负责人: MICHAEL J ECK
• 金额: $ 31.76万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10696099
• 关键词: Adult; Animals; Astrocytoma; BRAF gene; Biological Assay; Biomedical Engineering; Brain; Brain Neoplasms; CDKN2A gene; Cell Culture Techniques; Child; Childhood; Childhood Malignant Brain Tumor; Chimeric Proteins; Clinical; Clinical Trials; Collaborations; Colon Carcinoma; Daphne plant; Development; Disease Progression; Doctor of Medicine; Doctor of Philosophy; Drug Targeting; Excision; Funding; Fusion Oncogene Proteins; Ganglioglioma; Generations; Genetic; Genetically Engineered Mouse; Glioma; Grant; Hydrogels; Imatinib; In Vitro; Juvenile Pilocytic Astrocytomas; KRAS2 gene; MAP Kinase Gene; MEKs; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Medicine; Minor; Mitogen-Activated Protein Kinases; Monitor; Morbidity - disease rate; Mus; Mutate; Mutation; Oncogenes; Oncogenic; Oncology; Oncoproteins; Operative Surgical Procedures; Organoids; PTEN gene; Pathology; Pathway interactions; Patients; Pediatric Neoplasm; Pediatric cohort; Penetrance; Penetration; Peripheral Blood Lymphocyte; Pharmaceutical Preparations; Phase; Phospho-Specific Antibodies; Phosphorylation; Phosphotransferases; Point Mutation; Primary Neoplasm; Protein Kinase; Proteins; Protocols documentation; RAS inhibition; Ras/Raf; Recurrence; Research; Research Personnel; Resected; Scientist; Series; Signal Transduction; Signal Transduction Inhibitor; Solid Neoplasm; Specimen; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; System; Testing; Transformed Cell Line; Trastuzumab; Tube; Tumor Tissue; Variant; Visualization; Work; antagonist; chemotherapy; clinical material; counterscreen; drug development; experience; inhibitor; innovation; kinase inhibitor; melanoma; member; mutant; neoplastic cell; nerve stem cell; neuro-oncology; novel; pharmacokinetics and pharmacodynamics; precision medicine; protein purification; reconstitution; response; small molecule; spectroscopic imaging; standard of care; structural biology; targeted treatment; tumor; virtual

Project Summary/Abstract Low-grade astrocytomas are the most common brain tumor in children. Standard of care therapies have limited efficacy and treatment-related morbidity is significant. The broad objective of our study plan is to develop potent, brain-penetrant, targeted therapeutics for pediatric low-grade astrocytoma (PLGA). Towards this end, mutated, constitutively active forms of the BRAF protein kinase are expressed in ~75% of all PLGAs and are attractive targets for drug development. A minor cohort of PLGAs express V600E BRAF - a point mutation oncoprotein that is a frequent driver of malignant melanoma in adult patients. More commonly, PLGAs express a truncation/fusion oncoprotein known as KIAA1549:BRAF. Small molecule type 1 RAF inhibitors developed for adult melanoma have poor brain penetrance and are, moreover, ineffective antagonists of KIAA1549:BRAF. Against this backdrop, we have three specific aims: Aim 1 is to examine the clinical activity of TAK-580 in progressive, BRAF-mutant PLGAs. Under auspices of this SPORE, we showed that TAK-580 (a clinical stage type 2 RAF inhibitor) has good brain penetrance and targets both forms of the BRAF oncoprotein. A phase 0/I/II trial of TAK-580 in children with BRAF mutant low-grade gliomas tumors has been initiated. Using clinical materials from the phase I and II components of the trial we will establish the pharmacokinetics and pharmacodynamics of TAK-580 in children relative to adult patients where the drug has been previously evaluated. In the Phase 0 component of this trial, we will directly measure drug penetration into tumors. Aim 2 is to define the impact of cellular and genetic modifiers on response of PLGAs to TAK-580. An “inconvenient truth” in precision medicine is that target expression does not guarantee responsiveness to a targeted therapeutic. For example, type 1 RAF antagonists are effective inhibitors of V600E BRAF in melanoma but are ineffective on the same oncoprotein in colon cancers. Accordingly, as the TAK-580 clinical trial goes forward, we will conduct a series of in vitro “avatar” trials on primary patient tumor cells grown in a synthetic hydrogel system developed in collaboration with a bioengineering group at MIT. This system is similar to “organoid” systems developed for other solid tumors. Aim 3 is to develop second generation brain-penetrant drugs for BRAF-mutant PLGA with enhanced selectivity for KIAA1549:BRAF. TAK-580 targets both forms of the BRAF oncoprotein, but WT BRAF is also inhibited by the drug. Thus, TAK-580 is a “signal transduction inhibitor” but not a true targeted therapeutic. Although signal transduction inhibitors can be highly efficacious cancer medicines (e.g., imatinib or trastuzumab), a drug that is truly mutant-specific would be preferable for growing children. By far the most common form of BRAF oncoproteins in PLGA is a truncation/fusion protein known as KIAA1549:BRAF. In this aim, we take a mechanism-based approach to development of a drug that selectively targets KIAA1549:BRAF.

项目摘要/摘要低度星形细胞瘤是儿童中最常见的脑肿瘤。 标准护理疗法的疗效有限，且与治疗相关的发病率很高。广义的 我们研究计划的目标是开发有效的、脑渗透性的、有针对性的治疗方法来治疗儿科低级别疾病 星形细胞瘤（PLGA）。为此，BRAF 蛋白激酶的突变、组成型活性形式是 在约 75% 的 PLGA 中表达，是药物开发的有吸引力的靶标。一小群 PLGA 表达 V600E BRAF - 一种点突变癌蛋白，是成人恶性黑色素瘤的常见驱动因素 患者。更常见的是，PLGA 表达一种截短/融合癌蛋白，称为 KIAA1549:BRAF。小的 针对成人黑色素瘤开发的 1 型 RAF 分子抑制剂的脑外显率较差，而且， KIAA1549:BRAF 的无效拮抗剂。在此背景下，我们有三个具体目标： 目标 1 是检查 TAK-580 在进行性 BRAF 突变 PLGA 中的临床活性。在下面 在这个SPORE的主持下，我们证明了TAK-580（一种临床阶段2型RAF抑制剂）具有良好的大脑功能 外显率并针对 BRAF 癌蛋白的两种形式。 TAK-580 在儿童中的 0/I/II 期试验 BRAF突变低级别胶质瘤肿瘤已经启动。使用 I 期和 II 期临床材料 试验的组成部分我们将确定 TAK-580 在儿童中的药代动力学和药效学 相对于先前已评估过该药物的成年患者。在本试验的第 0 阶段部分中， 我们将直接测量药物对肿瘤的渗透。 目标 2 是确定细胞和遗传修饰剂对 PLGA 对 TAK-580 反应的影响。一个 精准医学中的“难以忽视的事实”是，靶点表达并不能保证对特定药物的反应。 针对性治疗。例如，1 型 RAF 拮抗剂是 V600E BRAF 的有效抑制剂 黑色素瘤，但对结肠癌中的相同癌蛋白无效。因此，随着 TAK-580 临床 试验继续进行，我们将对原发性患者肿瘤细胞进行一系列体外“阿凡达”试验。 与麻省理工学院的生物工程小组合作开发的合成水凝胶系统。这个系统是 类似于为其他实体瘤开发的“类器官”系统。 目标3是针对BRAF突变PLGA开发第二代脑渗透药物，具有增强的 KIAA1549:BRAF 的选择性。 TAK-580 靶向 BRAF 癌蛋白的两种形式，但 WT BRAF 也 被药物抑制。因此，TAK-580是一种“信号转导抑制剂”，但不是真正的靶向治疗药物。 尽管信号转导抑制剂可以是高效的癌症药物（例如伊马替尼或 曲妥珠单抗）这种真正针对突变体的药物对于成长中的儿童来说是更可取的。迄今为止最 PLGA 中 BRAF 癌蛋白的常见形式是一种截短/融合蛋白，称为 KIAA1549:BRAF。在这个 为了实现这一目标，我们采用基于机制的方法来开发选择性靶向 KIAA1549:BRAF 的药物。