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: 10019485
• 负责人: DAPHNE A. HAAS-KOGAN
• 金额: $ 36.41万
• 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/10019485
• 关键词: Address; 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; Lead; MAP Kinase Gene; MEKs; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Medicine; Minor; Mitogen-Activated Protein Kinases; Monitor; Morbidity - disease rate; Multi-Institutional Clinical Trial; Multicenter Trials; 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/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; Work; base; chemotherapy; clinical material; drug development; experience; inhibitor/antagonist; innovation; kinase inhibitor; melanoma; member; mutant; neoplastic cell; nerve stem cell; neuro-oncology; novel; pharmacokinetics and pharmacodynamics; precision medicine; 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/抽象的低度星形胶质细胞瘤是儿童中最常见的脑肿瘤。 护理疗法的效率有限，与治疗相关的发病率显着。宽阔 我们的研究计划的目的是开发有效的，脑培训剂的针对性疗法 星形细胞瘤（PLGA）。为此，BRAF蛋白激酶的突变，组成型活性形式是 在所有PLGA中的约75％中表示，是药物开发的有吸引力的靶标。少数PLGA Express V600E BRAF-点突变癌蛋白，它是成人恶性黑色素瘤的驱动力 患者。更常见的是，PLGA表达截断/融合癌蛋白称为KIAA1549：BRAF。小的 为成人黑色素瘤开发的1型RAF抑制剂1型分子抑制剂的脑部渗透不良，此外， KIAA1549的无效拮抗剂：Braf。在此背景下，我们有三个具体的目标： AIM 1是检查进行性BRAF突变PLGA中TAK-580的临床活性。在下面 该孢子的主持人，我们表明tak-580（临床阶段2型RAF抑制剂）具有良好的大脑 渗透和靶向两种形式的BRAF癌蛋白。 TAK-580的0/I/II阶段试验 BRAF突变体低度胶质瘤肿瘤已开始。使用I和II期的临床材料 试验的组件我们将建立儿童TAK-580的药代动力学和药效学 相对于先前已评估该药物的成年患者。在此试验的第0阶段组件中， 我们将直接测量药物渗透到肿瘤中。 AIM 2是定义细胞和遗传修饰剂对PLGA对TAK-580反应的影响。一个 精确医学中的“不方便的真理”是，目标表达不能保证对 靶向疗法。例如，1型RAF拮抗剂是V600E BRAF的有效抑制剂 黑色素瘤，但在结肠癌中的同一癌蛋白上无效。根据TAK-580临床 试验继续进行，我们将对在A中生长的原发性肿瘤细胞进行一系列体外“阿凡达”试验 合成水凝胶系统与麻省理工学院的一个生物工程组合作开发。这个系统是 类似于为其他实体瘤开发的“类器官”系统。 AIM 3是开发用于BRAF突变体PLGA的第二代脑渗透药物，并增强 KIAA1549的选择性：Braf。 TAK-580靶向两种形式的BRAF癌蛋白，但WT BRAF也是 被药物抑制。那是TAK-580是一种“信号转导抑制剂”，但不是真正的靶向疗法。 尽管信号转导抑制剂可能是高效的癌症药物（例如，伊马替尼或 Trastuzumab），一种真正特异性突变特异性的药物，比成长中的儿童更可取。到目前为止 BRAF癌蛋白在PLGA中的常见形式是一种截短/融合蛋白，称为KIAA1549：BRAF。在这个 目的，我们采用一种基于机制的方法来开发一种有选择地靶向KIAA1549：BRAF的药物。