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）

基本信息

批准号：
10013518
负责人：
DAPHNE A. HAAS-KOGAN
金额：
$ 33.74万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013518
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 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 oncology pharmacokinetics and pharmacodynamics precision medicine reconstitution response small molecule spectroscopic imaging standard of care structural biology targeted treatment tumor virtual

项目摘要

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。我们研究计划的目标是开发有效的、脑渗透性的、针对儿科低级别的靶向治疗方法为此，BRAF 蛋白激酶的突变、组成型活性形式被开发出来。在约 75% 的 PLGA 中表达，是药物开发的一小部分 PLGA 的有吸引力的靶标。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更常见的是，PLGA 表达一种称为 KIAA1549:BRAF Small 的截短/融合癌蛋白。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，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 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开始使用 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对该药物进行过评估的成年患者而言，在该试验的 0 期部分中，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。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。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，与 TAK-580 临床相同。试验继续进行，我们将对在培养皿中生长的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。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 的选择性针对 BRAF 癌蛋白的两种形式，但 WT BRAF 也是如此。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），一种真正针对突变体的药物，迄今为止最适合成长中的儿童。 PLGA 中 BRAF 癌蛋白的常见形式是一种截短/融合蛋白，称为 KIAA1549:BRAF。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。