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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：
10245084
负责人：
DAPHNE A. HAAS-KOGAN
金额：
$ 35.89万
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：
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/10245084
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

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.

低级别星形细胞瘤是儿童最常见的脑肿瘤。