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:
- 金额:$ 35.89万
- 依托单位:
- 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:
- 关键词:AddressAdultAnimalsAstrocytomaBRAF geneBiological AssayBiomedical EngineeringBrainBrain NeoplasmsCDKN2A geneCell Culture TechniquesChildChildhoodChildhood Malignant Brain TumorChimeric ProteinsClinicalClinical TrialsCollaborationsColon CarcinomaDaphne plantDevelopmentDisease ProgressionDoctor of MedicineDoctor of PhilosophyDrug TargetingExcisionFundingFusion Oncogene ProteinsGangliogliomaGenerationsGeneticGenetically Engineered MouseGliomaGrantHydrogelsImatinibIn VitroJuvenile Pilocytic AstrocytomasKRAS2 geneLeadMAP Kinase GeneMEKsMalignant NeoplasmsMass Spectrum AnalysisMeasuresMedicineMinorMitogen-Activated Protein KinasesMonitorMorbidity - disease rateMulti-Institutional Clinical TrialMulticenter TrialsMusMutateMutationOncogenesOncogenicOncologyOncoproteinsOperative Surgical ProceduresOrganoidsPTEN genePathologyPathway interactionsPatientsPediatric NeoplasmPediatric cohortPenetrancePenetrationPeripheral Blood LymphocytePharmaceutical PreparationsPhasePhospho-Specific AntibodiesPhosphorylationPhosphotransferasesPoint MutationPrimary NeoplasmProtein KinaseProteinsProtocols documentationRas/RafRecurrenceResearchResearch PersonnelResectedScientistSeriesSignal TransductionSignal Transduction InhibitorSolid NeoplasmSpecimenSpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationSystemTestingTransformed Cell LineTrastuzumabTubeTumor TissueVariantWorkbasechemotherapyclinical materialdrug developmentexperienceinhibitor/antagonistinnovationkinase inhibitormelanomamembermutantneoplastic cellnerve stem cellneuro-oncologynovelpharmacokinetics and pharmacodynamicsprecision medicinereconstitutionresponsesmall moleculespectroscopic imagingstandard of carestructural biologytargeted treatmenttumorvirtual
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DAPHNE A. HAAS-KOGAN其他文献
DAPHNE A. HAAS-KOGAN的其他文献
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{{ truncateString('DAPHNE A. HAAS-KOGAN', 18)}}的其他基金
Radiation Oncology at the Interface of Pediatric Cancer Biology and Data Science
儿科癌症生物学和数据科学交叉领域的放射肿瘤学
- 批准号:
10712290 - 财政年份:2023
- 资助金额:
$ 35.89万 - 项目类别:
Precision Medicine For Pediatric Low-Grade Gliomas
儿科低级别胶质瘤的精准医学
- 批准号:
9147009 - 财政年份:2015
- 资助金额:
$ 35.89万 - 项目类别:
Precision Medicine For Pediatric Low-Grade Gliomas
儿科低级别胶质瘤的精准医学
- 批准号:
9334330 - 财政年份:2015
- 资助金额:
$ 35.89万 - 项目类别:
Precision Medicine For Pediatric Low-Grade Gliomas
儿科低级别胶质瘤的精准医学
- 批准号:
8865159 - 财政年份:2015
- 资助金额:
$ 35.89万 - 项目类别:
Precision Medicine For Pediatric Low-Grade Gliomas
儿科低级别胶质瘤的精准医学
- 批准号:
9765413 - 财政年份:2015
- 资助金额:
$ 35.89万 - 项目类别:
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 - 财政年份:2013
- 资助金额:
$ 35.89万 - 项目类别:
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:
10013518 - 财政年份:
- 资助金额:
$ 35.89万 - 项目类别:
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