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

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

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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:
Administrative Core
行政核心
  • 批准号:
    10712291
  • 财政年份:
    2023
  • 资助金额:
    $ 35.89万
  • 项目类别:
Research Project 1: Diffuse Midline Glioma
研究项目1:弥漫性中线胶质瘤
  • 批准号:
    10712293
  • 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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