Project 04 - Develop a portfolio of agents for switching that match biology of residual tumor burden

项目 04 - 开发与残余肿瘤负荷生物学相匹配的切换药物组合

基本信息

  • 批准号:
    9360073
  • 负责人:
  • 金额:
    $ 48.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-08 至 2022-08-31
  • 项目状态:
    已结题

项目摘要

SUMMARY – PROJECT 4 Women with substantial residual disease after neoadjuvant chemotherapy (NAC) have poor prognosis with substantial risk of early recurrence. Conversely, women who achieve pathologic complete response or `pCR' (complete eradication of tumor) prior to surgery have very good outcomes. The I-SPY2 clinical trial is an innovative multicenter, multi-agent clinical platform trial that uses an adaptive randomized study design to accelerate the development of new agents and paired biomarkers of response in women with locally advanced breast cancer. To date, 10 novel agents have begun evaluation, and 3 have `graduated' having a high (>85%) probability of success in a phase III trial; over 1000 patients have enrolled, with 250 more each year. Despite these advances, may women still fail to reach pCR. Driven by advances in MRI imaging assesments, this Program Project aims to improve pCR rates by modifying I-SPY 2 to include non-invasive identification of patients with insufficient response to NAC, then redirecting their treatment to another, biologically targeted therapy selected based upon the presence of biomarkers of response present in their tumor. In this project, we will use the substantial archived specimens and data sets from I-SPY 2 to identify new biomarkers and develop the framework for evidence-based selection of substitute treatments. Our hypothesis is that tumor characteristics at time of presentation will assist in the identification drug strategies that will successfully convert a “non-responder” into a patient with a pCR. To achieve our goals of identifying successful drug regimens that can be used to redirect patient's therapies, we will follow a research plan consisting of three specific aims: 1) utilize the I-SPY2 qualifying biomarker evaluation (QBE) framework to identify biomarkers of drug response based upon tumor immune microenvironment analyses, and assign probability scores to each drug-biomarker pair; 2) expand the I-SPY2 predicted drug sensitivity portfolio to single agents or combination therapies not yet within the I-SPY 2 drug portfolio, based on gene expression profiles of responders/non- responders and drug-gene expression databases from breast and other cancer cell lines; and 3) create an integrated drug response prediction matrix from all sources, and establish quantitative and qualitative strategies for the rational, evidence-based selection of agents for reassignment.. We will work closely with the Project 1 clinical team to refine our models in a way that maintains clinical context. We anticipate a unique and important synergy to emerge through collaborations with Project 3, the goal of which is to characterize the dynamics of molecular pathways of resistance under therapeutic pressure. This project will also leverage the broad experience of the investigators and the bioinformatics expertise within the shared cores. The clinical goals of the overall program project are a significant motivating factor for this study, which will result in the development of important new information resources that will find utility within the I-SPY 2+ TRIAL and beyond.
摘要-项目4 新辅助化疗(NAC)后有大量残留疾病的女性预后不良, 早期复发的风险很大。相反,达到病理完全缓解或“pCR”的女性 (完全根除肿瘤)手术前有非常好的结果。I-SPY 2临床试验是一项 创新的多中心、多药物临床平台试验,采用适应性随机研究设计, 加速开发新的药物和配对的生物标志物,以应对局部晚期乳腺癌女性患者。 乳腺癌迄今为止,已有10种新药剂开始评价,3种药剂“毕业”,评价率很高(>85%)。 在III期试验中成功的可能性;超过1000名患者已登记,每年增加250人。尽管 这些进步,可能妇女仍然无法达到pCR。在MRI成像评估进步的推动下, 计划项目旨在通过修改I-SPY 2来提高pCR率,以包括非侵入性识别 对NAC反应不足的患者,然后将其治疗转向另一种生物靶向治疗, 基于其肿瘤中存在的反应生物标志物的存在选择治疗。本课题 将使用I-SPY 2的大量存档标本和数据集来确定新的生物标志物, 替代治疗的循证选择框架。我们的假设是 介绍时的特征将有助于确定药物策略, 将“无应答者”转化为pCR患者。为了实现我们识别成功药物的目标 方案,可用于重新定向患者的治疗,我们将遵循一个研究计划,包括三个 具体目标:1)利用I-SPY 2合格生物标志物评价(QBE)框架来鉴定以下生物标志物: 基于肿瘤免疫微环境分析的药物反应,并为每个概率评分 药物-生物标志物对; 2)将I-SPY 2预测的药物敏感性组合扩展到单一药剂或组合 根据应答者/非应答者的基因表达谱, 来自乳腺癌和其他癌细胞系的应答者和药物基因表达数据库;以及3)创建 整合所有来源的药物反应预测矩阵,并建立定量和定性 合理的,以证据为基础的选择代理重新分配的策略。我们将与 项目1临床团队以保持临床背景的方式完善我们的模型。我们期待一个独特且 通过与项目3的合作产生重要的协同作用,其目标是描述 在治疗压力下抵抗的分子途径的动力学。该项目还将利用 研究者的广泛经验和共享核心内的生物信息学专业知识。临床 总体计划项目的目标是本研究的一个重要激励因素,这将导致 开发重要的新信息资源,这些资源将在I-SPY 2+ TRIAL和其他领域中发挥作用。

项目成果

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Douglas Yee其他文献

Douglas Yee的其他文献

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{{ truncateString('Douglas Yee', 18)}}的其他基金

Disrupting insulin receptor function in breast cancer
破坏乳腺癌中的胰岛素受体功能
  • 批准号:
    10412979
  • 财政年份:
    2020
  • 资助金额:
    $ 48.65万
  • 项目类别:
Disrupting insulin receptor function in breast cancer
破坏乳腺癌中的胰岛素受体功能
  • 批准号:
    10625994
  • 财政年份:
    2020
  • 资助金额:
    $ 48.65万
  • 项目类别:
Disrupting insulin receptor function in breast cancer
破坏乳腺癌中的胰岛素受体功能
  • 批准号:
    10028995
  • 财政年份:
    2020
  • 资助金额:
    $ 48.65万
  • 项目类别:
Disrupting insulin receptor function in breast cancer
破坏乳腺癌中的胰岛素受体功能
  • 批准号:
    10171816
  • 财政年份:
    2020
  • 资助金额:
    $ 48.65万
  • 项目类别:
Admin
行政
  • 批准号:
    10474988
  • 财政年份:
    2019
  • 资助金额:
    $ 48.65万
  • 项目类别:
Core B
核心B
  • 批准号:
    10225393
  • 财政年份:
    2019
  • 资助金额:
    $ 48.65万
  • 项目类别:
Admin
行政
  • 批准号:
    10225392
  • 财政年份:
    2019
  • 资助金额:
    $ 48.65万
  • 项目类别:
Core B
核心B
  • 批准号:
    10474991
  • 财政年份:
    2019
  • 资助金额:
    $ 48.65万
  • 项目类别:
Admin
行政
  • 批准号:
    9804094
  • 财政年份:
    2019
  • 资助金额:
    $ 48.65万
  • 项目类别:
Core B
核心B
  • 批准号:
    9804095
  • 财政年份:
    2019
  • 资助金额:
    $ 48.65万
  • 项目类别:

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