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：
10013141
负责人：
Douglas Yee
金额：
$ 27.24万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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

来源：
https://reporter.nih.gov/project-details/10013141
关键词：
Archives Bioinformatics Biological Biological Markers Biological Products Biology Biopsy Breast Breast Cancer Risk Factor Cancer cell line Characteristics Classification Clinical Clinical Protocols Clinical Trials Collaborations Combined Modality Therapy Data Data Set Databases Development Disease Pathway Disease Resistance Early identification Elements Enrollment Evaluation Expression Profiling Gene Expression Goals Image Immunologic Markers In complete remission Information Resources Infrastructure Investigation Magnetic Resonance Imaging Methods Modeling Molecular Neoadjuvant Therapy New Agents Operative Surgical Procedures Outcome Pathologic Pathway Analysis Pathway interactions Patient Agents Patients Pharmaceutical Preparations Prior Therapy Probability Protocols documentation Qualifying Qualitative Methods Randomized Recurrence Regimen Research Research Design Research Personnel Residual Tumors Resistance Resources Risk Selection for Treatments Sequential Multiple Assignment Randomized Trial Sequential Treatment Source Specimen Techniques Therapeutic Time Tumor Biology Tumor Burden Update Woman Work advanced breast cancer base biomarker evaluation chemotherapy drug candidate drug response prediction drug sensitivity evidence base experience gene expression database high risk improved improved outcome innovation malignant breast neoplasm molecular dynamics molecular marker next generation non-invasive imaging novel outcome forecast phase III trial precision medicine pressure programs prospective responders and non-responders response response biomarker success synergism targeted treatment therapy resistant tool treatment response trial design tumor tumor eradication tumor-immune system interactions working group

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，患有大量残留疾病的妇女的预后不佳早期复发的重大风险。相反，获得病理完全反应或“ PCR”的女性（完全消除肿瘤）手术前的结局很好。 I-SPY2临床试验是创新的多中心，多代理临床平台试验，该试验使用自适应随机研究设计加速局部先进的女性的新代理商和配对的反应生物标志物乳腺癌。迄今在第三阶段试验中成功的概率；已有1000多名患者参加，每年增加250名。尽管这些进步，愿妇女仍然无法达到PCR。在MRI成像评估的进步的驱动下，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，然后将其治疗重定向到另一个具有生物学靶向的治疗根据其肿瘤中存在的反应生物标志物的存在选择的治疗。在这个项目中，我们将使用I-SPY 2中的大量存档标本和数据集来识别新的生物标志物并开发基于证据的替代治疗的框架。我们的假设是肿瘤演示时的特征将有助于成功的识别药物策略将“无反应器”转换为具有PCR的患者。为了实现我们确定成功药物的目标可用于重定向患者疗法的方案，我们将遵循由三个研究计划具体目的：1）利用I-SPY2合格生物标志物评估（QBE）框架来识别生物标志物基于肿瘤免疫环境分析的药物反应，并将概率得分分配给每个吸毒者对； 2）将I-SPY2预测的药物敏感性投资组合扩展到单个药物或组合基于响应者的基因表达谱/非 - 来自乳腺癌和其他癌细胞系的响应者和药物 - 基因表达数据库； 3）创建一个来自所有来源的综合药物反应预测矩阵，并建立定量和定性理性的，基于证据的代理进行重新分配的策略。我们将与项目1临床团队以保持临床环境的方式来完善我们的模型。我们期待一个独特的通过与项目3的合作而出现的重要协同作用，其目的是表征在热压下电阻分子途径的动力学。该项目还将利用共享核心内研究人员和生物信息学专业知识的广泛经验。临床整个计划项目的目标是这项研究的重要激励因素，这将导致开发重要的新信息资源，这些资源将在I-SPY 2+试验及其他地区中找到效用。