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

• 批准号: 9360073
• 负责人: Douglas Yee
• 金额: $ 48.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/9360073
• 关键词: Archives; Bioinformatics; Biological; Biological Markers; Biology; Biopsy; Breast; 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; Gene Expression; Goals; Image; Immune; Immunologic Markers; In complete remission; Information Resources; Investigation; Magnetic Resonance Imaging; Methods; Modeling; Molecular; Molecular Profiling; Neoadjuvant Therapy; New Agents; Operative Surgical Procedures; Outcome; Pathologic; Pathway Analysis; Pathway interactions; Patient Agents; Patients; Pharmaceutical Preparations; Prediction of Response to Therapy; Prior Therapy; Probability; Protocols documentation; Qualifying; Qualitative Methods; Randomized; Recurrence; Regimen; Research; Research Design; Research Infrastructure; Research Personnel; Residual Tumors; Resistance; Resources; Risk; Selection for Treatments; Sequential Treatment; Source; Specimen; Techniques; Therapeutic; Time; Tumor Biology; Tumor Burden; Update; Woman; Work; base; biomarker evaluation; chemotherapy; drug candidate; drug sensitivity; evidence base; experience; 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; predicting response; pressure; programs; prospective; randomized trial; responders and non-responders; response; response biomarker; success; synergism; targeted treatment; therapy resistant; tool; treatment response; trial design; tumor; tumor eradication; working group

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 相反，早期复发的巨大风险。 （完全消除肿瘤）在手术之前，HABE非常好的结局。 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Localy Advanced女性的新代理商和新代理的反应生物标志物 迄今 在III期试验中，超过1000名患者的概率每年有250名 这些进步，愿妇女仍然可以达到PCR。 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，然后将治疗重定向到另一个生物界面 根据在其肿瘤中存在的生物标志物，我们在肿瘤中选择了治疗。 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。 演示时的特征将有助于成功的识别药物策略 将“非响应者”转换为具有PCR的患者。 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 基于肿瘤免疫微环境分析的药物反应，并将概率得分分配给每个分析 毒品对2）扩大I-SPY2的药物敏感性 尚未在I-Spy 2药物组合中的疗法 来自乳腺癌和其他癌细胞的反应者和药物表达数据库； 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，基于证据的推理代理选择的策略。我们与他们紧密合作 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。 通过与项目3的合作而出现的重要协同作用，其目的是表征您 在治疗压力下抗性的分子途径的动力学。 共同核心中的研究人员和生物信息学专业知识的广泛经验。 整个计划项目的目标是研究的重要动机，这将导致 开发重要的新信息资源，这些新信息资源在I-SPY 2+试验中及其他方面进行了风用。