Research Project 1: Enhancing neoadjuvant therapy to prevent breast cancer recurrence

研究项目1：加强新辅助治疗预防乳腺癌复发

• 批准号: 10732951
• 负责人: Michael T. Lewis
• 金额: $ 19.79万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732951
• 关键词: Adjuvant; Adjuvant Chemotherapy; African American; African American population; American Indians; Asian population; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer therapy; Carboplatin; Caucasians; Cause of Death; Cisplatin; Clinical; Clinical Trials; Collection; Combination Drug Therapy; Combined Modality Therapy; Computing Methodologies; Coupled; Cytotoxic Chemotherapy; Data; Data Set; Disease; Disease Outcome; Distant; Dose; Epidermal Growth Factor Receptor; Ethnic Origin; Generations; Goals; Grant; Hand; Hispanic; Hispanic Populations; Human; Immune checkpoint inhibitor; In complete remission; Measurable; Metastatic/Recurrent; Modeling; Molecular Computations; Molecular Target; Monitoring for Recurrence; Neoadjuvant Therapy; Newly Diagnosed; Oncogenic; Operative Surgical Procedures; Organoids; Paclitaxel; Pathway interactions; Patient Selection; Patient-derived xenograft models of breast cancer; Patients; Platinum Compounds; Poly(ADP-ribose) Polymerase Inhibitor; Proteins; Publishing; Random Allocation; Recurrence; Recurrent Malignant Neoplasm; Refugees; Research Project Grants; Residual Neoplasm; Resistance; Salvage Therapy; Slice; Survival Rate; System; Testing; Time; Toxic effect; Woman; biomarker identification; cancer recurrence; chemotherapy; co-clinical trial; cohort; cytotoxic; docetaxel; drug candidate; drug response prediction; follow-up; hormone receptor-positive; improved; in vivo; malignant breast neoplasm; molecular targeted therapies; overexpression; patient derived xenograft model; pre-clinical; predicting response; predictive marker; predictive signature; prevent; prospective; racial population; responders and non-responders; response; response biomarker; screening; targeted agent; taxane; treatment response; triple-negative invasive breast carcinoma; tumor

RESEARCH PROJECT 1: Enhancing Neoadjuvant Therapy To Prevent Breast Cancer Recurrence PROJECT SUMMARY Based on our strong preliminary and published data, our overarching hypothesis guiding the project is that agents that enhance response to neoadjuvant combination chemotherapy will decrease recurrence rates by reduction or elimination of minimal residual disease. These targeted agents may also function in combination with one another, which may allow elimination of cytotoxic systemic chemotherapy. We further hypothesize that response data can be used to refine computational methods for drug response prediction. Aside from study of frank resistance to chemotherapies, which is also possible using our combined PDX platform, study of minimal residual disease, as well as both local and distant recurrence is also important, particularly in PDX derived from racial groups whose disease outcomes are worse than those in Caucasian women (i.e. African American and Hispanic women). Under our current PDTC, we have already identified seven PDX as recurrent after apparent complete response (CR) to combination carboplatin/docetaxel. We will apply a refined set of computationally determined predictive signatures of differential response to carboplatin and taxanes (paclitaxel going forward to match an upcoming clinical trial) to the remainder of TNBC in our combined PDX collection, as well as to TNBC PDX to be created in both PDTC projects to identify PDX most likely to show complete response to the combination. Importantly, response to either carboplatin or docetaxel correlates with response to their combination 86% of the time. Existing and new PDX will be evaluated for CR and recurrence in response to combination chemotherapy in Aim 1, with the ultimate goal of identifying a total of at least 20, but optimally 30, recurrent PDX models for testing of the ability of targeted agents computationally predicted to augment chemotherapy response in Aim 2 to reduce or prevent recurrence in Aim 3.

研究项目1：增强新辅助治疗以防止乳腺癌复发 项目摘要 基于我们强大的初步和发布的数据，我们的总体假设指导该项目 增强对新辅助组合化疗的反应将通过降低来降低复发率 或消除最小残留疾病。这些靶向剂也可能与一个合并 另一个可以消除细胞毒性全身化疗。我们进一步假设这种反应 数据可用于完善用于药物反应预测的计算方法。 除了研究对化学疗法的坦率抗性，这也可以使用我们的合并PDX平台， 研究最小残留疾病以及局部和远处复发也很重要，尤其是在 PDX来自种族群体，其疾病结果比白人妇女差的PDX（即非洲人 美国和西班牙裔妇女）。在当前的PDTC下，我们已经确定了七个PDX是经常性的 在明显的完全响应（CR）对卡铂/多西他的组合。我们将应用一组精致的 对卡铂和紫杉烷的计算确定的预测特征（紫杉醇 将在我们合并的PDX收藏中与TNBC的其余部分相匹配，以匹配即将进行的临床试验） 以及将在两个PDTC项目中创建的TNBC PDX，以识别最有可能显示完整的PDX 对组合的反应。重要的是，对卡铂或多西他赛的反应与对 他们的组合有86％的时间。现有和新的PDX将评估CR和复发的响应 在AIM 1中结合化学疗法，最终目的是确定至少20个，但最佳目的 30，重复的PDX模型，用于测试目标试剂的能力计算上预测的能力 AIM 2中的化学疗法反应减少或防止AIM 3中的复发。