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 项目摘要 基于我们强有力的初步和已发表的数据，我们指导该项目的总体假设是， 对新辅助联合化疗反应增强将通过减少 或消除微小残留疾病。这些靶向剂也可以与一种或多种药物组合起作用。 另一种是可以消除细胞毒性全身化疗。我们进一步假设， 数据可用于改进药物反应预测的计算方法。 除了研究对化疗的坦率耐药性，这也是可能的使用我们的组合PDX平台， 微小残留病变以及局部和远处复发的研究也很重要，特别是在 PDX来源于疾病结局比高加索女性（即非洲女性）更差的种族组 美国和西班牙裔女性）。在现时的PDTC下，我们已把7个PDX定为经常性的 在对卡铂/多西他赛组合的明显完全反应（CR）之后。我们将应用一套完善的 计算确定的对卡铂和紫杉烷（紫杉醇）的不同反应的预测特征 继续匹配即将到来的临床试验）与我们的组合PDX集合中的TNBC的剩余部分， 以及在两个PDTC项目中创建的TNBC PDX，以确定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应答与对 86%的概率都是他们的组合将评价现有和新PDX的CR和缓解复发 目标1中的联合化疗，最终目标是确定总共至少20个，但最佳 30，用于测试通过计算预测的靶向药物增强的能力的复发PDX模型 目标2中的化疗反应，以减少或预防目标3中的复发。

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.