Project 03 - Understanding the biology of non-responders to inform treatment selection

项目 03 - 了解无反应者的生物学，为治疗选择提供信息

• 批准号: 10249156
• 负责人: Laura J Van't Veer
• 金额: $ 15.94万
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249156
• 关键词: Aftercare; Alternative Therapies; Biological; Biological Markers; Biology; Biopsy; Carboplatin; Characteristics; Clinical; Clinical Trials; DNA; DNA Repair; Data; Development; Disease; Disease Pathway; Early identification; Early treatment; Epidermal Growth Factor Receptor; Gene Expression; Goals; Immune; In complete remission; Individual; Magnetic Resonance Imaging; Mammary Neoplasms; Messenger RNA; Molecular; Molecular Profiling; Neoadjuvant Therapy; Operative Surgical Procedures; Outcome; Output; Pathologic; Pathway interactions; Patients; Phase; Phosphoproteins; Portraits; Prognosis; Protein Array; Proteins; Proteomics; Proto-Oncogene Proteins c-akt; Publishing; Qualifying; Recurrence; Residual Tumors; Resistance; Selection for Treatments; Sequential Treatment; Signal Transduction; Testing; Therapeutic; Time; Toxic effect; Tumor Biology; Woman; Work; arm; base; chemotherapy; clinical decision-making; comparative genomics; design; druggable target; effective therapy; evidence based guidelines; high risk; immune checkpoint; improved; improved outcome; inhibitor/antagonist; knowledge base; laser capture microdissection; malignant breast neoplasm; membrane-associated placental tissue protein 1; molecular marker; next generation sequencing; novel; patient response; predictive marker; predictive modeling; programs; receptor; resistance mechanism; response; targeted agent; targeted treatment; therapy development; therapy resistant; tool; transcriptomics; tumor

SUMMARY – PROJECT 3 By delaying surgery until after neoadjuvant chemotherapy (NAC), it is possible to assess the impact of therapy on breast tumors in real time. Women with aggressive disease who respond well to NAC have a better prognosis than women who fail to respond. There needs to be a way to identify high risk non-responders early in treatment and determine what alternative or additional treatments may be of benefit to them. Prior molecular profiling studies have identified markers that are predictive of chemotherapy response or outcome using pre- treatment biopsies. However, treatment induces significant changes in tumor biology; and some of these changes are associated with response to therapy. Thus, we hypothesize that interrogating the dynamic molecular changes over the course of treatment will enable us to better characterize resistance mechanisms and improve our ability to predict non-response (or sensitivity). In this Project, we will use (or generate as needed) next generation sequencing (mRNA and DNA) and reverse phase protein arrays (protein/phospho- protein) to perform comprehensive molecular characterization of serial biopsies from I-SPY 2 patients treated with graduated experimental agents. In Aim 1 we will evaluate druggable/actionable pathways in residual disease of non-responding patients undergoing treatment with standard or targeted agents/combinations. In Aim 2 we will incorporate early treatment-induced changes to improve predictive models of treatment resistance/sensitivity. In Aim 3 we will leverage this data compendium to develop a dynamic portrait of how key molecular pathways evolve as patients move from pre-treatment through to surgery in the context of treatment and receptor subtype. Our goal is to determine whether the residual disease characteristics identified in Aim 1 are evident at the early treatment or pre-treatment time points, and to assess the stability of early predictive/resistance signals. These efforts will inform both mid-treatment assessments of patient response to therapy and the development of a molecularly rationalized strategy for switching predicted non-responding patients to more effective treatment, developed as part of other Projects within the overall Program Project.

摘要 – 项目 3 通过将手术推迟到新辅助化疗 (NAC) 之后，可以评估治疗的影响 对 NAC 反应良好的患有侵袭性疾病的女性有更好的效果。 需要有一种方法可以及早识别高风险无反应者。 并确定哪些替代或额外治疗可能对他们有益。 分析研究已经确定了可预测化疗反应或结果的标记物 然而，治疗会引起肿瘤生物学的显着变化； 变化与治疗反应相关，因此，我们认为这是对动态的询问。 治疗过程中的分子变化将使我们能够更好地表征耐药机制 并提高我们预测无响应（或敏感性）的能力。在这个项目中，我们将使用（或生成）。 需要）下一代测序（mRNA 和 DNA）和反相蛋白阵列（蛋白/磷酸化） 蛋白）对 I-SPY 2 治疗患者的连续活检进行全面的分子表征 在目标 1 中，我们将评估残留的可药物/可操作途径。 接受标准或靶向药物/组合治疗的无反应患者的疾病。 目标 2 我们将纳入早期治疗引起的变化，以改进治疗的预测模型 在目标 3 中，我们将利用此数据概要来动态描述关键性。 随着患者从治疗前到治疗过程中的手术，分子途径不断演变 我们的目标是确定目标 1 中确定的残留疾病特征是否存在。 在早期治疗或治疗前时间点很明显，并评估早期治疗的稳定性 这些努力将为患者反应的治疗中期评估提供信息。 治疗和开发分子合理化策略来改变预测的无反应 患者获得更有效的治疗，该治疗是作为整个计划项目内其他项目的一部分而开发的。