Functional precision approaches to overcome intrinsic and acquired drug resistance in melanoma

克服黑色素瘤内在和获得性耐药性的功能精确方法

• 批准号: 10733196
• 负责人: Jessie Villanueva
• 金额: $ 25.58万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733196
• 关键词: Address; BRAF gene; BRD2 gene; Biological; Bromodomains and extra-terminal domain inhibitor; Cancer Therapy Evaluation Program; Cell Cycle; Cells; Chemoresistance; Child; Clinical; Collection; Combined Modality Therapy; Complex; Critical Pathways; Data; Development; Disease; Dose; Drug Combinations; Drug Tolerance; Drug resistance; Failure; Gene Expression Profile; Genetic Transcription; Genomics; Goals; Growth; Heterogeneity; Immunotherapy; KDM5B gene; MAP Kinase Gene; MEKs; Malignant Neoplasms; Metabolic; Metastatic Melanoma; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Molecular; Molecular Profiling; Monitor; Mutation; Neoplasm Metastasis; Organoids; PD-1 inhibitors; Pathway interactions; Patient-Focused Outcomes; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phosphotransferases; Precision therapeutics; Property; Proteins; Proteomics; Recurrent tumor; Refractory; Relapse; Research Project Grants; Resistance; Safety; Signal Transduction; Somatic Mutation; Testing; Therapeutic; Toxic effect; Translating; Treatment Protocols; Treatment outcome; Validation; Work; acquired drug resistance; anti-PD-1; bench to bedside; beta catenin; biomarker identification; cancer therapy; clinical development; clinical predictors; clinical subtypes; clinical translation; design; digital; drug testing; exome sequencing; improved; improved outcome; individualized medicine; inhibitor; melanoma; mutant; neoplastic cell; novel; novel strategies; patient derived xenograft model; personalized approach; posters; pre-clinical; preclinical study; prevent; research clinical testing; response; response biomarker; targeted agent; targeted treatment; therapy design; transcriptome sequencing; transcriptomics; treatment optimization; treatment response; tumor; tumor heterogeneity

Project Summary – Project 1 Although significant progress has been made treating melanoma, less than 30% of patients achieve long-term responses and almost 70% of patients are resistant to any approved therapies including immunotherapies and targeted therapies. Therefore, novel strategies to overcome intrinsic and acquired drug resistance are sorely needed. This Patient Derived Xenograft (PDX) Development and Trial Center (T-PDTC) research project will capitalize on our extensive collection of >500 clinically annotated and molecularly characterized PDXs to develop functional precision therapies to offset melanoma drug resistance. Our working hypothesis is that the tumor’s genomic, molecular and drug response profiles in organoids and PDXs can be leveraged to develop clinically translatable precision therapies. We also posit that our pre-clinical pipeline will identify markers to select tumors that are most likely to respond to a given treatment, offsetting drug resistance and achieving long-term responses, with no overt toxicity. We expect that our pre-clinical studies will help prioritize the clinical testing of targeted agents for the treatment of melanoma. Our melanoma PDX collection has been extensively characterized for growth properties, metastasis formation, somatic mutations through targeted and whole exome sequencing, RNA expression and expression of ~500 proteins related to signal transduction. Our models are superbly suited to investigate combination therapies to overcome or prevent drug resistance as they represent the heterogeneity of melanoma. To do this, two Specific Aims are proposed: Aim 1, will test the hypothesis that drug resistant melanomas harboring a transcriptional signature termed ‘innate anti–PD-1 resistance signature’ (IPRES+), which is associated with resistance to anti-PD1 and MAPK inhibitors, will respond to the combination of BET and MEK inhibitors. We will optimize this treatment regimen and further define markers of response and resistance. For IPRESNeg tumors, we will integrate genomic, transcriptional and proteomic analyses to pair tumors with drugs matching their molecular profile; this will allow for establishing optimal combination and dosing strategies. In aim 2, we will conduct temporal and spatial transcriptomic and proteomic analysis to identify and profile drug tolerant subpopulations. Our goal is to monitor treatment response and intervene with combinations aimed at killing both the bulk of the tumor and rare drug tolerant/persister subpopulations preventing the emergence of resistance. We anticipate that our studies will provide critical information needed to translate effective and long-lasting precision therapies from the bench to bedside and improve the outcomes of melanoma patients.

项目摘要 - 项目1 尽管治疗黑色素瘤已经取得了重大进展，但不到30％的患者长期实现 反应和近70％的患者对任何批准的疗法都有抗性，包括免疫疗法和目标 疗法。因此，非常需要克服内在和获得的耐药性的新型策略。 该患者得出的异种移植（PDX）开发和试验中心（T-PDTC）研究项目将资本化 在我们广泛的> 500个临床注释和分子表征的PDX中，以发展功能 精确疗法可抵消黑色素瘤耐药性。我们的工作假设是肿瘤的基因组， 可以利用类器官和PDX中的分子和药物反应谱，以在临床上发展 可翻译精度疗法。我们还认为，我们的临床前管道将识别标记以选择肿瘤 最有可能应对给定的治疗，抵消耐药性和达到长期反应，没有 明显的毒性。我们预计我们的临床前研究将有助于优先考虑目标剂的临床测试 黑色素瘤的治疗。 我们的黑色素瘤PDX收集已广泛为生长特性，转移的特征 形成，通过靶向和整个表达测序的体细胞突变，RNA表达和表达 与信号转导有关的约500种蛋白质。我们的模型非常适合研究组合 在代表黑色素瘤的异质性时，可以克服或预防耐药性的疗法。为此， 提出了两个具体目标：AIM 1，将检验以下假设。 转录签名称为“先天抗PD-1电阻签名”（IPRES+），这与电阻有关 对于抗PD1和MAPK抑制剂，将对BET和MEK抑制剂的组合做出反应。我们将优化这个 治疗方案并进一步定义了反应和抗性的标志物。对于Ipresneg肿瘤，我们将整合 基因组，转录和蛋白质组学分析将肿瘤与与其分子谱相匹配的药物配对；这 将允许建立最佳组合和剂量策略。在AIM 2中，我们将进行临时和 空间转录组和蛋白质组学分析，以识别和介绍药物耐受亚群。我们的目标是监视 旨在杀死大部分肿瘤和稀有药物的治疗反应和干预 耐受性/持久亚群，以防止抗药性出现。我们预计我们的研究将提供 将有效且持久的精度疗法从长凳转换为床边所需的关键信息 改善黑色素瘤患者的结局。