权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Rational Approaches to Melanoma Therapy

黑色素瘤治疗的合理方法

基本信息

批准号：
10733192
负责人：
Michael Davies
金额：
$ 63.55万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
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/10733192
关键词：
Acral Lentiginous Malignant Melanoma BRAF gene Back Behavior Bioinformatics Biologic Characteristic Biological Biology Cataloging Clinical Clinical Trials Collaborations Collection Combined Modality Therapy Communities Cutaneous Melanoma DNA Integration DNA sequencing Data Development Disease Drug Combinations Drug resistance Evaluation Exhibits FDA approved Fostering Funding Genetic Genetic Drift Genetic Heterogeneity Goals Grant Heterogeneity Histologic Human Immunotherapy Incidence Individual Institution Investigational Drugs Knowledge Laboratories MEKs Malignant Neoplasms Maps Modeling Molecular Molecular Profiling Mutation Organoids Paper Patient Selection Patient-Focused Outcomes Patients Pharmaceutical Preparations Phase Phenotype Pilot Projects Pre-Clinical Model Precision therapeutics Property Protein Array Proteins Publishing RNA Recommendation Research Research Personnel Research Project Grants Resistance Resources Sampling Specimen Subgroup Therapeutic Therapeutic Studies Translating University of Texas M D Anderson Cancer Center Uveal Melanoma Work advanced disease bench to bedside biomarker identification combat combinatorial design early phase clinical trial efficacious treatment exome sequencing improved improved outcome inhibitor innovation melanoma mucosal melanoma multidisciplinary mutant novel novel therapeutic intervention novel therapeutics patient derived xenograft model patient subsets pre-clinical preclinical study preclinical trial prevent programs protein expression repository research clinical testing response success synergism targeted sequencing targeted treatment technology development transcriptome sequencing treatment response tumor

项目摘要

Project Summary – Overall The overarching goal of this Patient Derived Xenograft (PDX) Development and Trial Center (T-PDTC) is to develop functional precision combination therapies that can be translated into clinical trials to overcome drug resistance and produce to long-term responses improving the outcomes of melanoma patients. The melanoma treatment landscape has radically improved in the past decade due to availability of new immune- and targeted- therapies available. Targeted therapies using BRAF and MEK inhibitors have been approved for patients with BRAFV600E/K mutations, which are present in ~50% of cutaneous melanomas. These treatments elicit clinical responses in ~80% of BRAFV600 mutant patients. However, most patients eventually progress. Additionally, there are no effective targeted therapies for patients whose tumors harbor wild-type BRAF. Thus, there is an urgent unmet clinical need to develop efficacious treatments to prevent or overcome resistance to current FDA- approved therapies. To facilitate the development of new therapeutic strategies that can be translated into clinical trials, we have developed a broad collection of PDX models that reflects the clinical, histological, and genetic heterogeneity of melanoma. Our collection of >500 PDX models represents one of the largest collections for any human malignancy. Our initial studies have demonstrated that our PDX collection recapitulates the molecular heterogeneity observed in patients. This collection also includes a subset of PDX established from patients with intrinsic and acquired resistance to targeted- and immune-therapies and rare melanoma subtypes. These efforts have generated a robust pre-clinical resource to develop, refine, and prioritize new functional precision combinatorial therapies for melanoma patients. This T-PDTC constitutes a multi-disciplinary and multi- institutional Program focused on the use and continued expansion of our melanoma PDX collection and organoids to identify new therapeutic combination approaches that will fill important clinical gaps. The Program consists of two research projects and three Cores from a team that has worked extremely well together over the last five years, publishing high-impact collaborative papers. The Research Projects are designed to develop functional precision combination therapies for the most challenging types of melanomas: those that are resistant to current therapies and tumors that lack BRAF-mutations (BRAFWT). We will map the molecular landscape of our melanoma PDXs and organoids by integrating DNA, RNA, and protein data to nominate combination therapies matching their molecular profile. We will develop and implement mechanism-based preclinical trials of drug combinations in our large set of molecularly characterized PDXs. To do this, we will focus on NCI- Investigational New Drug (IND) agents to advance melanoma precision therapy, while offsetting drug resistance and producing durable responses. We expect to gain new mechanistic knowledge about the biology of drug resistant melanoma that will lead to improved and durable precision therapies. We expect to identify biomarkers to select tumors for specific treatments and provide data-driven recommendations for early phase clinical trials.

项目摘要--总体该患者衍生异种移植(PDX)开发和试验中心(T-PDTC)的首要目标是开发可转化为临床试验的功能精密联合疗法，以克服药物对长期反应产生抵抗力，改善黑色素瘤患者的预后。黑色素瘤在过去的十年里，由于有了新的免疫和靶向治疗，治疗环境得到了根本的改善可用的治疗方法。使用BRAF和MEK抑制剂的靶向治疗已被批准用于 BRAFV600E/K突变，存在于约50%的皮肤黑色素瘤中。这些治疗引起了临床约80%的BRAFV600突变患者有应答。然而，大多数患者最终都会进步。此外，还有对于肿瘤中含有野生型BRAF的患者，目前还没有有效的靶向治疗方法。因此，有一个紧急的尚未满足的临床需要开发有效的治疗方法，以防止或克服对当前FDA的耐药性- 批准的治疗方法。促进可转化为临床的新治疗策略的开发通过试验，我们开发了广泛的PDX模型集合，反映了临床、组织学和遗传学黑色素瘤的异质性。我们的&gt；500 PDX型号系列是最大的系列之一人类的恶行。我们的初步研究表明，我们的PDX集合概括了分子在患者中观察到异质性。该集合还包括从患有以下疾病的患者建立的PDX子集对靶向治疗和免疫治疗以及罕见的黑色素瘤亚型的内在和获得性抵抗。这些努力已生成强大的临床前资源，用于开发、改进和确定新的功能精确度黑色素瘤患者的联合治疗。这个T-PDTC构成了一个多学科、多领域的机构计划侧重于使用和继续扩大我们的黑色素瘤PDX集合和有机化合物，以确定新的治疗组合方法，将填补重要的临床空白。该计划由两个研究项目和来自一个团队的三个核心组成，该团队在在过去的五年里，发表了具有高度影响力的合作论文。研究项目旨在开发功能性精密联合疗法治疗最具挑战性的黑色素瘤类型：耐药黑色素瘤到目前的治疗方法和缺乏BRAF突变的肿瘤(BRAFWT)。我们将绘制分子地貌图我们的黑色素瘤PDX和有机类化合物通过整合DNA、RNA和蛋白质数据来提名组合与它们的分子特征相匹配的疗法。我们将开发和实施基于机制的临床前试验在我们大量的分子表征的PDX中的药物组合。为此，我们将重点关注NCI- 用于推进黑色素瘤精确治疗的研究新药(IND)，同时抵消耐药性并产生持久的反应。我们期望获得有关药物生物学的新的机械知识。抵抗黑色素瘤，将导致改进和持久的精确治疗。我们希望确定生物标记物选择肿瘤进行特定治疗，并为早期临床试验提供数据驱动的建议。