University of Texas PDX Development and Trial Center

摘要 我们德克萨斯大学PDX开发和试验中心(UTPDTC)的首要目标是优化 基于生物标记物的肿瘤个体化治疗和基于分子的有效靶向药物识别 每种肿瘤的特征。我们的短期目标是建立一个临床和分子生物库- 注释PDX，并将PDX用作临床前药物开发和生物标记物发现的平台。这个 UTPDTC研究人员的主要目标将是开发用于单一药物临床前测试的PDX试验策略 毒剂和药物组合。这些模型将允许确定最佳治疗方案(单一药物 或组合)，应在临床试验中以日益个性化的、分子定义的子集进行测试 肿瘤的症状。在本申请中，我们提出了优先考虑多个目标药物临床测试的项目 关于非小细胞肺癌(NSCLC)、结直肠癌(CRC)、胰腺癌(PDAC)和三阴性 乳腺癌(TNBC)肿瘤亚型，以及其他肿瘤亚型中有特定基因组改变的患者 组织学。在过去的9年里，德克萨斯大学MD安德森分校(UTMDACC)和德克萨斯大学 德克萨斯大学西南医学中心(UTSW)已在整个机构范围内努力创造 新的PDX模型并进行临床前测试。这两个机构累计拥有数百个PDX 不同肿瘤类型的模型，包括非小细胞肺癌(NSCLC， N=190，其中UTMDACC 150例，UTSW 40例)，结直肠癌(CRC，n=127模型) 腺癌(PDAC，n=145个模型)和三阴性乳腺癌(TNBC，n=44个模型)；四种疾病 在那里迫切需要新的治疗方法。我们已经表征了我们现有的许多肿瘤亚型 并计划表征更多的药物，最终目标是开发定义的药物组合 在可能导致临床试验的背景下，肿瘤亚群将验证实验结果。我们计划 重点关注实验治疗临床试验网络主要使用的NCI-IND药物。这个 数百种不同组织类型和分子图谱的PDX的问世提供了一个独特的机会 UTPDTC调查员、PDXNet和ETCTN之间的协同互动。每个项目都将确定 分子亚型，然后用针对可能途径的药物进行测试。相似的分子亚型图谱 将在项目和组织分类中确定。这提供了一个测试活动的机会 针对特定分子通路的药物，这些分子通路可能在几个组织学上不同的亚型中活跃。是这样的 泛组织学活动可以极大地促进药物的开发。我们建议的研究重点是有针对性的 用于治疗尚未满足医学需求的疾病和/或分子亚型的治疗剂。这个 拟议的研究与公共健康高度相关，因为它们的成功将导致有效的精确治疗 癌症，目前的治疗方法无效。

SUMMARY Our overarching goal for the University Texas PDX Development and Trial Center (UTPDTC) is to optimize personalized biomarker-based cancer therapy and identify effective targeted drugs based on the molecular characteristics of each tumor. Our short-term goals are to establish a biobank of clinically, and molecularly- annotated PDXs and to use PDXs as a platform for preclinical drug development and biomarker discovery. The primary goal for UTPDTC investigators will be to develop PDX trial strategies for preclinical testing of single agents and drug combinations. These models will allow the determination of the optimal treatments (single drugs or combinations) that should be tested in clinical trials in increasingly individualized, molecularly defined subsets of tumors. In this application we propose projects to prioritize the clinical testing of many targeted agents focused on non-small cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic cancer (PDAC), and triple negative breast cancer (TNBC) tumor subtypes, as well as patients with selected genomic alterations across other histologies. Over the past 9 years, both University of Texas MD Anderson (UTMDACC) and The University of University of Texas Southwestern Medical Center (UTSW) have established institution-wide efforts to generate novel PDX models and perform preclinical testing. Cumulatively the two institutions have hundreds of PDX models of different tumor types, including clinically-annotated models in non-small cell lung cancer (NSCLC, n=190 with 150 at UTMDACC and 40 at UTSW), colorectal cancer (CRC, n=127 models) pancreatic adenocarcinoma (PDAC, n=145 models), and triple negative breast cancer (TNBC, n=44 models); four diseases where there is an urgent need for novel therapeutics. We have characterized many tumor subtypes in our existing PDXs and plan to characterize many more with the ultimate goal of developing drug combinations in defined tumor subsets in a context that can lead to clinical trials which will validate the experimental results. We plan to focus on NCI-IND agents that are primarily used by the Experimental Therapeutics Clinical Trials Network. The availability of hundreds of PDXs of diverse histologic types and molecular profiles provides a unique opportunity for synergistic interactions among the UTPDTC investigators, PDXNet, and ETCTN. Each Project will identify molecular subtypes and then test with drugs targeted to putative pathways. Similar molecular subtype profiles will be identified across projects and histologic classifications. This provides an opportunity to test the activity of drugs targeting specific molecular pathways that may be active in several histologically distinct subtypes. Such pan-histologic activity could greatly accelerate drug development. Our proposed studies focus on targeted therapeutic agents for treatment of diseases and/or molecular subtypes that have unmet medical needs. The proposed studies are highly relevant to public health, as their success will lead to effective precision therapy for cancers, for which current therapies are ineffective.