University of Texas PDX Development and Trial Center

总结 德克萨斯大学PDX开发和试验中心（UTPDTC）的首要目标是优化 个性化的基于生物标志物的癌症治疗并根据分子识别有效的靶向药物 每个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- 注释的PDX，并使用PDX作为临床前药物开发和生物标志物发现的平台。的 UTPDTC研究者的主要目标是制定PDX临床前试验策略， 药剂和药物组合。这些模型将允许确定最佳治疗（单一药物 或组合），应在临床试验中在日益个性化的分子定义的子集中进行测试 肿瘤。在这个应用程序中，我们提出的项目，优先考虑临床试验的许多目标代理人集中 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，以及在其他肿瘤中具有选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）已经建立了机构范围的努力，以产生 新型PDX模型并进行临床前测试。这两家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，UTMDACC 150例，UTSW 40例），结直肠癌（CRC，n=127个模型），胰腺癌 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 迫切需要新的治疗方法。我们已经在现有的研究中描述了许多肿瘤亚型的特征。 PDX，并计划表征更多，最终目标是开发定义的药物组合。 肿瘤亚群的背景下，可以导致临床试验，这将验证实验结果。我们计划 专注于NCI-IND药物，主要由实验治疗药物临床试验网络使用。的 数百种不同组织学类型和分子特征的PDX的可用性提供了独特的机会， UTPDTC研究人员、PDXNet和ETCTN之间的协同互动。每个项目将确定 分子亚型，然后用针对推定途径的药物进行测试。相似的分子亚型谱 将在项目和组织学分类中进行识别。这提供了一个机会，以测试的活动， 靶向特定分子通路的药物，可能在几种组织学上不同的亚型中具有活性。等 泛组织学活性可以大大加速药物开发。我们建议的研究重点是有针对性的 用于治疗具有未满足的医学需求的疾病和/或分子亚型的治疗剂。的 拟议的研究与公共卫生高度相关，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.