Implantable device for high-throughput in vivo drug sensitivity testing

描述（由申请人提供）：我们的目标是开发一种快速、高通量的诊断设备技术，用于原位检测肿瘤对多种抗癌药物的局部反应。该测定与其他临床标准相结合，可以潜在地用于预测癌症患者的最佳治疗。该技术由一个小型化的可植入装置组成，该装置直接放置在肿瘤中，并含有大量的储库，每个储库都装有微剂量的单一药物或联合治疗。该装置以精确控制的方式从多个储库以生理相关浓度原位释放药物微剂量到肿瘤的局部不同区域。确定每个储库的局部药物反应，提供关于哪些药物在给定肿瘤中最有效的信息。光学分析方法被集成到该装置中，以实现每个储库的药物作用的真实的时间连续读数。该技术优于现有体外测定的优点在于其研究天然肿瘤组织中的药物作用， 从而考虑表观遗传学、肿瘤微环境、基质和免疫系统的影响。这项技术将有可能对临床前和临床癌症研究和治疗产生变革性影响。它将能够在单个生物体中并行研究数十种化合物或组合，而现在每个实验只能研究一种疗法。这将使更强大的联合治疗或合成致死率的研究，并可能在未来被用作一种工具，以确定适应性临床试验的早期反应。我们实施这项技术的战略分为三个阶段。在第一阶段，我们将为八种广泛使用的抗癌药物设计从装置储库到组织的精确释放和运输动力学。药代动力学参数将与这些药物全身治疗期间获得的参数相匹配。然后，我们将开发通过组织学方法提取和分析肿瘤组织相关区域的方法，以评估每个储库的药物反应。最后，我们将把小型化的光学技术整合到植入式装置中，以便真实的实时测量肿瘤细胞如何受到局部药物暴露的影响。我们将在一项研究中证明该设备技术的影响，该研究在两种描述良好的肿瘤模型中测量了多种治疗的差异药物反应。该技术的植入建立在我们实验室通过植入式设备精确控制药物量的广泛经验基础上。与我们的贡献者罗伯特兰格，泰勒杰克和布雷特布玛，我们已经汇集了专业知识，使每个项目的具体目标的实现，这将付诸实践，一个强大的， 癌症的变革性新技术。

DESCRIPTION (provided by applicant): Our aim is to develop a rapid, high-throughput diagnostic device technology that assays a tumor in situ for its local response to a wide range of anti-cancer agents. This assay, combined with other clinical criteria, can potentially serve to predict the optimal therapy for a cancer patient. This technology is comprised of a miniaturized implantable device that is placed directly into the tumor and contains a large number of reservoirs, each loaded with a microdose of a single agent or combination therapy. The device releases drug microdoses in situ in a precisely controlled manner from multiple reservoirs in physiologically relevant concentrations into locally distinct regions of tumor. The local drug response is determined for each reservoir, providing information on which drugs are most effective in a given tumor. Optical analysis methods are integrated into the device to achieve real time continuous readouts of drug action for each reservoir. The advantage of this technology over existing in vitro assays is that it studies drug action in the native tumor tissue, thus taking into account the effects of epigenetics, tumor microenvironment, stroma and immune system. This technology will potentially have a transformative effect on preclinical and clinical cancer research and treatment. It will enable the study of dozens of compounds or combinations in parallel in a single organism, where now only a single therapy can be studied per experiment. This will enable more powerful studies of combination therapies or synthetic lethality, and may in the future be used as a tool to identify early response in adaptive clinical trials. Our strategy for implementing this technology is divided into three phases. In the first phase, we will engineer precise release and transport kinetics from device reservoirs into tissue for eight widely used anticancer drugs. The pharmacokinetic parameters will be matched to those achieved during systemic treatments with these drugs. We will then develop methods to extract and analyze relevant regions of tumor tissue by histological methods to assess drug response for each reservoir. Lastly, we will integrate miniaturized optical technologies into the implantable device in order to measure in real time how tumor cells are affected by local drug exposure. We will demonstrate the impact of the device technology in a study that measures differential drug response of mukltiple therapies in two well-described tumor models. The implantation of this technology builds on the extensive experience in our laboratory in the delivery of precisely controlled amounts of drugs via implantable devices. With our contributors Robert Langer, Tyler Jacks and Brett Bouma, we have assembled the expertise that enables the fulfillment of each of the project's specific aims, which will put into practice a powerful and transformative new technology in cancer.