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The 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.
PUBLIC HEALTH RELEVANCE: This project seeks to develop an implantable device technology that is capable of screening a large number of cancer drugs simultaneously, in vivo, by delivering precisely controlled microdoses of each drug directly into a spatially confined region of the tumor, and measuring the anti-tumor effect of each of these drugs. The information gained from this assay is significantly more impactful than currently available technologies, because it assays the tumor in its native environment, thus taking into account the effects of the microenvironment, stroma and immune system, and can test for up to 30 compounds in a single assay. Our technology presents a new paradigm for identifying which drug therapy, out of the many available choices, a given patient may respond to optimally and for greatly increasing efficiency in how novel agents or combinations are studied preclinically.