The rapid drug sensitivity assessment from a panel of drugs within the tumor environment can realize the potential of individualized medicine in oncology. Our current work includes numerous collaborations that illustrate how the technology will be used in the future. We identified three areas i) in vivo use in a clinical setting, ii) ex vivo use in a clinical setting, iii) preclinical use to relate molecular phenotype of cancer to drug response. The focus of this R33 proposal is to address the major feasibility gaps that we identified for these uses. The gaps are identified in the following aims:
Aim 1 : Increasing the yield of sample collection in a surgical setting. Clinical users achieved very low successful sample recovery in our early experiments compared with our trained technical staff in a preclinical environment.
This aim will develop technology to achieve high sample yield with comparatively less skilled operators.
Aim 2 : Increasing the rate at which individual devices can be loaded with many chemotherapeutic agents. Many important preclinical experiments require numbers of devices that exceed that which that can be prepared using our current method. Reservoir filling currently takes between 30 and 45 minutes for each device.
This aim will reduce the time required to of the order of one minute with higher reliability.
Aim 3 : Decreasing the time required to analyze the large number of histology slides that result from any one experiment. Microdosing using our device dramatically increases the number of histological sections that must be interpreted. Secondly, unprecedented spatial precision and accuracy are required to collocate the section with individual reservoirs on the device.
This aim will ensure the spatial accuracy and not sacrifice the rate at which samples can be processed. Our innovations center on addressing each of these gaps. Specifically, we have designed and prototyped and specialized biopsy instrument that will retrieve the device and surrounding tissue while being operated by a surgeon. Secondly, we have designed a dispensing device that can fill devices with 18 different drugs at high rates with the required accuracy and is capable of producing dozens such devices in a lot. Finally, we have prototyped a system to that can make precision specimens for histology and the resulting slides can be analyzed at high rates.
This project seeks to develop and validate a technology platform for high-throughput in situ drug sensitivity testing to significantly increase its preclinical and translational impact. The proposed study seeks to develop a method to enable selective retrieval of microdevices, increase capacity and consistency of device preparation, and develop an automated method for sample analysis and quantification. This approach will enable broad applicability of the platform for preclinical and clinical users.
|Arai, Seiji; Jonas, Oliver; Whitman, Matthew A et al. (2018) Tyrosine Kinase Inhibitors Increase MCL1 Degradation and in Combination with BCLXL/BCL2 Inhibitors Drive Prostate Cancer Apoptosis. Clin Cancer Res 24:5458-5470|