Towards Personalized Cancer Therapy: Microfluidic Approaches for Drug Screening

Abstract

The ability to predict a patient's response to chemotherapy is a major challenge in oncology. Despite the years of research and development with countless investments, clinical trials in oncology still experience high failure rates, resulting in patients suffering from severe side effects with little benefits. Therefore, there is a critical need to tailor chemotherapies to individual patients. Personalized approaches could lower treatment toxicity, improve patients' quality of life, and ultimately reduce mortality. In order to pursue personalized chemotherapy, advanced technologies and tools are urgently needed. One of the major challenges in oncology is tumor heterogeneity from individual patients. To demonstrate the potential for quantifying tumor heterogeneity, we developed a simple approach by using a user-friendly microwell array device to allow for tracking key cell behaviors from large numbers of single cells. We demonstrated the utility of these arrays by quantifying the proliferation and senescence of isogenic cells which expressed or had been depleted of the human Werner syndrome protein. Our results allowed us to reveal and quantify cell-to-cell heterogeneity in proliferation and senescence during clonal growth. Current drug testing assays are either based on cell lines, which enable high-throughput screening but lack the physiological relevance of the tumor microenvironment, or xenograft models which are time- and resource-intensive and may lack important tumor components. As a result, drug candidates that emerge from drug screening cannot accurately predict how drugs act in patients to select the best possible treatment. Therefore, we propose to use intact tissue slices and biopsies which preserve the tumor microenvironment for drug screening. To allow for testing large numbers of compounds on intact tissues, we developed a microfluidic device that integrates live tissue slice cultures with an intuitive multi-well platform that allows for exposing the slices to multiple compounds at once or in sequence. In order to demonstrate our microfluidic platform, we performed the response of live mouse brain slices to a range of drug doses in parallel. Drug response was measured by imaging of markers for cell apoptosis and for cell death and was quantified by the fluorescence intensity and cell counts from epifluorescence and confocal microscopy images, respectively. We further extended the application by producing tumor slices and biopsies from mouse xenografts to demonstrate selevtive drug testing on mouse xenograft slices. Our drug testing results demonstrated the feasibility to allow for identifying the subset of therapies of greatest potential value to individual patients, on a timescale rapid enough to guide therapeutic decision-making.