(402f) Microfluidic Cancer Cell Array Based Parallel Screening of Combination Chemotherapeutic Drug Treatments for Prostate Cancer

Prostate cancer is the most commonly diagnosed cancer in men and results in the second largest number of fatalities. Tumor necrosis factor Related Apoptosis Inducing Ligand (TRAIL) has been shown to selectively induce apoptosis in malignant cells while having reduced toxicity in healthy cells. The effects of TRAIL often are limited by cellular resistance but such resistance can be overcome with treatments that sensitize the cell to the effects of TRAIL. Parallel screening of FDA-approved cancer drugs was carried out in order to facilitate the discovery of lead candidates that acted synergistically with TRAIL in order to induce apoptosis in prostate cancer cells. Drugs were pre-screened in order to eliminate drugs with significant toxicity from the combination treatment screen. Toxic drugs were screened at lower concentrations subsequently. Combination drug/TRAIL treatments were carried out to identify chemotherapeutic drugs that sensitized cancer cells to TRAIL. Lead drug candidates identified in the screen were further employed for lead optimization in traditional well-plates and also in novel microfluidic cancer cell arrays that facilitated orthogonal treatment of the two components of the combination treatment (drug and TRAIL). Lead optimization involved investigation of the combination treatment over an expanded dose range in different cancer cell lines including those of the prostate, pancreas, and breast. Our investigations indicated that the plate-based and microfluidic cancer cell array-based lead identification and optimization results are analogous. This indicates that future drug screens can be carried out faster and more efficiently using microfluidic devices. The investigations were able to identify currently known sensitizers in addition to identifying novel leads whose TRAIL-sensitization properties were previously unknown.