Relapse from tumor dormancy after prolonged remission initiates metastatic cancer spread and leads to patient mortality. Tumor dormancy represents a specialized phenotype of cancer, characterized by low division rates and metabolism, and high resistance to conventional anticancer drugs that ablate only the dividing cells. Elimination of dormant cancer will not only completely remove the disease, but also will prevent future relapse and metastases.<br/>There is a need to develop high throughput in-vitro systems (HTS) that can capture important tumor phenotypes such as complete dormancy and relapse in a 96 well plate format. High-throughput systems (HTS) can allow the discovery of phenotype-specific drugs and their combinations. However, there is a clear dearth of such in-vitro platform technologies. We have exclusively developed a first of its kind, an aminoglycoside-antibiotic based hydrogel (Amikagel) system that uniquely captures tumor dormancy, relapse and micrometastases in a high-throughput in-vitro platform. Not only did dormant cells exhibit low rates of division, but also very high resistance to conventional chemotherapy such as docetaxel. While 2D dividing cells showed LC50 of approximately 9 uM, 100 uM of the drug caused only 10% death in the dormant systems.<br/>Utilizing our high-throughput dormancy platform, we screened for drugs that can ablate the dormant phenotype. We observed a significant increase in per cell protein content in the dormant cells compared to the dividing cells. Screening drugs that target the protein folding pathway, we identified that drugs inducing chronic ER stress can synergistically work towards dormant cancer ablation. We found that ER stress inducing drugs along with proteasome inhibitors can synergistically induce cell death. The CI of the drug combination was calculated to be 0.1 +/- 0.025 indicating strong synergy between the drugs. In addition, we also showed that drug induced dormant apoptotic cell death can be significantly accelerated by cytoplasmic divalent cation modulation.<br/>Regarding relapse, we show that amikagel chemo-mechanical engineering induces relapse from dormancy and they invade the hydrogel and form micrometastases like colonies. Utilizing the platform, we then identified specific drugs that can inhibit relapse and metastases formation from dormancy. We believe this is the first such platform for phenotype specific drug discovery and first report of dormant cell death acceleration by cation modulation.

Novel aminoglycoside-hydrogel based in-vitro models of tumor dormancy, relapse and metastases: Phenotype specific drug screening, discovery and delivery

251st National Meeting (2016)

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