Effect of Extended Exposure Topotecan on Drug Resistance Using a Novel 3D Spheroidal Model of Castrate-Resistant Prostate Cancer

Abstract

Cancer consistently commands the highest number of therapeutic drug approvals each year, however, this has yet to yield significant clinical benefits for metastatic disease. Instead, most drugs are likely to increase survival a few months before quickly succumbing to resistance. A major reason for these poor results is the absence of resistance as an early drug screening criterion, which is due in part to lacking in vitro models capable of assessing long-term potency. In this project, we developed a novel 3D spheroidal model system of castrate-resistant prostate cancer to assess the long-term potency of maximum tolerable dosed (MTD) topotecan, extended exposure (EE) topotecan, and docetaxel to assess whether this model system could accurately predict previous clinical results and whether alternative treatment schedules could impact drug resistance. We found that MTD topotecan led to a 40-fold reduction in potency over a 3-month study duration, while EE topotecan and docetaxel maintained similar potency throughout the study. These results suggest that MTD topotecan likely has a low barrier to drug resistance and is likely to generate rapid resistance clinically, while EE topotecan and docetaxel likely have higher barriers to drug resistance. Using transcriptomic approaches, we found that MTD treated cells displayed increased heterogeneity and rapidly underwent epithelial-mesenchymal transition, leading to increased production of efflux pumps and altered production of topoisomerases. Interestingly, EE treated cells were less heterogeneous and did not undergo these changes. Importantly, docetaxel is the gold standard for prostate cancer and MTD topotecan failed clinically. EE topotecan was successful in previous in vivo trials but has not been assessed clinically. Thus, our model correctly predicted poor clinical results from MTD topotecan and excellent clinical results from docetaxel. It also supports the need for further evaluation of EE topotecan for use in metastatic castrate-resistant prostate cancer. Overall, this project proposes that stable long-term potency is an excellent predictor of clinical outcomes and should be implemented early in the drug screening process and suggests that treatment scheduling can have a profound effect on the underlying cancer cell population and impacts clinical efficacy more than previously expected.