High-throughput screening as a tool to identify novel therapies for treatment of bladder cancer: a proof of principle study

Authors

• R Railkar
• K Lewi
• A Nair
• SJ Brancato
• I Hsu
• Q Li
• X Zhang
• R Guha
• A Apolo
• D Theodorescu
• C Thomas
• M Ferrer
• PK Agarwal

Abstract

Introduction and Objectives: Cancer of the urinary bladder (CaB) is the fourth most common cancer among men and the most expensive malignancy to treat from diagnosis to death. Since the introduction of intravesical BCG immunotherapy almost two decades ago, there have been no new therapies for CaB. Similarly, systemic chemotherapy imparts a slight survival advantage but has not been widely adopted. As a result, the mortality rate for CaB has remained stagnant. This suggests an urgent need for newer intravesical and systemic therapies for CaB. Methods: We performed high-throughput screening (HTS) of several bladder cancer cell lines against 1,912 oncology focused drugs to determine the potency and activity of the compounds in a dose dependent manner. Selected pan-active drugs were validated in an expanded panel of cell lines. Some drugs with potential systemic toxicity were further explored for possible intravesical use. Results: In the first round of screening, an epithelial (RT4) and a mesenchymal (UMUC3) cell line were tested. 225 compounds including Topoisomerase II inhibitors and proteasome inhibitors were active in both cell lines. A second round of screening was carried out with 7 CaB cell lines (including RT4 and UMUC3) which demonstrated 95 pan-active drugs. The top 50 compounds were further analyzed for different physical properties. This identified mitomycin C and 8 additional compounds that were further tested for potential intravesical use. Conclusions: HTS is an efficient way to elicit novel targets and therapies for cancer. We identified novel candidates for intravesical therapy and are currently confirming activity.

Scientific Focus Area: Cancer Biology

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