In Vitro Modeling of the Resistance to the Antibody-drug Conjugate Sacituzumab Govitecan in Urothelial Carcinoma

Authors

• S Weng
• I Stukes
• M Lee
• A Yousefi-Rad
• S Boudjadi
• AB Apolo

Abstract

Urothelial carcinoma (UC) is the most common type of bladder cancer and the sixth most common cancer in the United States. According to the NCI, UC is predicted to represent 4.2% of all new cancer cases in 2024. It is a highly heterogenous disease which contributes to its high mortality rate, especially in the metastatic setting. For decades, cisplatin-based chemotherapy has been established as the standard of care in UC. However, it has been proven that tumors develop evasive mechanisms to chemotherapy, thereby limiting its effectiveness.

Antibody-drug conjugates (ADCs) are a type of targeted therapy designed to enhance the delivery of toxic payloads to tumors. This can potentially lead to improved outcomes in patients with advanced or metastatic UC. However, clinical studies have shown that some advanced UC patients receiving sacituzumab govitecan (SG), a second-line ADC treatment, become less and less sensitive to the drug over time. This project aims to investigate the acquired mechanisms of resistance to SG in advanced UC, with the goal of developing strategies to overcome this resistance.

We are currently developing pre-clinical models of SG resistance in multiple UC cell lines. Early in vitro investigations showed that many UC cell lines, such as HT1376 and RT4, easily develop resistance after 4-5 cycles of SG. After validating these models, we aim to study their gene expression profile, DNA alterations, and pathway dysregulation to identify potential mechanisms of resistance. From there, potential strategies to overcome resistance, such as combination therapy or inhibitors, will be explored.

Scientific Focus Area: Cancer Biology

This page was last updated on Tuesday, August 6, 2024