AXL and TYRO3 signaling pathways as therapeutic targets in bladder cancer: preclinical study

Faculty-development competitive research grants program for 2020-2022 (batch 2)

An average age of bladder cancer patients at the time of diagnosis is 73 years. Currently, bladder cancer is the 11th leading cause of cancer death in Kazakhstan. However, the age-adjusted death rate of bladder cancer is 7.71 per 100,000 of population, which ranks Kazakhstan #2 in the world. As life expectancy in Kazakhstan is increasing, it is anticipated that the mortality rate of bladder cancer will be continuously growing in this country, and development of novel effective treatment schemes is very important. This project is based on extensive in vivo and in vitro preliminary data which indicate that receptor tyrosine kinase AXL is implicated in aggressive bladder cancer. The project is aiming to study crosstalk between AXL and a related receptor TYRO3 that is phosphorylated at a cytoplasmic tyrosine in response to AXL inhibition. The proposed work will address two strategies of AXL inhibition, use small molecule inhibitors and repurposing approved drugs, which interfere with AXL expression. The effects of AXL inhibition on TYRO3, viability of bladder cancer cells and their differentiation status will be analysed in 2D cultures. We will also test if concentration of soluble AXL correlates with AXL expression levels and activity, and has a potential to serve as urine biomarker for patients’ stratification and tumour response to AXL-targeted therapy. Additionally, we propose to create patients-derived organoid cultures from excised bladder tumours and transurothelial resection material. This bladder cancer model will allow us to validate the data generated in bladder cancer cell lines. Overall, we believe the completion of this proposal will assess the perspective of AXL-targeted therapy in bladder cancer and pave the way for organization of clinical trials.