Inhibition of CD73 Provides Novel Treatment in Cancer Immunotherapy
Current procedures to treat cancer such as surgery, radiation, and chemotherapy have limitations, as these treatments are non-selective and harm normal cells in addition to cancerous cells. Furthermore, cancer that has spread throughout the body also becomes a challenge to treat with only conventional therapies. A method to overcome these concerns is being addressed by the Sharma lab, a drug development lab that focuses on developing novel small molecule therapeutics targeting cancers.
The drug development process begins with computational modeling to find possible drug candidates that can bind to a target of interest. These drug compounds then enter drug screenings to assess on-target effects and overall cytotoxicity. A current project in the lab is focused on cancer immunotherapy, which is a progressive treatment that aims to activate the immune system to fight off cancer.
CD73 is an ecto-5’-nucleotidase that has been shown to contribute to immunosuppression. This occurs through the hydrolyzation of adenosine monophosphate (AMP) into adenosine (ADO) and a phosphate group. High expression of CD73 in cancer leads to upregulated levels of ADO that suppresses the immune system by limiting anti-tumor T-cell production. By using this developmental strategy, we have identified a potential drug candidate, TGN-2127, as a cancer immunotherapeutic.
By inhibiting CD73 in cancers, it is hypothesized that ADO levels will decrease, thereby activating the tumor to fight off cancer. So far, TGN-2127 has shown strong binding affinity to CD73 by demonstrating a significant thermal shift of 4°C. In addition, TGN-2127 demonstrated inhibition of CD73 activity by showing decreased levels of phosphate production in an indirect enzymatic assay. Future experiments will investigate if TGN-2127 can activate the immune system in vitro and in vivo, followed by optimization for clinical application.