Using a CD73 Activity Assay to Study the Adenosine Pathway and Cancer
Tumor Immunosuppression and a CD73 Activity Assay – To say cancer is complex would be an understatement. From the cause, to treatment, to living with the disease, nothing about it is easy. As one of the leading factors of death worldwide and the burden on families and the healthcare system as a whole, it’s no wonder why scientists have been fighting cancer at all angles for decades. Cells can become cancerous when DNA is damaged or mutations occur. The number of genes that can be affected and contribute to cancer is astounding; from tumor suppressor genes to oncogenes (for example). And, even more, genes play a role once the cancer is established and metastases taking on an environment of its own unlike that of a normal cell.
Immunosuppressive Adenosine
Suppressing the immune response is one-way cancer cells can remain active and prolific, causing more harm to the individual with the disease. What if we could remove this suppression in order to stop cancer in its tracks? Adenosine suppresses the immune response in a myriad of ways and is abundant due to the inflammatory tumor conditions.1 When the tumor environment becomes deprived of oxygen, hypoxia-inducible factors (HIF) activate other members of the pathway such as CD73. This enzyme catalyzes the dephosphorylation of AMP to create adenosine.1 Specifically, hypoxic conditions release ATP which gets converted to AMP by CD39 and then CD73 comes in to generate adenosine.2 Therefore, targeting adenosine and/or CD73 has gained interest in treating cancer.
CD73 Inhibitor to the Rescue
A large amount of research has been done showing the relevance of the adenosine pathway to cancer and its progression. Additionally, several studies have examined the likelihood of blocking targets such as CD73 in order to abate the spread of disease. Indeed, CD73 has shown promise in blocking tumor progression.3 Corvus Pharmaceuticals is an example of this promise. The company consists of a group of scientists capitalizing on the inhibition of adenosine production thereby promoting anti-tumor immune responses leading to tumor regression.
Another exciting revelation is the possibility of being able to use CD73 as not only a treatment to cancer but a biomarker given the correlation between CD73 expression and the prognosis of oncologic patients.3 Overexpression of CD73 has been associated with a worse prognosis as well as chemotherapy resistance in cancer patients.3
A CD73 Activity Assay to Aid in Future Research
There is still important research to be done and therapeutic potential in CD73 along with other proteins in the adenosine pathway. A CD73 activity assay can aid in this research and discovery. Recently scientists at BellBrook Labs developed an assay for CD73 by measuring adenosine produced by the enzyme. The method uses the Transcreener ADP² Assay along with a coupling enzyme to determine enzymatic activity. The assay allowed scientists to study the enzyme, perform dose-response curves, and even a 1,600 compound pilot screen. It is our hope the method will provide a simple, mix-and-read, HTS approach to accelerate drug discovery for institutions interested in CD73. The result of this work is presented a poster at the Discovery on Target 2019 Conference.
References
- Young A, Mittal D, Stagg J, Smyth MJ. Targeting cancer-derived adenosine: New therapeutic approaches. Cancer Discov. 2014;4(8):879-888. doi:10.1158/2159-8290.CD-14-0341 https://www.ncbi.nlm.nih.gov/pubmed/25035124
- Antonioli L, Haskó G, Fornai M, Colucci R, Blandizzi C. Adenosine pathway and cancer: where do we go from here? Expert Opin Ther Targets. 2014;18(9):973-977. doi:10.1517/14728222.2014.925883 https://www.ncbi.nlm.nih.gov/pubmed/24958495
- Riaz N, Wolden SL, Gelblum DY, Eric J. Percutaneous endoscopic gastrostomy in oropharyngeal cancer patients treated with intensity-modulated radiotherapy with concurrent chemotherapy. HHS Public Access. 2016;118(24):6072-6078. doi:10.1002/cncr.27633. https://www.ncbi.nlm.nih.gov/pubmed/22707358
