Chronicling How a Cancer Drug Works by Triggering the Immune System

03/12/2019

A new paper published in Proceedings of the National Academy of Sciences shows for the first time how 5-azacytidine (AZA), a drug commonly prescribed to treat myelodysplastic syndromes and acute myeloid leukemia, causes cancer cell death and identifies several therapeutic targets that may help to amplify the drug’s already powerful disease-fighting effects.

AZA belongs to a class of drugs called DNA methyltransferase inhibitors, which prevent changes to the chemical structure and function of genes caused by a process called methylation. Preventing methylation, as a result, increases the expression of double-stranded (dsRNA).

The researchers, led by Robert Silverman, PhD, Department of Cancer Biology, elucidated how AZA, dsRNA and cell death are connected and mediated by the interactions of the OAS (2′,5′-oligoadenylate synthetase) family of genes and an antiviral protein called RNase L.

Viruses often use dsRNA to replicate within a host, so the body typically recognizes dsRNA as the sign of a foreign invader and launches an innate immune response. This immune response involves expression of interferons, as well as many interferon-stimulated genes, including the genes OAS1 to 3. dsRNA not only increases expression of OASs, but also activates these proteins. When active, OAS1 to 3 synthesize the molecule needed to “turn on” a critical protein called RNase L, which causes cell death.

Implicating the OAS-RNase L pathway in this process provides a more comprehensive understanding about how AZA and dsRNA prevent the proliferation of cancer cells, which may prove helpful in other types of cancers, too. It also offers important insights about how a host antiviral protein can, under some conditions, function against cancer cells. Engineering and training the body’s cells to use “self” to fight cancer is a growing area of interest among researchers.

Understanding this pathway has led to the identification of several actionable targets that can help turn up AZA’s cytotoxic effects. Some of which include silencing specific genes or their encoded proteins, such as ADAR1 (adenosine deaminase acting on dsRNA 1) or PDE12 (phosphodiesterase 12), and using ionizing radiation. Future studies will be important to test and validate these targets.

Shuvojit Banerjee, PhD, is first author on the study, which was supported in part by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health.

A VeloSano award, Cleveland Clinic’s flagship philanthropic initiative to advance cancer research, also helped make this project possible, demonstrating the value of early philanthropic funding to generate the data needed to secure larger extramural funding.