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Disease and treatment

Cancer drug makes the body think that a virus is attacking

Blood cancer affects both young and old people, but treatment options for older people are especially limited, since bone marrow transplantation is not usually carried out among older people. The only drug that prolongs life is therefore 5-azacytidine (AZA). However, only about 50% of people with blood cancer respond to this treatment. Why this is the case has not been understood, but now researchers have found that AZA activates the immune system so that it thinks a virus is attacking. This may help to make the medicine effective for more patients and may even help to combat viral infections.

When researchers first tried 5-azacytidine (AZA) to treat people with cancer, the results were somewhat of a fiasco. It was disappointingly ineffective against most types of cancer, but in the early 2000s, the results were revisited and it turned out that, at lower doses, AZA was effective in treating leukaemia and other forms of blood cancer. Today, it is almost the only medication that can be used to treat older people with myelodysplastic syndrome, a type of blood cancer.

“AZA is very effective in keeping myelodysplastic syndrome at bay for around half the patients. However, its effectiveness decreases over time, and it is not effective at all for the other half. We could not discover why this happened because we did not really understand how AZA works. Our new trial suggests that it is effective because it activates some elements of our DNA that originate from ancient virus infections. Now we hope to find other methods to stimulate the same mechanisms among the people for whom AZA is not effective,” explains Kirsten Grønbæk, Professor, Department of Haematology, Rigshospitalet, Copenhagen.

Virus alarm system

AZA has been known and used especially to treat people with blood cancer since 2009. It is similar to cytosine, one of the four main bases in DNA. The original idea for using AZA was that cancer cells, which divide faster than other cells, would incorporate the false base into their DNA to a greater extent and thus destroy their DNA. This is also the case at high doses, but lower-dose AZA has proved far more effective against cancer and less harmful to the body’s other cells.

“At low doses, AZA inhibits DNA methyltransferase, which normally regulates the gene expression in cells by adding methyl groups to our DNA. And since many previous studies have shown that DNA methylation is greatly increased in cancer cells, 5-azacytidine is very effective against the cancer cells by disrupting DNA methylation,” says Kirsten Grønbæk.

However, this turned out to be only part of the story and of why AZA effectively combats blood cancer. One study showed that the demethylation in the cell apparently triggered a kind of viral alarm that caused the body’s innate immune system to attack foreign and abnormal cells. The researchers examined this somewhat surprising effect of AZA in their new study.

“We therefore examined 150 RNA samples from two groups of adults and a group of children with different types of blood cancer. We took samples before, during and after treatment with AZA. Because only about half normally respond positively, it was interesting to determine which genes AZA upregulated and downregulated and whether this was associated with whether the drug was effective or not,” explains Kirsten Grønbæk.

These experiments confirmed the earlier laboratory experiments: the demethylation caused by AZA activates some elements of the human genome that we inherited millions of years ago from various types of viruses that have copied parts of their genome into ours. Today, these transposons comprise up to 40% of the human genome. The transposons are unique in being able to change their position within the genome.

“In response to AZA treatment, these transposons are copied into single- and double-stranded RNA, which in turn causes our immune system to think that the body is being attacked by a virus. This therefore activates the body’s immune system and thus has the beneficial side-effect of eliminating cells that behave abnormally, such as cancer cells,” says Kirsten Grønbæk.

Possibly effective against COVID-19?

The new results provide new important knowledge for the future treatment of various types of blood cancer such as leukaemia but especially myelodysplastic syndrome, which affects 250 older people each year. And since bone marrow transplantation is seldom carried out on older people, AZA treatment is the only option today. Unfortunately, treatment is effective for only half the people with myelodysplastic syndrome, and AZA gradually loses effectiveness among these.

“We have started a large international clinical trial, since our current trial only included 40 patients. If the new trial confirms the effects seen here, we hope to find other methods to kickstart the immune system similarly for those who do not respond to AZA or for whom the effectiveness has declined. We may be able to help the rest of the patients if we can achieve this,” explains Kirsten Grønbæk.

The new clinical trials will also test another hypothesis the researchers want to confirm. Indeed, as many as 80% of the people with myelodysplastic syndrome appear to have severe vitamin C deficiency, and preliminary experiments indicate that combining AZA and vitamin C is very effective in activating the immune system alarm for viruses. The researchers therefore hope to be able to use the new clinical trials to understand this effect more closely at the genetic level.

“Unfortunately, we do not expect that AZA will work very well on solid tumours, probably primarily because the cells inside the tumour do not divide as quickly as leukaemia cells,” says Kirsten Grønbæk.

However, a new idea has emerged in the COVID-19 era.

“When we realized that AZA causes the body to think that it is being attacked by viruses and because this boosts the immune system, we imagine that AZA could also boost the immune system through early treatment in viral infection. We are participating in a European initiative on this. The question to be answered is probably whether the effectiveness of AZA outweighs its side-effects,” concludes Kirsten Grønbæk.

Activation of a Subset of Evolutionarily Young Transposable Elements and Innate Immunity are Linked to Clinical Responses to 5-Azacytidine” has been published in Cancer Research with support from the Stand Up to Cancer Epigenetics Dream Team and others. In 2013, the Novo Nordisk Foundation awarded a 5-year grant to Kirsten Grønbæk for the project Translational Epigenetics in Blood Cancer. Kirsten Grønbæk is one of the initiators of the Program for Translational Haematology the Foundation has supported since 2017 through the Novo Nordisk Foundation Center for Stem Cell Biology, DanStem.

Kirsten Grønbæk
Professor and chief physician
A main focus of the Grønbæk group is molecular aberrations in MDS, with a particular focus on the pre-MDS phase. Patients are often referred with cytopenia, the cause of which remains unknown after standard diagnostic work up. These patients were previously followed for years with no definite diagnosis, however recent studies from the Grønbæk group and others show that around half of these patients have clonal hematopoiesis (i.e. clonal cytopenia of undetermined significance, CCUS). Although these mutated cells may be excellent candidates for being pre-cancer stem cells (CSCs) additional work is required to understand this. It is still unclear why some patients with CCUS develop overt MDS/AML, while others stay cytopenic with no disease progression for years. It is clear that additional mutations in classical tumor suppressors and oncogenes are generally required for disease progression; however, whether other factors such as germline genetics, immune mechanisms, and life style play a role is still unclear. Together with the other members of PTH and the van Andel Research Institute, Stand up to Cancer, Epigenetics Dream Team, the Grønbæk group is currently exploring these mechanisms, with a particular focus on whether the progression of CCUS can be prevented or postponed. Our first studies focus on the role of vitamin C and its potential for rescuing TET2 deficiency, which we are currently perusing in clinical/translational trials.