Scientists from St. Jude Children’s Research Hospital conducted a study that illuminates a mechanism by which leukemia cells resist steroids, a key factor detrimental to the success of chemotherapy. This discovery could help create more effective cancer drugs and improve the treatment of many autoimmune related diseases.
The researchers looked at a certain type of steroid hormones involved in the immune system, known as glucocorticoids. These hormones are crucial components to the chemotherapy drug cocktail that has helped increase long-term survival for the most prevalent childhood cancer – acute lymphoblastic leukemia (ALL) – up to 85 percent in the nation. At St. Jude Children’s Research Hospital, 94 percent of children with this cancer become long-term survivors using this treatment. However, young patients who have ALL that also show steroid resistance are not as likely to survive and, unfortunately, the underlying cause of such resistance is not often known. The research team led by scientists from St. Jude Children’s Research Hospital attempted to understand the reason for this resistance.
In their study recently published in Nature Genetics, a group of scientists pinpointed a mechanism thought to be responsible for nearly one-third of steroid resistance in adolescents and young children diagnosed with ALL. Further investigation is necessary to find out if the same steroid resistance comes into play for adults diagnosed with ALL, as resistance to steroids is actually more prevalent and surviving long-term is much less promising for adults with this disease.
William Evans, Pharm.D., part of the St. Jude Department of Pharmaceutical Sciences says, “Based on these findings, research has already begun to identify small molecules with the potential to reverse glucocorticoid resistance, leading to more effective treatment and increased survival. Glucocorticoids are widely used to treat asthma, rheumatoid arthritis, colitis and other autoimmune disorders. That means these results have the potential to benefit a wide range of patients.”
In their research, the scientists used cells from bone marrow collected from 444 patients who had been recently diagnosed with ALL and were receiving treatment at St. Jude or were in clinical trials that the Dutch Childhood Oncology Group and the German Cooperative Study Group for Childhood ALL sponsored. They also obtained cells from 49 pediatric patients with ALL when they were diagnosed and when they relapsed during their enrollment in clinical trials which were supported by the Children’s Oncology Group.
The researchers investigated the genome to identify variations in the activity of genes or gene expression in leukemia cells between individuals who were resistant or sensitive to steroids. Two genes – CASP1 (caspase 1) and NLRP3 (NLR family, pyrin domain containing 3) – were among those that had increased expression and activity found in cells that were resistant to glucocorticoids. NLRP3 is involved in activating or switching on CASP1 by producing a specific protein.
DNA methylation is a well-known epigenetic mechanism that turns off genes by adding methyl (CH3) groups onto DNA at the 5-carbon position of cytosine. DNA methylation was identified by the researchers as one potential explanation for the upregulated gene activity. The researchers found cancer cells over-expressing CASP1 and NLRP3 had decreased methylation levels in comparison to DNA methylation levels of cells that had normal expression of CASP1 and NLRP3.
In addition, other research has shown that young ALL individuals who relapsed were more likely to display steroid resistance compared to new patients. In the current study, scientists assessed the expression of NLRP3 and CASP1 in patients with ALL who relapsed. They discovered that the expression of CASP1 and NLRP3 genes were significantly higher.
By regulating certain gene activity, such as genes involved in the cell’s apoptosis or cell death pathway, glucocorticoids can kill cancer cells. In order to work properly, the drugs need to bind to the glucocorticoid receptors located inside the cells. Then, the receptors can transport the drug to the nucleus of the cell and allow the receptors and the steroid to work hand-in-hand to bind to DNA and regulate gene activity.
The researchers found that CASP1 prevents glucocorticoids from accessing the nucleus. This blocking occurs because CASP1 splits the glucocorticoid receptor. Specifically, researchers reported that CASP1 overexpression “resulted in cleavage of the glucocorticoid receptor, diminished the glucocorticoid-induced transcriptional response and increased glucocorticoid resistance.”
“Cells that over-express CASP1 are chewing up their glucocorticoid receptor,” Evans said. “That means when steroids enter the cell, there is no receptor for the drugs to bind to or fulfill its therapeutic function.”
To test whether the cleavage of the glucocorticoid receptor by CASP1 was central to steroid resistance in ALL patients, researchers created a receptor lacking the CASP1 cleavage site. The ALL cells that expressed high amounts of CASP1 were introduced to the genetically engineered receptors and, as expected, the cells did not become resistant to steroids.
By employing a collection of techniques and focusing on the level of CASP1, the research team demonstrated the rise or fall of steroid resistance in leukemia cells. Overall, their evidence more clearly illuminates the mechanism of glucocorticoid resistance and how chemotherapy drugs could be improved for ALL patients and potentially for patients suffering from other autoimmune diseases.
Paugh, S.W. et al. NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells. Nature Genetics, 2015; DOI: 10.1038/ng.3283
St. Jude Children’s Research Hospital. Discovery could help reverse glucocorticoid resistance in some young leukemia patients. 4 May 2015.
St. Jude Children’s Research Hospital. Preserving the power of glucocorticoids to fight leukemia. 4 May 2015.