UI study suggests new approach to treating kids with relapsed cancer

UI researchers have identified a new target that may help improve treatment for children with relapsed B-cell acute lymphoblastic leukemia (B-ALL), the most common type of childhood cancer.

By measuring the effect of every gene, one by one, in the genome, the researchers have found that a combination of Aurora kinase B inhibitors and steroids may help treat relapsed patients. 

B-ALL is highly treatable, and almost 85 percent of children are cured with current therapies. However, when patients relapse or the chemotherapy fails, the outcomes are much worse and there is a need to improve treatments for this group of patients.

The research team—which included collaborators from the Univesity of Southern California and University of California, San Francisco—was led by Miles Pufall, PhD, associate professor of biochemistry at the UI Carver College of Medicine. 

cancer cell

Example of B-cell acute lymphoblastic leukemia

Making chemotherapy more effective

Pufall’s team used functional genomic techniques to understand the causes of relapse and look for ways to make glucocorticoids, a standard chemotherapy for B-ALL, more effective in relapsed patients. The findings were published recently in the journal PNAS.

Miles Pufall Portrait“We found that relapsed B-ALL cancers make too much of a protein called Aurora kinase B,” says Pufall, who also is a member of Holden Comprehensive Cancer Center at the UI. “When we inhibit Aurora kinase B, glucocorticoids are much more toxic to B-ALL cells.”

Glucocorticoids such as dexamethasone and prednisone are used as front-line treatments for B-ALL. Pufall and his colleagues examined the effect of glucocorticoids on all the genes in a variety of B-ALL specimens and compared this data to B-ALL cells from patients who had relapsed

They showed that glucocorticoids work by regulating a set of genes that cause cell death in leukemia cells. Upon relapse, this cell-killing mechanism is disrupted. By looking at which genes were abnormally expressed in cells from patients with relapsed B-ALL, the team identified Aurora kinase B as a key protein that stifles glucocorticoids’ cell-killing effects. When the team inhibited Aurora kinase B in cells from patients with relapsed B-ALL, the glucocorticoid treatment regained its leukemia-killing activity.

“Functional genomics makes this approach possible because rather than guessing, we measured the effect of every gene on sensitivity to glucocorticoid chemotherapy,” Pufall says.  

Implications for other treatments

Pufall notes the findings may have benefits beyond improving therapies for relapsed B-ALL cancers. This type of functional genomic analysis could in principle be done with most chemotherapies for any cancer, and may provide insight on new approaches or combination therapies to improve other forms of chemotherapy and limit side effects.  

In addition, steroids like prednisone and dexamethasone are among the most highly prescribed drugs in the world. Identifying what makes them work better or worse might allow physicians to use them more effectively and safely for many purposes.

The research team

In addition to Pufall, the research team included Mimi Fang and Karina Kruth at the UI; Coralie Poulard, Hye Na Kim, Celine Gagnieux, Daniel Gerke, Deepa Bhojwani, Yong-Mi Kim, and Michael Stallcup at USC; and Martin Kampmann at University of California, San Francisco.

The study was funded in part by grants from the National Cancer Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the Roy J. Carver Charitable Trust, and the American Cancer Society.

Date: 
Tuesday, March 5, 2019