Newswise – Patients with some types of lymphoma that become resistant to standard treatments could benefit from a therapy that researchers at the University of Wisconsin-Madison are currently evaluating after discovering a key process that drives resistance of blood cancers to current drugs. Here are the details:

An effective treatment until it is no longer there: The UW-Madison team wanted to understand why some patients with certain types of non-Hodgkin lymphoma, which originate in white blood cells called B cells, develop resistance to drugs that have become the standard treatment for the disease.

  • In patients with B-cell malignancies, including mantle cell lymphoma and diffuse large B-cell lymphoma, the cancer often initially responds well to treatments that include drugs called Bruton’s tyrosine kinase inhibitors, or BTK inhibitors.
  • BTK inhibitors, including the commonly used drug ibrutinib, block the B cell signaling pathway. This is helpful in treating B-cell lymphomas because cancers arise when this pathway fails and B-cell production goes out of control. BTK inhibitors short-circuit this overproduction.
  • “However, most patients who respond to these medications relapse after perhaps a year or two of treatment. That’s a big problem,” he says Lixin RuiProfessor of hematology, medical oncology and palliative care at the University of Wisconsin School of Medicine and Public Health who led the research.

Identification of a new resistance mechanism: Researchers have tried to understand why and how BTK inhibitors often lose their effectiveness, and Rui and his colleagues specifically examined resistance to ibrutinib.

  • Ibrutinib was approved in 2013 as the first BTK inhibitor to treat B-cell lymphomas and remains one of the most commonly prescribed drugs in its class to treat these cancers.
  • The UW-Madison team conducted genetic and pharmacological analyzes that linked a single gene to the development of ibrutinib resistance. The gene is responsible for producing a protein known as Early Growth Response 1, or EGR1.
  • The EGR1 protein performs a number of biological functions, including the regulation of cell proliferation. Rui and his colleagues found that the ibrutinib-resistant malignant B cells they studied had more active EGR1 genes than cells that were not resistant to the drug.
  • This activity became even more evident after treatment with ibrutinib, as EGR1 triggered a cascade of changes in the cells’ metabolism, increasing their energy.
  • “This is a novel mechanism that we have identified,” says Rui. “EGR1 can increase energy production in resistant lymphoma cells and therefore promotes drug resistance.” The discovery was made recently detailed in Blood magazine.

Overcoming relapse: Figuring out how cancerous B cells develop resistance to BTK inhibitors like ibrutinib was just part of the goal of the UW-Madison team, which will ultimately seek new effective treatments for lymphoma patients who have relapsed due to drug resistance.

  • In the same study, Rui and his colleagues tested a new treatment regimen designed to counteract EGR1 overactivity.
  • The team arrived at an experimental treatment with two drugs that lower cell metabolism: metformin, used to treat type 2 diabetes, and a newer drug called IM156.
  • In combination, these two drugs effectively slowed the growth of ibrutinib-resistant lymphoma cells in drug-resistant B-cell lymphoma mouse models.
  • Rui is confident the experimental treatment can eventually make its way into clinical trials with human patients. “I always want findings from my laboratory to be transferred to the clinic,” says Rui. “If patients could benefit from this research, that would be very worthwhile.”

This research was supported by the National Institutes of Health, the National Cancer Institute (R01 CA266354), the UW-Madison Forward Lymphoma Fund, the ASH Bridge Grant, the UW Center for Human Genomics and Precision Medicine SeedGrant, and the Midwest Athletes Against Childhood Cancer, Inc. Fund supported. Pilot grant from the UW Carbone Cancer Center, NIH, NCI (P30 CA014520) and the Intramural Research Program from the NIH, NCI.

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