A New Treatment for Lymphomas Targets drug-resistant Pathway

Patients with certain form of lymphomas who have become resistant to regular therapies may benefit from a medication that University of Wisconsin-Madison researchers are testing after discovering a crucial pathway that promotes blood cancer resistance to current drugs.

Here are the details:

An effective treatment, until it isn’t. The UW-Madison team wanted to know why some people with non-Hodgkin’s lymphomas that start in white blood cells called B cells acquire resistance to medications that have been the standard of care for the condition.

• Patients with B-cell malignancies, such as mantle cell lymphoma and diffuse large B-cell lymphoma, frequently see their malignancy react positively to treatments that involve medications known as Bruton tyrosine kinase inhibitors, or BTK inhibitors.

• BTK inhibitors, such as the regularly used medicine ibrutinib, suppress the signaling pathway of B cells. This is useful for treating B-cell lymphomas because the tumors develop when this signaling system fails, resulting in an out-of-control generation of B cells. BTK inhibitors prevent overproduction.

• “However, most patients who respond to these medications relapse within one or two years of treatment. That’s a major deal,” sa Lixin Rui, a professor of hematology, medical oncology and palliative care at the University of Wisconsin School of Medicine and Public Health, who directed the study.

Identifying a new mechanism of resistance: Researchers have been trying to figure out why and how BTK inhibitors cease working, and Rui and his colleagues focused on resistance to ibrutinib in particular.

• In 2013, ibrutinib became the first BTK inhibitor licensed to treat B-cell lymphomas, and it is still one of the most commonly prescribed medications in the class for cancer treatment.

• The UW-Madison team processed genomic and pharmacological investigations to identify a specific gene involved in the development of ibrutinib resistance. The gene produces a protein called early growth response 1, or EGR1.

• The EGR1 protein has a variety of biological activities, including regulating cell proliferation. Rui and colleagues discovered that ibrutinib-resistant malignant B cells had more activated EGR1 genes than cells that were not resistant to the treatment.

• This activity increased even more after ibrutinib treatment, since EGR1 triggered a cascade of metabolic changes in the cells, increasing their energy.

• “This is a novel mechanism that we identified,” said Rui. “EGR1 can promote more energy production in resistant lymphoma cells and, therefore, it promotes drug resistance.” The findings were recently published in the journal Blood.

Overcoming relapse: Understanding how malignant B cells develop resistance to BTK inhibitors such as ibrutinib is only half of the UW-Madison team’s ultimate goal, which is to find new, effective treatments for lymphoma patients who have relapsed due to drug resistance.

• In the same investigation, Rui and his colleagues investigated a new therapy regimen designed to mitigate EGR1 overactivity.

• The scientists devised an experimental medication that combines two pharmaceuticals that slow cell metabolism: metformin, which is used to treat type 2 diabetes, and IM156, a newer agent.

• These two medications worked together to successfully limit the growth of ibrutinib-resistant lymphoma cells in mouse models with drug-resistant B-cell lymphomas.

Rui hopes that the experimental medicine will eventually make its way into human clinical trials. “I always want findings from my lab translated to the clinic,” Rui says. “If patients can benefit from this research, that would be very rewarding.”

More information: Yunxia Liu et al, EGR1-mediated metabolic reprogramming to oxidative phosphorylation contributes to ibrutinib resistance in B-cell lymphoma, Blood (2023). DOI: 10.1182/blood.2023020142

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