New Biomarker Identifies Patients with Aggressive Lymphoma Who Don’t Respond to Precision Therapy

Newswise — PHILADELPHIA—A new biomarker discovered by a team that includes researchers from Penn Medicine identifies patients with an aggressive form of lymphoma unlikely to respond to the targeted treatment ibrutinib. It’s a clinically actionable finding that will help guide physicians toward the right treatment for patients with activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) who harbor these newly exposed mutations in the BCL10 gene.

The findings were presented during the plenary scientific session at the 62^ndAmerican Society of Hematology Annual Meeting & Exposition on Dec. 6 (abstract #3).  Kojo S. J. Elenitoba-Johnson, MD, the Peter C. Nowell, MD, Professor in the Perelman School of Medicine at the University of Pennsylvania and Director of the Center for Personalized Diagnostics, serves as a co-author.

“This is a mechanism of resistance that was previously underappreciated,” Elenitoba-Johnson said. “Ibrutinib would have been a candidate for such patients, but if they have these BCL10 mutations, another route for treatment should be prioritized.”

Ibrutinib is a targeted therapy that blocks a protein called “Bruton's tyrosine kinase,” which is part of a pathway that helps B cells thrive. Blocking BTK can make B cells, including cancerous B cells, die or prevent them from dividing. The drug has been shown to be useful in the treatment of relapsed and refractory forms of lymphomas and leukemias, but not all.

Mutations in BCL10, the researchers found, promote abnormal signaling pathways that allow cells to circumvent the drug’s blockade.

The normal BCL10 binds to two other proteins known as CARD11 and MALT1 to trigger NF-kB signaling, which is important in normal B cell function. However, mutations in BCL10 subvert this pathway, and the mechanisms by which this is achieved are not well understood. The researchers discovered using a number of sophisticated techniques, including cyroelectron microscopy, that mutated BCL10 could be joining forces with other cellular culprits to drive lymphoma growth and resistance to treatment, but it wasn’t clear what those were.

That’s where Penn Medicine researchers came in, with their deep expertise in a technology known as mass spectrometry-based proteomic analyses, which drills down even further into the nuances of protein complexes. They identified new interactors—including NF-κB2 and TAB1—that showed how cells are capable of evading the drug through auxiliary signaling. If the process were a relay race, in a “normal” patient, the drug would knock the baton out of the first runner’s hand to thwart cancer. But with these mutations, a runner from another team swoops in with a new baton to help finish.

“Cutting off the signaling up top would be immaterial because this protein has now acquired a new capability that subverts the mechanism by which the drug could effectively act as an inhibitor in lymphomas harboring these mutations,”  Elenitoba-Johnson said.

The findings will be presented by Min Xi, PhD, from the Melnick lab at Weill Cornell Medical College in New York.

The biomarker adds to the growing list of genetic drivers of cancers that continue to help inform treatment plans for lymphoma patients. DLBCL is the most common subtype of adult lymphomas, with more than 25,000 new cases a year in the United States. ABC-DLBCL is one of its most aggressive forms.

“Precision medicine is the goal, where individualized therapy, based on genetics and other factors, lets us treats patients with the right drug for the right disease at the right dose and at the right time,” Elenitoba-Johnson said. “Identifying these new mechanisms strengthens that approach for patients with this type of lymphoma.” 

Penn co-authors include Ozlem Onder, PhD, in the Elenitoba-Johnson Lab. Other co-authors include Liron David, PhD, of Boston Children's Hospital, and Matthew Teater, PhD, Lorena Fontan, PhD, Hao Wu, PhD, and Ari Melnick, MD, of Weill Cornell Medical College in New York.

##

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $8.6 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $494 million awarded in the 2019 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 43,900 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2019, Penn Medicine provided more than $583 million to benefit our community.