Diffuse lymphoma (DLBCL) is the most common form of lymphoma, affecting thousands of people each year. American researchers have recently discovered a surprising mechanism that gives some cancers resistance to treatment.
Through a combination of basic research and clinical trials, a team from Weill Cornell Medicine and NewYork-Presbyterian demonstrated that the simultaneous use of several types of chemotherapy, one of which targets the DNA repair process, could be beneficial in treating these persistent cases.
The study, recently published in the journal Cancer Research, revealed that a process involving the movement of messenger RNA (mRNA) from the nucleus to the cytoplasm facilitates DNA repair in cancer cells. This mechanism allows cancer cells to resist treatments designed to damage their DNA. Although the research focused on diffuse large B-cell lymphoma (DLBCL), the findings appear to apply to other types of cancer, according to the researchers.
DLBCL affects approximately 30,000 patients annually in the United States alone. Although initial therapies cure about two-thirds of patients, patients who do not respond or relapse typically have difficulty achieving favorable outcomes with standard chemotherapy-based treatments, according to co-senior author Sarah Rutherford, PhD, assistant professor of medicine at Weill Cornell Medicine and hematologic oncologist at NewYork-Presbyterian and Cornell Medical Center.
Previous studies have shown that treatment-resistant DLBCL cells often express high levels of a protein called XPO1.
In 2019, the US FDA (Food and Drug Administration) approved a new drug, selinexor, designed to target XPO1 and inhibit its activity. This drug, also used in the European Union for multiple myeloma, prevents the growth of lymphoma cells that express high levels of this protein, being used to treat refractory cases.
However, although the treatment is effective, it does not have the same effectiveness for all patients with treatment-resistant disease. “The drug is effective, but not as much as we would like,” said Dr. Rutherford. This finding led to the exploration of ways to improve the effectiveness of the treatment.
The team wanted to better understand selinexor’s exact mode of action. XPO1, its target, transports hundreds of proteins and certain RNAs from the cell nucleus to the cytoplasm to separate proteins that should not be present in the nucleus, such as ribosomal proteins.
However, the researchers found that some of the proteins exported by XPO1 are bound to mRNA molecules; thus, these mRNAs are exported from the nucleus to the cytoplasm, where they can be converted into proteins.
This new mechanism suggests that the levels and activity of XPO1 in a cell can influence the expression of a large number of genes.
“We found that XPO1 does not regulate just a few proteins, but coordinates these extensive programs, allowing cells to rapidly adjust their proteome and survive the varied stress that cancer cells constantly face,” explained lead author Dr. Leandro Cerchietti, associate professor of Hematology and Oncology and a member of the Meyer Cancer Center at Cornell Medicine.
The experts took treatment-resistant DLBCL cells from patients and introduced them into preclinical models, finding that increased levels of XPO1 ultimately lead to increased expression of genes that protect cells from death caused by DNA damage.
XPO1 inhibition with selinexor in these models increased the sensitivity of lymphomas to DNA-damaging chemotherapies and immune-based treatments. “We were excited and thought that selinexor might have synergy with other chemotherapies,” noted Dr. Rutherford.
To test this hypothesis in patients, she initiated a phase 1 clinical trial to assess the safety and, if so, the dosage of such a combination. The study, which mainly involved patients with treatment-resistant DLBCL, showed that the combination regimen is not only safe, but also appears to have positive effects.
Although the data are still too limited to draw definitive conclusions, several patients had better results than expected.
Dr. Rutherford plans to continue testing and refining the new regimens in further studies. “In this disease, we now have many more therapeutic options than at the beginning of the study,” she pointed out.
Given that every cell in the body expresses XPO1, the new results appear to be relevant to a wider range of applications. According to the authors, there are other types of tumors in which XPO1 is overexpressed.
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