Getting to grips with chemoresistance

Scientists develop drug-resistant cell line for lymphoma to better model disease development and drug reactions

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PITTSBURGH—Model cell lines enable close study of pathogenesis, cell behavior and even drug response, making them a valuable tool in a variety of diseases. And that is doubly the case in cancer, both because of how rapidly it can change or metastasize, and because in-vitro testing with such cell models can prevent patients from undergoing unnecessary treatments to which their cancer won't respond—a boon for patients with already-taxed immune systems.
Along those lines, researchers at Carnegie Mellon University have a cell model for a rare type of cancer: mantle cell lymphoma. The most promising aspect of their work is that this cell line accurately mimics the chemoresistance seen in patients suffering from this disease. They published the results of their work in Experimental Biology and Medicine in August in a paper titled “Development of a clinically relevant chemoresistant mantle cell lymphoma cell culture model.”
Mantle cell lymphoma, an aggressive subtype of non-Hodgkin’s lymphoma, is currently incurable. As detailed in the Experimental Biology and Medicine paper, “Non-Hodgkin lymphoma is the seventh most common cancer in the United States, accounting for approximately 4 percent of all cancer diagnoses. According to the American Cancer Society’s estimates for 2018, about 75,000 people will be diagnosed with non-Hodgkin lymphoma, and  19,000 people will succumb to the disease ... Mantle cell lymphoma comprises 6 percent of all non-Hodgkin lymphoma cases in the United States. With a median age of diagnosis of over 60 years, many mantle cell lymphoma patients are unable to withstand intensive chemotherapy regimens. Furthermore, the disease is typically discovered in its later stages after metastasis to secondary sites such as the gastrointestinal tract and the bone.”
Though the current standard of care—the CHOP chemotherapy regimen—has a high response rate, mantle cell lymphoma is highly chemoresistant and patient response to this treatment is often less than three years. In addition, prior to this work, research into the cancer and potential treatments has suffered without cell cultures and preclinical models that can replicate mantle cell lymphoma's chemoresistance.
“This cell model exhibits low levels of chemoresistance that are reflective of the chemoresistance observed in patients,” explains Dr. Kathryn Whitehead of the Departments of Biomedical Engineering and Chemical Engineering at Carnegie Mellon, who led this research. “Most chemoresistant mantle cell lymphoma lines are far more resistant to chemotherapy than is observed in the clinic. Our new cell line is expected to have gene expression changes that better recapitulate clinical cancer. As such, treatments developed with this cell line may be more readily translated into humans compared to previous versions of chemoresistant mantle cell lymphoma cell lines.”
While Whitehead notes that nearly all mantle cell lymphoma patients see their cancer develop resistance and recur after initial treatment, she says the existing models of the cancer “were overly resistant to chemotherapy, sometimes hundreds of time more resistant than what is observed in the clinic. The response of these overly resistant cells to treatment could potentially be much different than what is observed in humans.”
Whitehead and her colleagues worked with the JeKo-1 cell line in this effort, and found that cells that were treated with CHOP eventually not only developed resistance to the treatment, but proliferated rapidly when treated with therapeutic levels of the regimen.
“We begin with a standard mantle cell lymphoma cell line that has never been previously exposed to chemotherapy,” Whitehead tells DDNews. “We then gradually expose the cells to increasing levels of a chemotherapeutic mixture called CHOP, which is a blend of four anti-cancer drugs. Although many cells will die, the ones that remain do so because they have developed resistance to treatment.”
“Once we developed the model, we began looking at changes in gene expression that occur with the development of chemoresistance,” she adds. “Our initial data suggests that there are numerous oncogenes that are upregulated in resistant mantle cell lymphoma compared to untreated mantle cell lymphoma. We hope to publish these results in the future.”
Three such oncogenes were expressed at higher levels in the new cell model compared to their parent cells: Cyclin D1, Mcl-1 and Bcl-2. As noted by the authors, “Mcl-1 expression was 50 percent higher in resistant cells, while Bcl-2 and CyclinD1 expression increased by 38 percent and 11 percent, respectively … While the overexpression of cyclin D1 is a hallmark of mantle cell lymphoma, increased expression of the antiapoptotic proteins Mcl-1 and Bcl-2 is also involved in resistance to cell death.”
Whitehead says that in addition to further studying oncogenes in resistant vs. untreated mantle cell lymphoma, the team also hopes to develop therapeutics “that directly target the gene expression changes that occur upon development of resistance. Such gene therapies would have the potential to make the mantle cell lymphoma cells more susceptible to chemotherapy and other anti-cancer drugs.”

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