Aggressive lymphoma: Low doses of approved drug switches on pathway that allows chemotherapy to kill cancer

Researchers from Weill Cornell Medical College and NewYork-Presbyterian Hospital, who led the study published in Cancer Discovery, say their strategy has the potential to change the standard of care for patients with diffuse large B-cell lymphoma (DLBCL) -- and possibly other kinds of tumors.

The targeted drug they used, azacitidine, is designed to reawaken molecular mechanisms that typically trigger cell death but are switched off as cancer -- including lymphoma -- progresses. The research team discovered that pretreating aggressive lymphoma with azacitidine enables the death signal to turn back on when chemotherapy triggers it.

In a proof-of-concept, Phase 3 study of 12 high-risk DLBCL patients led by Dr. Peter Martin, assistant professor of medicine and a hematologist/oncologist at NewYork-Presbyterian Hospital/Weill Cornell Medical Center, 11 achieved a complete remission of their cancer, and 10 remained cancer-free for up to 28 months. The patients were given low doses of azacitidine for five days before standard chemotherapy was used.

"To have any hope for helping patients with aggressive lymphoma, we need to make this resistant cancer sensitive to treatment. We found we could do this by reprogramming the cancer to a more benign disease, which can then respond to chemotherapy," says the study's senior investigator, Dr. Leandro Cerchietti, the Sackler Scholar in Biomedical and Physical Sciences and assistant professor of hematology and oncology at Weill Cornell Medical College, who also collaborated with the Medical College's Dr. Ari Melnick, the Gebroe Professor of Hematology and Oncology and professor of medicine.

"In this remarkable study, Dr. Cerchietti discovered an important new disease mechanism that causes chemotherapy resistance in aggressive lymphomas, developed a new treatment regimen and completed the first clinical trial, demonstrating that his findings are true and directly relevant to those patients with the most severe forms of this tumor," Dr. Melnick says.

Approximately one-third of patients have DLBCL that either does not respond to initial chemotherapy or relapses after treatment. Because the majority of those patients will die within two years of their diagnoses, new treatments that will increase the time patients survive free of their disease are urgently needed, Dr. Cerchietti adds.

"By pretreating patients with a low-dose of azacitidine -- a targeted drug approved for use in myelodysplastic syndrome -- we achieved a profound and stable degree of reprogramming and chemosensitization that was very surprising to us," Dr. Cerchietti says.

"Oncologists have long believed that using high doses of an anti-cancer drug is the best strategy," he continues. "Our study shows that is not the case in this kind of lymphoma, and suggests this new approach can potentially be translated to other tumor types."

The researchers are expanding the study to additional DLBCL patients in a multi-center clinical trial that will soon enroll patients, and they also plan to study their pretreatment strategy in other tumor types, including additional lymphomas.

Failure at First, but Success After Understanding How the Drug Works

It took five years and collaborations with universities in Canada and Italy to translate laboratory findings to human cancer treatment. The clinical trial, and majority of cell and animal experiments, was conducted at Weill Cornell Medical College.

"This was truly a bench-to-bedside and back team effort, as being able to link the direct effects of azacitidine on primary tumor tissue from patients receiving the drug has allowed us to advance the epigenetic priming treatment strategy in a very precise fashion," says Dr. John Leonard, associate dean for clinical research and the Richard T. Silver Distinguished Professor of Hematology and Medical Oncology at Weill Cornell Medical College, and director of the Joint Clinical Trials Office at Weill Cornell Medical College and NewYork-Presbyterian Hospital.

The researchers studied azacitidine because of growing evidence that most cancers resist the killing powers of chemotherapy because of an inability to turn on cell death mechanisms. A major cause of this genetic resistance is the addition of silencing chemicals, called methyl groups, to death-inducing genes. These silencing chemicals prevent chemotherapy from activating the genes, making the treatment less effective. Azacitidine removes the methyl groups, allowing the chemotherapy drugs to activate these genes again and cause tumor cells to die.

But their early experiments were failures. Cell and animal studies demonstrated that powerful doses of azacitidine were not effective.

"We thought that maybe we were giving the drug in the wrong way, so we started doing experiments to see how it could work," Dr. Cerchietti says. "One of the first things we realized is that the drug has to be given in a concentration that will remove methyl groups without affecting other cellular processes.

"After that we investigated the genes and the pathways that were modified and were activated, and found that one important pathway that azacitidine could switch back on was the ability of the cell to die if its DNA was damaged -- which is what chemotherapy does," Dr. Cerchietti adds.

Successful animal experiments then led to studying the agent in newly diagnosed, previously untreated patients with aggressive DLBCL, many of whom likely had cancer that would not have responded to chemotherapy, he says.

"Elderly patients and patients with aggressive forms of lymphoma, such as those who participated in the clinical trial, have a higher chance of recurrence and less survival than younger patients," Dr. Cerchietti says. "They tend to have more chemo-resistant disease, which is why we focused our study on this population."

He added, "The worse the disease is, the higher the degree of aberrant methylation. In about 20 to 30 percent of patients, this aberrant methylation is associated with chemoresistance. Our pretreatment strategy reversed it."

"We are in the process of tailoring treatments to achieve a more personalized treatment, and we are very excited about the potential to help make chemotherapy and other treatments more beneficial for cancer patients," Dr. Cerchietti says.