DDNews Cancer Research News Exclusive: Changing the program
PHILADELPHIA—A team of researchers from Weill Cornell Medical College in New York has discovered a method for reprogramming diffuse, large B-cell lymphomas (DLBCLs) that are resistant to chemotherapy, through the use of the drug azacitidine. Azacitidine, also known as VIDAZA, is a nucleoside metabolic inhibitor indicated from the treatment of the bone marrow disorder myelodysplastic syndrome. DLBCL is a cancer of the white blood cells that produce antibodies, and represents the most common type of non-Hodgkin lymphoma in adults.
The researchers conducted a Phase I trial in 12 patients recently diagnosed with DLBCL, 11 of whom were more than 60 years old at diagnosis, putting them at a high risk for tumor recurrence after initial treatment. The patients received azacitidine, in escalating doses, eight days before beginning six cycles of standard chemotherapy. Of the dozen patients, 11 demonstrated a complete response, and 10 remained in complete remission for up to 28 months. Additionally, side effects from azacitidine were minimal, though two patients who received the maximum dose of the drug had dose-limiting toxicities.
"When lymphomas are formed, they shut down the cellular programs that sense that something is wrong in the cells. Once these fail-safe mechanisms that trigger cell death are shut down, it becomes difficult to kill the tumor with chemotherapy," said Leandro Cerchietti, M.D., assistant professor at the Hematology and Oncology Division of Weill Cornell Medical College in New York and a corresponding author for the study. "Our study showed that using low concentrations of the DNA methyltransferase inhibitors decitabine or azacitidine, these fail-safe mechanisms can slowly be awakened to induce lymphoma cell death when chemotherapy is administered."
"We showed that aggressive lymphomas can be reprogrammed to a more benign disease," he added. "We think this work has the potential to change the standard of care for patients with aggressive lymphomas."
Preclinical experiments helped Cerchietti and his colleagues determine how lymphomas, which demonstrate a significant resistance to chemotherapy, avoid these cancer-killing drugs. What they found was that all DLBCLs present with a high degree of aberrant DNA methylation, which "silences" certain genes, leads to chemotherapy resistance. SMAD1 was among the genes that were found to be silenced in DLBCLs.
"SMAD1 is part of a family of intracellular proteins involved in informing the cellular nucleus about the conditions of the microenvironment," Cerchietti explains. "Specifically, SMAD1 respond to the presence of extracellular proteins called BMP (and in lymphoma cells also TGFB) and acts a transcription factor regulating the expression of genes involved in cell cycle arrest and senescence induction."
In biopsy specimens collected from the study participants, the researchers found that following azacitidine treatment, methylation of SMAD1 decreased while the SMAD1 protein increased, giving them proof of principle. Tests with DLBCL cells and mice with human lymphoma xenografts showed that DNA methyltransferase inhibitors, such as azacitidine, are most effective when administered before chemotherapy, not simultaneously.
The aberrant DNA methylation seen in DLBCL is common in several hematological malignancies and solid tumors, says Cerchietti, such as colorectal, lung, breast, prostate and ovarian cancers. And while targeting SMAD1 in other cancers might not be an option, since the gene is tissue specific, "we think this approach will work in other cancer types in which aberrant DNA methylation is associated with silencing of genes that are important for response to chemotherapy and other treatments."
The next step, says Cerchietti, is to test this approach in a larger cohort of those with aggressive DLBCL, with the drug administered for a longer period of time. Cerchietti and colleagues have clinical trials underway to test this approach in lymphoma patients whose tumors did not respond to standard therapies, and they are moving into larger, multi-center trials of this treatment in other cancer types as well.