PHILADELPHIA—A team of researchers from Weill CornellMedical College in New York has discovered a method for reprogramming diffuse,large B-cell lymphomas (DLBCLs) that are resistant to chemotherapy, through theuse of the drug azacitidine. Azacitidine, also known as VIDAZA, is a nucleosidemetabolic inhibitor indicated from the treatment of the bone marrow disordermyelodysplastic syndrome. DLBCL is a cancer of the white blood cells thatproduce antibodies, and represents the most common type of non-Hodgkin lymphomain adults.
The researchers conducted a Phase I trial in 12 patients recentlydiagnosed 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. Thepatients received azacitidine, in escalating doses, eight days before beginningsix cycles of standard chemotherapy. Of the dozen patients, 11 demonstrated acomplete response, and 10 remained in complete remission for up to 28 months.Additionally, side effects from azacitidine were minimal, though two patientswho received the maximum dose of the drug had dose-limiting toxicities.
"When lymphomas are formed, they shut down the cellularprograms that sense that something is wrong in the cells. Once these fail-safemechanisms that trigger cell death are shut down, it becomes difficult to killthe tumor with chemotherapy," said Leandro Cerchietti, M.D., assistantprofessor at the Hematology and Oncology Division of Weill Cornell MedicalCollege in New York and a corresponding author for the study. "Our study showedthat using low concentrations of the DNA methyltransferase inhibitorsdecitabine or azacitidine, these fail-safe mechanisms can slowly be awakened toinduce lymphoma cell death when chemotherapy is administered."
"We showed that aggressive lymphomas can be reprogrammed toa more benign disease," he added. "We think this work has the potential tochange the standard of care for patients with aggressive lymphomas."
Preclinical experiments helped Cerchietti and his colleaguesdetermine how lymphomas, which demonstrate a significant resistance tochemotherapy, avoid these cancer-killing drugs. What they found was that allDLBCLs present with a high degree of aberrant DNA methylation, which "silences"certain genes, leads to chemotherapy resistance. SMAD1 was among the genes thatwere found to be silenced in DLBCLs.
"SMAD1 is part of a family of intracellular proteinsinvolved in informing the cellular nucleus about the conditions of themicroenvironment," Cerchietti explains. "Specifically, SMAD1 respond to thepresence of extracellular proteins called BMP (and in lymphoma cells also TGFB)and acts a transcription factor regulating the expression of genes involved incell cycle arrest and senescence induction."
In biopsy specimens collected from the study participants,the researchers found that following azacitidine treatment, methylation ofSMAD1 decreased while the SMAD1 protein increased, giving them proof ofprinciple. Tests with DLBCL cells and mice with human lymphoma xenograftsshowed that DNA methyltransferase inhibitors, such as azacitidine, are mosteffective when administered before chemotherapy, not simultaneously.
The aberrant DNA methylation seen in DLBCL is common inseveral hematological malignancies and solid tumors, says Cerchietti, such ascolorectal, lung, breast, prostate and ovarian cancers. And while targetingSMAD1 in other cancers might not be an option, since the gene is tissuespecific, "we think this approach will work in other cancer types in whichaberrant DNA methylation is associated with silencing of genes that are importantfor response to chemotherapy and other treatments."
The next step, says Cerchietti, is to test this approach ina larger cohort of those with aggressive DLBCL, with the drug administered fora longer period of time. Cerchietti and colleagues have clinical trialsunderway to test this approach in lymphoma patients whose tumors did notrespond to standard therapies, and they are moving into larger, multi-centertrials of this treatment in other cancer types as well.