'Reprogrammed' treatment-resistant lymphomas respond to cancer drugs

A phase I clinical trial showed diffuse, large B-cell lymphomas (DLBCLs) resistant to chemotherapy can be reprogrammed to respond to treatment using the drug azacitidine, according to a study published in Cancer Discovery, a journal of the American Association for Cancer Research.

Patients whose lymphomas recur after initial are treated with a combination of approaches, including high-dose chemotherapy followed by a . However, some patients have tumors that do not respond to these extensive second treatments, and many of these patients die within two years of diagnosis.

"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. "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 when chemotherapy is administered."

Cerchietti and colleagues conducted a phase I trial in patients with newly diagnosed DLBCL. Eleven of the 12 patients enrolled were more than 60 years old when diagnosed, which meant that they were at high risk for after initial treatment. The patients were treated with azacitidine, in escalating doses, eight days prior to initiation of six cycles of standard chemotherapy. Side effects from pretreatment with azacitidine were minimal. Two patients who were treated with the of azacitidine had dose-limiting toxicities.

Of the 12 patients, 11 had a complete response and 10 remained in complete remission for up to 28 months.

"We showed that aggressive lymphomas can be reprogramed to a more benign disease," said Cerchietti. "We think this work has the potential to change the standard of care for patients with aggressive lymphomas."

The researchers conducted the clinical trial based on the results of their extensive preclinical experiments to determine the mechanisms by which lymphomas evade chemotherapy drugs. They found that compared with normal cells, all DLBCLs possess a high degree of aberrant DNA methylation, a process which "silences" certain genes, causing resistance to treatment.

Using DLBCL cells and mice bearing human lymphoma xenografts, the researchers showed that DNA methyltransferase inhibitors are most effective if administered prior to chemotherapy, but not concurrently. They also found the gene SMAD1 to be silenced in the unresponsive tumors.

When the researchers looked for SMAD1 status in the biopsy specimens collected from patients enrolled in the phase I trial, they found that after treatment with azacitidine, there was a decrease in SMAD1 methylation and increase in SMAD1 protein, providing proof of principle.

Cerchietti and colleagues are currently conducting clinical trials with with lymphomas whose tumors failed to respond to standard therapies. They are in the process of conducting larger, multicenter trials to extend this treatment to other cancers as well.

add to favorites email to friend print save as pdf

Related Stories

High-dose Vorinostat effective at treating relapsed lymphomas

Feb 04, 2013

Patients whose aggressive lymphomas have relapsed or failed to respond to the current front-line chemotherapy regimen now have an effective second line of attack against their disease. Reporting the results of a first-of-its-kind ...

New hope for hormone resistant breast cancer

Jul 22, 2013

A new finding provides fresh hope for the millions of women worldwide with oestrogen receptor positive breast cancer. Australian scientists have shown that a specific change, which occurs when tumours become resistant to ...

Recommended for you

The fine line between breast cancer and normal tissues

7 hours ago

Up to 40 percent of patients undergoing breast cancer surgery require additional operations because surgeons may fail to remove all the cancerous tissue in the initial operation. However, researchers at Brigham ...

Pancreatic cancer risk not higher with diabetes Rx DPP-4i

8 hours ago

(HealthDay)—There is no increased short-term pancreatic cancer risk with dipeptidyl-peptidase-4 inhibitors (DPP-4i) compared to sulfonylureas (SU) and thiazolidinediones (TZD) for glycemic control, according ...

Good bowel cleansing is key for high-quality colonoscopy

10 hours ago

The success of a colonoscopy is closely linked to good bowel preparation, with poor bowel prep often resulting in missed precancerous lesions, according to new consensus guidelines released by the U.S. Multi-Society Task ...

New rules for anticancer vaccines

12 hours ago

Scientists have found a way to find the proverbial needle in the cancer antigen haystack, according to a report published in The Journal of Experimental Medicine.

User comments