New drug type developed to kill lymphoma cells

Scientists have developed a new type of drug designed to kill non-Hodgkin lymphoma tumour cells.

The breakthrough could lead to potential non-toxic therapies for cancer patients.

The researchers, including Dr. Ari Melnick, of Weill Cornell Medical College, Dr. Alexander MacKerell, of the University of Maryland and Dr. Gilbert Prive, of the University of Toronto, have identified a drug that targets an oncogene known as BCL6.CL6 functions as a master regulatory protein.

"It's a protein that controls the production of thousands of other genes. Because of that, it has a very profound impact on cells and is required for lymphoma cells to survive and multiply," said Melnick.

BCL6 causes the majority of diffuse large B cell lymphomas, the most common form of non-Hodgkin lymphoma.

Currently, about 60 percent of diffuse large B cell lymphomas can be cured with chemo-immunotherapy, said Melnick.

"The hope is that we can improve that to a higher percent, and in the long term reduce the need for chemotherapy," he added.

Traditional cancer drugs target enzymes, which have small pockets on their surfaces that can be blocked with molecules.

Until now, pharmaceutical companies have been reluctant to create drugs that target a protein like BCL6 because they function through a different mechanism involving interactions with cofactor proteins involving extensive protein surfaces.

"And because the real estate covered by these interactions is so large, the drug companies have viewed these as being not druggable targets," said Melnick.

The researchers could identify a "hot spot" on BLC6 that they predicted would play a critical role in protein interactions.

They showed that their BCL6 inhibitor drug was specific to BCL6, and did not block other master regulatory proteins.

The drug had powerful lymphoma killing activity and yet was non-toxic to normal tissues.

"This is the first time a drug of this nature has been designed and it shows that it's not actually impossible to target factors like BCL6," he said.

Emerging data from other investigators suggests that BCL6 is important in many other tumor types, including forms of leukemia.

The study has been published in a recent issue of Cancer Cell. (ANI)

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New vasculitis therapy may help patients keep infertility, cancer at bay

A drug previously approved for the treatment of non-Hodgkin’s B cell lymphoma and rheumatoid arthritis, can treat severe ANCA-associated vasculitis as effectively as cyclophosphamide, the current standard therapy, say researchers.

The finding of Rituxan has been presented at the annual meeting of the American College of Rheumatology in Philadelphia.

“The reason this is a big deal is that this is a disease where people would come in and be told ‘listen, we are probably going to be able to get on top of your life-threatening disease by using cyclophosphamide, there is the potential for major side effects down the road from this drug,’” said Robert Spiera, M.D., an associate attending rheumatologist at Hospital for Special Surgery in New York.

“This study provides strong evidence that Rituxan works as well as cyclophosphamide, at least in terms of getting patients into remission, and over that acute hump of being very ill. And, we can treat patients without the likelihood of causing infertility or causing secondary cancers, which have been a concern with the use of cyclophosphamide,” the expert added.

Hospital for Special Surgery was one of nine centers involved in the Phase III trial, which was led by Ulrich Specks, M.D., a professor of medicine in the Department of Pulmonary and Critical Care Medicine at the Mayo Clinic, and John Stone, M.D., MPH, director, Clinical Rheumatology, Massachusetts General Hospital.

Vasculitis, an inflammation of the blood vessels, can damage tissues and organs and, in severe cases, lead to death. Specifically, the study examined something known as ANCA-associated vasculitis that includes Wegener’s granulomatosis and microscopic polyangiitis.

“The reason this is such a significant study is that this is an uncommon but devastating group of diseases,” said Dr. Spiera.

Prior to the use of cyclophosphamide treatment, 70 percent of patients who were diagnosed with severe forms of ANCA-associated vasculitis could be expected to be dead within three years. In the 1970s, doctors discovered that cyclophosphamide was extremely effective at combating the disease and could put people into remission. In the ensuing decades, however, doctors recognized that these drugs came with a price.

“If you followed patients long enough, you found they had a higher risk of leukemias, lymphomas and solid tumors,” said Dr. Spiera, who is also an Associate Professor at Weill Cornell Medical College. “People would sometimes develop terrible infections. Women, almost reliably, would become infertile, as did many men. So, although it was a dramatically effective drug at reducing remissions in these patients, it came at a price.”

In the current study, nine centers enrolled a total of 197 patients with severe Wegener’s granulomatosis or microscopic polyangiitis, two of the more common types of ANCA-associated vasculitis. Patients were given steroids and randomized to receive either the standard treatment with cyclophosphamide or Rituxan given at a dose of 375 mg/m2 weekly for four weeks.

At the time of the data analysis, 84 of the 99 patients in the Rituxan arm and 81 of the 98 patients in the cyclophosphamide arm had completed six months of follow-up. Investigators found that the treatments were equally effective in putting patients into remission and that, in fact, the treatment outcomes looked slightly better in patients receiving Rituxan.

“These results show that the Rituxan worked at least as well as cyclophosphamide,” Dr. Spiera said. “If anything, there was almost a hint of it maybe looking a little better, and even in the short term, it looked safer in some respects. This study shows that there is strong evidence that Rituxan may be an alternative to cyclophosphamide in this disease. It might help manage flares in patients who have gone into remission, and it could be a consideration as first-line therapy, especially in women of child bearing potential who have a good chance of losing their fertility if treated with cyclophosphamide.”

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