April 4, 2011

Scientists Devise Targeted Therapy Strategy For Rare Form of Childhood Cancer

(Ivanhoe Newswire) -- Scientists have achieved one of the oldest and most rarely achieved goals of cancer research"”they have found a way to "distract" cancer cells from their normal activities and make them act like normal cells.

The scientists, from Dana-Farber Cancer Institute and Brigham and Women's Hospital, managed to distract the cancer cells of a rare form of cancer called NUT midline carcinoma (NMC) that usually affects children and young adults. NMC is lethal; according to researchers, most patients suffering from the cancer only live about nine and a half months after diagnosis.

The cause of NUT midline carcinoma is a "translocation""”two genes from different chromosomes bond and form an abnormal, fused protein called BRD4-NUT.  BRD4-NUT causes cells to become cancerous by attaching to proteins called histones, which are part of the machinery for switching genes on and off. In effect, BRD4-NUT prevents the changes that allow cells to develop into adult cells and leaves them in a state of perpetual youth.

To combat the effect of BRD4-NUT, scientists treated the NUT midline carcinoma cells with a substance called an HDAC (histone deacetylase) inhibitor, which creates competing binding sites for BRD4-NUT throughout the cell nucleus. The idea behind using HDAC was to lure BRD4-NUT away from certain locations in the genome, distracting it from its normal activity. Scientists found that NMC cells treated with the HDAC inhibitor turned into regular, non-dividing skin cells. This process is called "differentiation," and it has been a main goal of cancer research for over fifty years.

"What happened was that the cells remembered what type of cell they initially were and switched back to being normal skin-like cells. BRD4-NUT, it turns out, interferes with cell memory. Blocking the protein with HDAC inhibitors restores that memory," Christopher French, M.D., senior author of the study and the person who discovered the cause of NMC, was quoted as saying.

The success of HDAC was further proved in studies with animals engrafted with NMC tissue"”when treated with HDAC inhibitors, animals with NMC had slower growing tumors and lived longer than those who did not receive the HDAC inhibitors. The results led to the first clinical trial of the HDAC inhibitor in a child with NMC. The results were positive-- after five weeks of treatment, PET scans showed the child's tumor was less active than at the start of the therapy. Though the child eventually died of NMC, the response to the HDAC inhibitors left scientists hopeful about the potential of using HDAC inhibitors to combat NMC.

"We're optimistic that future versions will be both more effective and easier for patients to tolerate"¦To our knowledge, this study represents the first time a targeted drug has demonstrated anti-cancer activity against this devastating tumor. The same approach may prove beneficial against other cancers as well,"  James Bradner M.D., the study's senior co-author, at Dana-Farber Cancer Institute, was quoted as saying.

SOURCE: Cancer Research, March 29, 2011