New drug target for cancer

Scientists have developed a new drug that blocks a transcription factor -- previously thought to be un-blockable -- that has been causally linked to leukemia and several other cancers of the lungs, ovaries, pancreas, and gastrointestinal tract, they report in linkurl:Nature;http://www.nature.com/nature/index.html this week.

Bone marrow smear showing acute
lymphoblastic leukemia
Image: Furfur, Wikimedia Commons

The Notch transcription factor regulates cell-cell communication in the Notch signaling pathway, a system governing cell growth and development. Mutations in the transcription factor can result in uncontrolled cell growth, often causing cells to turn cancerous. But transcription factors are notoriously hard for medicinal chemists to target because they work by forming complexes with multiple proteins, leaving no open binding sites for small molecules to fit into. "It's exciting research," said linkurl:Andrew Weng,;http://www.terryfoxlab.ca/people/aweng/andrew.aspx a molecular biologist at the British Columbia Cancer Agency in Canada, who was not involved in the study. "A lot of people have been asking for a way to inhibit transcription factors, but efforts have been unsuccessful for so long. This new study holds a lot of therapeutic potential." Faulty Notch proteins aren't the only transcription factors that stimulate disease. Other flawed transcription factors in various systems have been linked to illnesses such as diabetes and autoimmune diseases. "Entire drug development companies have been created to target transcription factors," said linkurl:Gregory Verdine,;http://glviris.harvard.edu/people.d/GLVBiosketch.htm a chemical biologist at Harvard University and the corresponding author of the study. "But for years, no one was successful." In the process of activation, different components of the transcription factor complex fit together like puzzle pieces one after another. The final piece, a mastermind-like (MAML) protein that activates the system, must bind to the complex along a long, shallow groove created as the other pieces come together. Verdine and Jay Bradner, another corresponding author of the study and a cancer biologist at the Broad Institute, wondered whether blocking this landing spot, and therefore inhibiting the attachment of the mastermind-like proteins, could effectively shut down the transcription factor. That groove, however, has a helical shape. The two researchers and their colleagues developed a way to essentially "staple" a synthetic peptide into a complementary helical shape, allowing it to fit into the groove. Without a place to land, the mastermind-like proteins would pass by the complex and the Notch signaling pathway would remain inactive. The researchers tested the stapled peptides on human T-cell acute lymphoblastic leukemia (T-ALL) cell lines and found that the drug inhibited cell proliferation associated with the Notch transcription factor, but did not block the growth of cells that are not regulated by Notch. This led them to believe that the peptides were effectively targeting the transcription factor complexes in the right spot. The researchers also found that mice injected with T-ALL cells and treated with the stapled peptides showed lower leukemia counts in the bone marrow and spleen than those that went untreated. Next, Verdine and his colleagues injected mice with bioluminescent leukemia cells to examine how different doses of the stapled peptide drug would affect the disease's progression. In nearly 90% of the untreated mice, the cancer progressed at a steady rate. Mice who received the peptides once daily showed slightly less disease progression. Mice treated twice daily showed significant tumor regression. "The exciting results described in this paper may help dispel deeply-rooted reservations among medicinal chemists regarding the vast potential of... peptides as leads for drug discovery," linkurl:Paramjit Arora,;http://chemistry.fas.nyu.edu/object/paramjitarora.html a chemist at New York University and author of an accompanying commentary on the study, wrote in an email. Weng, however, cautioned that the drug could have side effects, as it blocks a widely-present signaling mechanism. "If you are inhibiting the entire Notch pathway, you should see things like immune suppression," he said, "or impacts on the gastrointestinal system." Still, he said, the paper is a "remarkable step forward in both targeting potential transcription factors with drugs... and furthering our understanding of Notch biology."
**__Related stories:__***linkurl:A ticketmaster transcription factor;http://www.the-scientist.com/blog/display/55806/
[29th June 2009]*linkurl:Notch-ing up cancer genes;http://www.the-scientist.com/article/display/21120/
[18th February 2003]*linkurl:Interpreting the signaling of Notch;http://www.the-scientist.com/article/display/12270/
[19th February 2001]