Volume 4, Issue 32 October 2007
The Chemotherapy of the Future
Michael Rape is an assistant professor of cell and develomental biology. In 2007, he was named one of 20 Pew Scholars in the Biomedical Sciences and awarded $240,000 for his cancer research.
If a woman is diagnosed with breast cancer, chances are her doctors will prescribe Taxol. First purified from the bark of the Pacific yew in the 1960s, the drug has since become one of the most prescribed cancer drugs of all time.
Like many other chemotherapies, Taxol stops cancer cells from proliferating out of control. But as these drugs arrest the growth of tumors, they also affect all other dividing cells in the body.
"If you have breast cancer, you don't need to kill all your bone marrow cells," says assistant professor of cell and developmental biology Michael Rape. "If we can find something only needed for cell division in breast tissue, you'll have a better probability for success because the side effects are much less severe, and you can give bigger doses for a longer time."
Rape has plans to exchange the brute force of today's cancer drugs for more fine-tuned therapies. The secret of his optimism: a class of enzymes called ubiquitin ligases. Over 1,000 different versions usher human cells through the steps required before they can divide. If these enzymes aren't functioning right, tumors often result. Taxol and many other chemotherapy drugs hinder these rogues and check cell division.
Enzymes called ubiquitin ligases are involved in cell division. Their job is to flag substrate proteins with a protein called ubiquitin. The structure of the ubiquitin flag determines whether the substrate is destroyed or recycled. Image credit: Michael Rape
"Many ubiquitin ligases are required for cells to divide, and they are often expressed in a tissue-specific manner. That gives us evidence that inhibiting them might affect cell proliferation in one tissue and not another," Rape says.
In a cell, ubiquitin ligases operate like tiny meter maids. They tag molecular machinery involved in cell division with a small protein called ubiquitin. The ligases may also link ubiquitin molecules into long single or branched chains. The structure of these chains determines whether the protein is destroyed or recycled for other purposes.
"We know that specific linear chains are important, but don't know what branched chains do.If you understand this reaction mechanistically, you can look for inhibitors at specific stages and get good tools for interfering with the process," Rape says.
Until now, Rape has focused on studying a handful ubiquitin ligases linked to breast, colon, and other cancers. He examines how these enzymes interact with other cell components, and how they build their ubiquitin chains. His ultimate goal is to find drugs that block these enzymes when they malfunction.
Ubiquitin ligases such as E3 have been linked to cancer. The red and green blocks show that E3 production often shifts in tissues with cancer. Image credit: Michael Rape
Rape's research is about to enjoy a dramatic expansion in scope. In September, he received a $1.5 million National Institutes of Health New Innovator Award. The award will help him screen the entire human genome for ubiquitin ligases expressed only in a specific tissue.
Rape will complement this work with a new method to find enzyme substrates. With it, Rape can screen every human protein for a match in just a few weeks. Once he finds a promising substrate-enzyme pair, he can then look for drugs that block it. The result could be that holy grail of cancer treatment—a tissue-specific chemotherapy.