Arul Chinnaiyan is not by nature a gambler. He wouldn't plunk down his retirement savings at the gaming tables in Las Vegas. But when it comes to science, he has some ideas with which he's willing to go "all in," as poker players put it.
Chinnaiyan, a pathologist at the University of Michigan School of Medicine, is working to uncover the molecular flaws at the heart of the most common and deadly human cancers.
"We're looking for things that shift the paradigm," Chinnaiyan says of his admittedly high-risk plans. The paradigm he's referring to is a long-held assumption that the molecular defects that generate "liquid" cancers like leukemia are fundamentally different from those that cause the much more common solid tumors—breast, colon, lung, prostate, and so forth. Recently, Chinnaiyan made a stunning discovery that calls this notion into question, with promising implications for improving cancer therapy.
According to current thinking, leukemia, lymphoma, and other blood cancers are caused when chromosomes inappropriately swap pieces of genetic material in a process called translocation. By contrast, most solid tumors are caused by mutations that affect one or more growth-regulating genes in the cell, making it more difficult to design drugs to treat them.
In blood cancers, the reshuffling of broken chromosome segments can lead to a forced marriage between a promoter (a gene control element) and a cell growth gene, creating fusion genes that can spur rapid and uncontrolled cell division. The most well-known fusion event is between two genes known as Bcr and Abl, and it produces a product known as the Philadelphia chromosome. The Philadelphia chromosome triggers the runaway growth of white blood cells characteristic of chronic myelogenous leukemia (CML).
In the past several years, researchers have devised targeted drugs such as Gleevec (imatinib) that kill cancer cells selectively by shutting down their overactive fusion gene products—and they have dramatically improved the survival of patients with CML and other cancers. But such drugs have had far less impact in most solid tumors because of their myriad of DNA mutations, amplifications, and deletions.
In 2005, Chinnaiyan used DNA microarray technology and powerful computational analysis to analyze biopsies from patients with prostate cancer and found that almost 80 percent contained the same translocation-caused gene fusion. The fusion joined a male hormone-regulated gene, TMPRSS2, to DNA transcription factors of the ETS (erythroblast transformation specific) family, creating an overactive "on" switch for growth-stimulating genes in prostate cells.
Because that discovery did not fit with current dogma, "We didn't believe our result at first, and we had to carry out further studies before we convinced ourselves it was true," Chinnaiyan observes. "We think this is the causative lesion—it's the 'Bcr-Abl' in prostate cancer."
The fusion gene discovery inspired Chinnaiyan's current ambitious plans to use high-throughput search methods to find fusion genes he believes may be the key to many solid tumors. "We're working diligently in breast cancer, because we believe there is an estrogen-regulated gene fusion comparable to the androgen-regulated gene fusion we found in prostate cancer," he says.
The massive hunt for gene fusions in a range of solid tumors is challenging, he says. It will require developing thousands of molecular probes to perform large-scale fluorescence in situ hybridization and DNA sequencing. If his gamble is successful, gene fusions identified in solid tumors might provide targets for new drugs that are better than the current therapies for major, deadly forms of cancer.