Searching For The Right Genes

Staff Writer
Tuesday, October 20, 2009
Women with breast cancer have seen a modest increase in survival rates over the past decade, as both prophylactic and combative treatment options become more widely available, and as expertise in genetics and molecular biology continue to expand on the clinical level. In this context, Jewish women in particular may benefit from genetic testing to determine whether or not they have BRCA1 and 2 gene deficiencies, which make one more susceptible to breast and ovarian cancers. Worldwide, breast cancer patients can also benefit now from hormonal chemotherapy treatments like tamoxifen, which inhibits estrogen from binding to its receptor, and herceptin, which inhibits the over-expressed HER2 cancer-causing growth factor receptor protein. But what about those women — and men — who don’t respond to these targeted drugs, and therefore must be subjected to general chemotherapy? (While the majority of breast cancer patients are women, men also get breast cancer.) Among people with breast cancer, about 15 percent of those in the United States and 15 to 20 percent in Israel, have a type of aggressive breast cancer that is extremely difficult to cure because the patients express neither the estrogen, the progesterone nor the HER2 receptors. Dan Canaani, professor of biochemistry at Tel Aviv University, is searching for a solution to this problem. Through his ongoing research — sponsored by the Israel Cancer Research Fund — Canaani aims to determine which molecular pathways are the culprits in question and then ablate their signaling pathways with specific molecular-targeting drugs. The patients, whom Canaani calls “triple negative,” also often display BRCA1 or BRCA2 deficiency as well. “It’s not utterly clear what are the targets I should concentrate on,” Canaani said, noting that there are hundreds, often even thousands, of differences between healthy and cancerous tissues. “What would happen if your reality was the Manhattan phone book?” Twelve years ago, Canaani began devising screening methods for new drugs or new targets that would take advantage of those differences, by meticulously lining up two cells side by side (cancerous versus normal) and testing them for potentially synergistic lethal target genes. While he could also technically imitate the same process using the entire human genome instead of specific molecular pathways, this type of research would be extremely costly as it encompasses thousands of genes expressed in the malignant breast. “In a way, it’s a guesswork, but one can make educated guesses,” Canaani said. “We’re not rich enough to try all the 25,000 human genes as potential drug targets.” The process is laborious — Canaani and his team start off with candidate genes, perhaps those that might be particularly expressive in these breast cancer patients. From there, he explained, they go on to select 10 or so genes and again test out the genetic suppressors among one or two of the final 10, to see whether or not triple negative tumor cell lines respond positively when those genes are suppressed. These tests take place both in cell cultures as well as in vivo, and the researchers investigate whether or not patients’ cell lines are particularly sensitive to the inhibitors, in comparison to healthy cell reactions. Other groups have begun to conduct similar types of research, but Canaani says that his laboratory was among the initiators behind this hunt for molecular targeting solutions in triple-negative breast cancer cases. One of Canaani’s collaborators includes Dr. Joerg Hoheisel, head of Functional Genome Analysis at The German Center for Cancer Research DKFZ in Heidelberg. Locally, another scientist looking at solutions to the triple negative problem is Deborah Toppmeyer, an associate professor of medicine at University of Medicine and Dentistry of New Jersey’s Robert Wood Johnson Medical School. Canaani credits much of his work to the Israel Cancer Research Fund, which has been financing his project to a large extent for the past 20 years. Because Israeli government funding to universities is currently insufficient in Canaani’s opinion, he said he is grateful to receive this grant that goes directly and entirely to his research efforts. “What was unique about it is this is an organization started by professionals who wanted to fund cancer research in Israel,” Canaani said. “Here, 100 percent net is going to research.” And he hopes that their continued research will allow scientists to combat yet another cause of breast cancer, saving the lives of many men and women along the way. He added, “Now we are simply going gene after to gene to find out.”

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