Most cells do metabolic somersaults to survive under stressful a condition – which is to say, they enlist the most expedient biochemical pathways to produce essential molecules in order to survive. By comparison, cancer cells perform high-wire cartwheels to recruit alternative pathways to thwart cancer drugs. As cancer cells do their best to dodge therapies aimed at destroying them, experts like Kathryn E. Wellen, PhD, an assistant professor of Cancer Biology and others across Penn Medicine, are looking for new ways to beat them at their own game by coming up with new targets for therapies.
One of the targets that Wellen is focused on is acetyl-coenzyme A (acetyl-CoA), a molecule that plays an essential role in energy production, fat metabolism, and gene expression. Because all of these basic functions rely on acetyl-CoA, researchers suspect that the enzymes involved in making it may be good targets for killing cancer cells. This approach has been the focus of many labs’ research since the 1990s. However, many types of tumors have found ways to get around the drugs that target these pathways, outsmarting them and continuing to spread throughout the body.
Knowing how clever cancer cells can be, Penn Medicine oncology researchers are well known for finding and exploiting new targets, starting with findings from the laboratory demonstrating how cancer cells behave in Petri dishes, for example, and probing them for clues about how that knowledge could be applied in patient care.
Every part of the cell seems to harbor a potential target. For instance, the ends of chromosomes, called telomeres, allow cells to continuously divide by keeping the ends of DNA from fraying. Breakdowns in this process are what eventually cause 15 percent of cancers. Roger Greenberg, MD, PhD
, an associate professor of Cancer Biology, developed a first-of-its-kind system to observe repair to broken DNA in newly synthesized telomeres
, an effort that has implications for designing new cancer drugs.
At another level, studies about a significant, yet poorly understood, part of the genome – the “dark matter of DNA” – and their alterations in human cancer are being investigated by Lin Zhang, MD, the Harry Fields Associate Professor of Obstetrics and Gynecology, and Chi V. Dang, MD, PhD, director of the Abramson Cancer Center. While, most studies of genomic alterations in cancer have focused on the miniscule portion of the human genome that encodes protein, Lin and Dang’s teams have mined these “dark matter” genetic sequences to an extent previously not uncovered. They mapped sequences not associated with the production of proteins and their relationship to 13 different types of cancer to provide clinicians with possible new ways to diagnose and treat cancer.
Taking a different approach, Wellen’s team in her cancer metabolism lab is working on determining whether the mechanisms that take over cancer cells and cause them to go rogue could also be exploited for fighting cancer. When ACLY (the gene for an enzyme that helps make acetyl-CoA) is deleted, Wellen’s team showed that both normal and cancer cell lines stayed alive and multiplied, although at a slower rate. Turns out those cells use an alternate pathway for metabolism – a proverbial bypass - to produce the essential acetyl-CoA. Without the ACLY enzyme, cells use acetate produced by gut bacteria to make acetyl-CoA to manufacture fats, epigenetic markers, and other needed molecules.
“With the knowledge gained in our study, we aim to target both paths of acetyl-CoA production in cancer cells – the path governed by the ACLY enzyme and the other using acetate metabolism,” Wellen said. “Cancer cells are smart, but we're hopeful our strategy of hitting both the regular and backup paths at same time will knock them down."
Image: Cartwheel by Ben Aston via Flickr Creative Commons