Scientists have long known that when a normal cell becomes cancerous, certain genes — the ones that make sure cells grow in an orderly way — get out of whack. But much later on, trouble finds other genes, too; these aren’t involved in making cancer, but in driving it, and these genes can become mutated, deleted, or duplicated.
At Hopkins and elsewhere, investigators have dedicated their lives to identifying the aberrant genes that cause cancer, with the hope that they can target these genes, and stop the disease. But David Shortle, M.D., Ph.D., and Alan Meeker, Ph.D., are taking a different tack: What if, they wonder, instead of focusing on controlling cell growth, they could target the central metabolism in cancer cells? It takes hundreds of reactions, driven by enzymes, to generate the chemical energy and small molecules that cells need to survive and keep on growing.
Scientists already know quite a lot of the biochemistry of cancer cells; for instance, “they’ve documented a variety of metabolic abnormalities and deficiencies, plus heightened sensitivities to inhibitors of metabolism,” says Shortle. “Numerous cancer researchers have commented on these observations as possible avenues for new forms of chemotherapy. As cancer cells experience increasing physiologic stress as a result of these alterations, they become vulnerable to killing by additional stresses, induced with metabolic inhibitors.”
Metabolic inhibitors are drugs or agents that throw the proverbial monkey wrench in the clockwork of a cell; Shortle and Meeker believe that using several inhibitors — each one blocking a different reaction in a cells’ handling of the energy it needs to keep going — in combinations, at very low, nontoxic levels, will cause metabolism to fail in cancer cells, but not normal cells. “Our logic is that random genetic events, especially deletions and duplications of parts of chromosomes, have altered both the amounts of enzymes required for metabolism and the intricate feedback mechanisms responsible for their control,” Shortle says. “Because this network of reactions is so tightly interconnected, if we partially inhibit multiple reactions, it should be much more harmful to cancer cells than to normal cells with these mechanisms intact.”