Lung cancer kills more Americans than does any other type of cancer. Arguably one of the worst forms of the disease, lung cancer often goes undiagnosed until it reaches advanced stages, and its resilient and aggressive cells survive most types of chemotherapy while continuing to grow and invade. In recent years, very little progress has been made in —until now.
APU assistant professor of biology and chemistry Melissa LaBonte ’04, Ph.D., in a multidisciplinary collaboration with her husband, Peter Wilson, Ph.D., senior research associate at the Norris Comprehensive Cancer Center, and colleagues at the University of Southern California and the University of California, Davis, is a pioneer in what is rapidly becoming a radical change in the war against cancer. These scientists joined efforts with the common belief that the key to improving the treatment of lung cancer with chemotherapy lies not only in the identification of new drugs, but also in looking at current drugs and identifying why, in some patients, these drugs do work.
This new era of cancer treatment based on “personalized medicine” tailors treatment to individual patients and rejects the one-size-fits-all approach of past chemotherapy. “Every patient should be treated as a unique individual, not only based on specific personal circumstances, but also on the molecular level as well,” said LaBonte. “Every human being has a unique DNA profile, and in a similar way, every cancer is unique and should be treated accordingly. If we can identify the biological reasons why some patients do extremely well during chemotherapy and apply this knowledge in future patient selection strategies, we introduce the possibility of delivering the most effective treatments the first time around and sparing other patients the burden of receiving a type of chemotherapy that does not work.”
Based on this premise, LaBonte and her colleagues began their preclinical research into individual cases of successful chemotherapeutics, and in particular, Pemetrexed, one of the most effective drugs used to treat lung cancer today. Pemetrexed, which shrinks tumors in approximately one in three lung cancer patients, works by inhibiting the cancer cells’ ability to replicate its DNA, the blueprint for every critical function of the cell including survival. If the cancer cell cannot replicate its DNA, or its DNA becomes damaged and is prevented from repairing itself, it cannot survive and replicate; therefore, the growth of the tumor stops and then the tumor shrinks as the cancer cells die. “Although cancer cells often find ways to beat this drug, we identified one way in which they resist Pemetrexed and have demonstrated that we can reverse it, making lung cancer cells that were virtually unaffected by Pemetrexed die very rapidly,” said Wilson.
“By analyzing tumor specimens from lung cancer patients and from cell line models in the laboratory, we ascertained that in some lung cancer patients, the tumor cells have extremely high levels of an enzyme called dUTPase, much higher than normal cells,” said LaBonte. “This leads to a very strong protective effect and resistance to treatment with Pemetrexed, making chemotherapy with this drug ineffective in those patients. When we inactivated dUTPase in our lung cancer cell line models and prevented dUTPase from protecting DNA during treatment with Pemetrexed, the lung cancer cells died rapidly. We are currently in the process of developing new drugs to target dUTPase.”
This ability to take a cancer drug that has historically proven ineffective against cancer cells and make it highly effective has the potential to revolutionize cancer treatment and benefits millions of patients worldwide. The groundbreaking study earned the cover of the March 2012 Journal of Molecular Cancer Therapeutics and has inspired ongoing research targeting other difficult-to-treat cancers, such as pancreatic, breast, and colorectal, using similar drugs that prevent cancer cells from replicating their DNA.