Stopping Lung Cancer Before It's Too Late
Lung cancer causes one in every three cancer-related deaths. More than 400 people die of the disease every day, which is more than breast, prostate, melanoma, colon, liver and kidney cancers combined. Lung cancer is difficult to treat because it can silently progress for decades before symptoms develop. “One of the biggest problems is that patients only get symptoms when the cancer is at an advanced stage” said Cincinnati Children’s researcher Dr. Vrushank Davé. “In terms of treatment, it becomes very hard to target a specific molecule or a pathway, because it has gone on for so long by the time it is detected that myriad pathways are already involved.”
Davé wants to understand the initial change in a cell that causes lung cancer. By getting at the root of the cancer, his lab can develop methods for early detection. He can also develop better treatments.
Davé is especially interested in a protein called PTEN. “PTEN serves as a brake on cell growth and suppresses tumor growth,” said Davé. PTEN is responsible for keeping a cell survival molecule called a PI3 Kinase under control. When PTEN is missing, PI3 Kinase can run rampant, causing uncontrolled cell growth and cancer. Davé believes that the mutation of PTEN may be the molecular switch that causes lung cancer in many patients—and this mutation might occur up to 30 years before a patient is diagnosed. “Our research indicates that the mutation could occur in the teenage years, but the obvious symptoms of the cancer might not appear until the patient is much older and the cancer has progressed to advanced stages,” said Davé. He hopes that in the future, an annual bronchial swab could check to make sure that young predisposed patients—due to genetics or smoking--have not had this mutation. If it is found, researchers might be able to head off the cancer before it develops further and becomes impossible to cure.
By mutating PTEN in mice, Davé can create lung cancer within a few months. Not only does this lend credence to the idea that PTEN mutations are involved in lung cancer initiation in humans, it also gives him a tool for other avenues of research. His mutated mice develop lung cancer much faster than standard lab mice, which are usually exposed to carcinogenic chemicals in order to develop cancer over a much longer period of time.
Davé’s more efficient mouse models have allowed him to expand his research to learn more about cancer stem cells. Even after the cancer seems to be destroyed in a patient, quiescent populations of cancer stem cells can become active and cause the cancer to come back. “Removing most of the cancer without getting the stem cells is like removing weeds without removing the roots,” said Davé. A better understanding of cancer stem cells might allow researchers to treat cancer in the later stages and make it go away for good. “One of the major hallmarks of cancer stem cells is that they divide very slowly compared to normal cancer cells, and since they divide slowly they are resistant to treatment,” said Davé. Current treatments target cancer cells that are dividing.
There is currently no method for targeting a cancer stem cell in the lungs, but Davé and his colleague Yi Zheng have been trying to identify the cancer stem cells by meticulously noting unique characteristics from cells in mouse tumor tissue, and then returning them to a healthy mouse. If these re-introduced cells cause lung cancer in healthy mice, they know they have characterized true cancer stem cells.
Since PTEN is important in regulating the normal stem cell population required for tissue maintenance, Davé thinks there is a good chance that PTEN modulates cancer stem cells. “Gene profiling of lung cancer cells carrying the PTEN mutation has given us a good handle on identifying critical molecules that can be targeted for cancer therapy” said Davé. “If we are able to target lung cancer stem cells in patients, then even lung cancers in the late stages can be treated. We can design drugs to target the cancer stem cells, which will reduce the chance of cancer remission and significantly increase survival."
