Detection and Treatment Possibilities for Rare Form of Colon Cancer opened by a Tumor Metabolism Discovery
Peutz-Jeghers syndrome, a rare inherited cancer syndrome causes, in those who suffer from it, gastrointestinal polyps and they get predisposed to colon cancer and other tumor types. The researchers at the Salk Institute for Biological Studies exploited the tumors’ weak spot and published their study in this week’s online edition of the Proceedings of the National Academy of Sciences.
This study proves that precancerous cells’ insatiable appetite for glucose reveals their existence before they can develop into full-fledged colon cancer, and hands targeted drugs the power to cut-off the tumors’ lifeline.
Reuben Shaw, a Howard Hughes Medical Institute Early Career Scientist and Hearst Endowment assistant professor in the Salk’s Molecular and Cell Biology Laboratory, said that there is no treatment for Peutz-Jeghers syndrome and that those who suffer from it must undergo several surgeries in order to get rid of the polyps and the tumors, as they arise.
He also stated that “Now, for the first time, FDG-PET scans, which detect increased glucose metabolism, can be used to monitor the development of these polyps and guide surgeries, since repeat surgeries are often necessary”.
A mutation in the tumor suppressor LKB1 causes the Peutz-Jeghers syndrome. Those who have a flawed version of the LKB1 gene have a much greater risk of developing a malignant tumor. This gene suffers a mutation in 20 percent of cervical carcinomas and 30 percent of non-small cell lung carcinoma.
In previous studies, Shaw showed that a metabolic master switch (an enzyme known as AMPK) was activated by LKB1. AMPK remains inactive and the cell carries out its normal processes, when a cell has plenty of energy. Otherwise, LKB1 turns on AMPK, which puts a damper on cell growth and proliferation. Therefore, by this process, cells do not know they face starvation and continue to divide.
The path way used by AMPK is mTOR, named after the powerful immunosuppressant rapamycin. postdoctoral researcher and lead author David Shackelford, Ph.D. stated that “Since a loss of LKB1 results in a hyperactive mTOR signal, we wondered whether we could use rapamycin as a targeted drug to treat the tumors that arise as a result of Peutz-Jeghers”.
In order to find out whether it works in practice as well as it sounds in theory, he treated mice which developed polyps in their intestines with rapamycin. After this experiment, he realized that the polyps were much smaller or non-existent in the treated mice.
After this discovery, Shackelford examined whether he could observe the drug’s effectiveness using a technique called FDG-PET, which stands for “Fluoro Deoxyglucose – Positron Emission Tomography”. This technique is used to visualize the level of glucose in cells, because tumor cells use glucose to fuel their growth.
After realizing that the mice lacking one copy of LKB1 expressed increased levels of glycolytic genes, he teamed up with imaging expert David R. Vera, Ph.D., Professor and Director of the Small Animal Imaging Research Program at the University of California, San Diego, to observe the presence of gastrointestinal polyps by using a microPET scanner.
Shackelford said that “When the first images came back, they confirmed what we had seen in our biochemical experiments. Their intestines lit up, and an autopsy confirmed that a polyp had caused the signal.” This represents hope for the people with Peutz Jeghers syndrome, but not only.
This work was supported by the the National Cancer Institute at the National Institutes of Health, the American Cancer Society, and the V Foundation for Cancer Research.
