Click on a research brief to learn more about the leading-edge research being conducted at Jefferson:
Making Cancer Drugs More Effective
In 2001, Paul Nurse won a Nobel Prize for discovering a protein he called WEE1, which was important in monitoring cell division. Since uncontrolled cell division is a hallmark of cancer, researchers showed that tumors turn up the production of the WEE1 protein to resist the effects of chemotherapy. Recently, researchers used that knowledge to develop drugs that block the WEE1 protein in cancer, and are using these drugs in early clinical trials to make some chemotherapy treatments more effective and improve patient outcomes.
To date, however, scientists still don’t know how cancer overproduces the WEE1 protein to bypass chemotherapy. Further, cancers often find ways around some drugs, like the ones used to treat pancreatic cancer.
Jefferson researchers led by Jonathan Brody, PhD, director of the Research Division of the Department of Surgery, started to look at proteins that might control WEE1 activation in the hopes of making chemotherapy more effective against cancer cells. In work published in the journal Cancer Research, Dr. Brody and colleagues showed that a protein named HuR (which is active and supportive of cancer) turns WEE1 on in cancer cells when exposed to clinically utilized chemotherapies and allows one of the most lethal types of cancer (i.e., pancreatic) to resist this therapy. Therefore, blocking HuR by itself may block WEE1 and enhance standard chemotherapy against a deadly cancer.
Waking a Desire for Sleep
People run on a 24-hour clock that governs our desire to sleep, our metabolism and the efficiency of other bodily functions. That cycle, called our circadian rhythm, follows the sun’s schedule of daylight and darkness. Researchers have uncovered a number of genes that drive these functions, but just how these genes are involved in making us feel sleepy at the end of the day has been a mystery.
Researchers at Jefferson, together with collaborators at Johns Hopkins, searched for fruit fly mutants with disruptions in their sleep patterns and found one mutant that went to sleep later than others after lights-out. The researchers, co-led by Jefferson’s Kyunghee Koh, PhD, an assistant professor in the Department of Neuroscience, called the mutated gene “Wide Awake,” or “WAKE” for short. They found that the Wake protein is expressed in a class of neurons in the brains that are involved in keeping fruit flies alert and awake. When the researchers got rid of the Wake protein in these “alert” neurons, the flies stayed up longer after the lights were turned off. The Wake protein cycles throughout the day, accumulating at its highest levels at dusk. Once accumulated, the Wake protein muffles the alert neurons, dimming their excitability, and making it easier to fall asleep. The research was published online in the journal Neuron.
The researchers then looked at the expression pattern of the mammalian homolog of the Wake gene in the mouse brain and found that it is highly expressed in neurons similar to the fly “alert” neurons, suggesting that a similar mechanism could be at play in mice and humans. If that turns out to be the case, the work could one day help people who have difficulty getting to sleep.
Antiviral Therapy Stalls Cancer
For patients with chronic hepatitis B, the biggest worry is developing liver cancer (hepatocellular carcinoma, or HCC). These patients are often put on antiviral (anti-HBV) medication to help prevent the disease. However, before these drugs were available for preventative treatment, patients who developed HCC were not expected to live long, because of a high rate of cancer recurrence. Now, research from Jefferson shows that treating these patients with antiviral therapy during and after their tumor ablation – which kills tumor cells by heat, cold or chemotherapy – can stall the recurrence of liver tumors.
The study, published in the journal Cancer Medicine, was the first U.S.-based study of its kind and followed patients for up to 13 years after initial treatment, making it the longest follow-up study in the world. It evaluated patients with HBV-associated liver cancer who underwent tumor ablation. Patients who had received antiviral therapy after ablation lived a median of 6.6 years – the longest lived for more than 13 years – whereas the untreated group lived a median of 1.3 years.
“This novel treatment strategy offers an alternative to liver transplantation in patients with HBV-associated HCC,” write the researchers, led by Hie-Won Hann, MD, professor of Medicine at the Liver Disease Prevention Center, Division of Gastroenterology and Hepatology at Jefferson, along with Robert Coben, MD, associate professor of Medicine, and Anthony DiMarino, MD,William Rorer Professor of Medicine and director of the Division of Gastroenterology and Hepatology.