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A Cure for Leukemia?

by SARAH LAJEUNESSE

Wait a minute. Cured? Really?


The compound pictured closely resembles delta-12-prostaglandin J3; photo illustration courtesy of Robert Paulson and Sandeep Prabhu

The compound pictured closely resembles delta-12-prostaglandin J3, or J3, a compound that targeted and killed the stem cells of chronic myelogenous leukemia, or CML, in mice during experiments. PHOTO ILLUSTRATION: COURTESY OF ROBERT PAULSON AND SANDEEP PRABHU

 

Two college researchers in the Department of Veterinary and Biomedical Sciences have cured leukemia in mice without any side effects, and they think their therapy will work in humans too.

As a science journalist, I have been trained to be skeptical of such dramatic claims. To me, finding a cure for cancer that doesn’t leave patients nauseous, bald, and downright exhausted is as elusive as finding Shangri-La.

Yet, professors Robert Paulson and Sandeep Prabhu have cured leukemia in mice, and they seem to have done it without the side effects and relapse risks that come with surgery, chemotherapy, and radiation treatments.

Here’s how.

 

A Partnership Is Born

It was a frosty morning in January when Robert Paulson knocked on Sandeep Prabhu’s office door with a paper that, unknown to either of them at the time, would change the course of their research and their lives.

“There was one sentence in this paper stating that the compound 15d-PGJ2 is part of a class of compounds that may be able to treat leukemia stem cells,” Paulson, a professor of veterinary and biomedical sciences, tells me as he, Prabhu, and I walk through his laboratory in Henning Building. “So I wondered if the compound Sandeep worked on, which is similar to 15d-PGJ2, would also treat leukemia stem cells.”

Paulson had been reading the paper because he studies leukemia, a cancer of the blood cells.

His lab is filled with several high-tech machines and dozens of chemical-containing glass jars stacked high on the shelves. Students staring at computers and surrounded by stacks of papers are so immersed in their work, they seem not to notice us as we pass by.

Paulson and his lab group are especially interested in understanding the differences between leukemia cells and leukemia stem cells, which make leukemia cells. They also are working to improve models of leukemia in animals, and are devising a method for growing leukemia stem cells in the lab so they can study them in detail.

Prabhu, an associate professor of immunology and molecular toxicology whose lab shares a wall with Paulson’s lab, studies various molecules that are created by the body in order to figure out what they do. One of his recent studies focused on the molecules that our bodies make when they metabolize fish oil.

“We were looking at the metabolism of omega-3 fatty acids to examine the production of new and novel metabolites by immune cells because omega-3s are known to have all kinds of health benefits, such as protecting against heart attacks and strokes and assisting with brain development,” said Prabhu. “What we found is that if you give your cells omega-3s from fish oil, they make this compound called ∆12-PGJ3 [delta-12-prostaglandin J3—or J3, for short], which no one ever knew existed before.”

Although the researchers had worked for years on opposite sides of a wall, the pair had never before worked together. Yet armed with Prabhu’s knowledge that human cells produce J3 when given fish oil, and also knowing that J3 is similar to the compound that had could be useful in treating leukemia cells, the scientists teamed up in a two-year quest to determine whether giving fish oil to mice would cure their leukemia.

What they found surprised them both.

 

The Big C

Cancer. It’s one of the most feared diagnoses in human health, and rightly so because half of all people with the disease die from it or its treatment. But some cancers are worse than others. Lung cancer, pancreatic cancer, and esophageal cancer, for example, are often deadly, while testicular cancer, breast cancer, and skin cancer, if caught early, can be cured with surgery, radiation, chemotherapy, or a combination of these treatments.

Leukemia sits somewhere in the middle. Some forms of it are curable, but others are more resistant to treatment. For instance, 90 percent of people diagnosed with chronic myelogenous leukemia (CML) are still alive five years after diagnosis, while only 40 percent of people diagnosed with acute myelogenous leukemia (AML) make it past five years. In total, some 245,000 people in the United States have a form of leukemia, with 40,000 new cases added and more than 20,000 deaths each year.

Since leukemia is a disorder of the white blood cells, which normally are responsible for fighting off pathogens, individuals with the disease may experience higher-than-normal rates of infection, such as infected tonsils or pneumonia. They also may bruise or bleed more readily than people without the disease because as abnormal white blood cells proliferate in their bone marrow, their platelets—those ever-important blood clotters—become displaced. Some patients also suffer from fevers, fatigue, and other flu-like symptoms.

Experts have suggested radiation, viruses, chemicals, tobacco use, and just plain crummy genetics as possible causes of leukemia, but no one really knows for sure what causes the disease.

Paulson and Prabhu in Paulson’s Henning Building Lab; photo by Steve Williams

Paulson and Prabhu in Paulson’s Henning Building Lab. PHOTO: STEVE WILLIAMS

 

Killing Stem Cells

While plenty of researchers worldwide are investigating leukemia’s origins, even more are searching for cures. Paulson and Prabhu are focusing specifically on curing AML and CML, two of the four forms of leukemia.

Shailaja Hegde, a graduate student in pathobiology, has been helping them from the beginning.

Part of Hegde’s job is to generate leukemia stem cells in culture and then inject them into mice. Once they have the disease, she injects 600 nanograms of the J3 compound into the abdomens of the mice every day for a week.

According to Paulson and Prabhu, once inside the rodents’ bodies, the J3 compound activates the p53 tumor suppressor gene, which is responsible for maintaining genomic stability and regulating how cells respond to DNA damage.

“If there’s a problem with a cell, p53 gets induced and the cell dies by programmed cell death,” Paulson said. “Cells in our bodies are pretty altruistic. They die when they’re told to die. That’s how the body gets rid of abnormal cells that could cause problems. But cancer subverts this process. We found that by treating the cells with the J3 compound, we turn on the p53-dependent cell death pathway, which causes not only the leukemia cells to die, but the leukemia stem cells to die as well.”

Killing the leukemia stem cells, he added, is essential if you want to cure leukemia.

“Leukemia stem cells make what are referred to as bulk leukemia cells,” he explains. “Part of the problem with chemotherapy is that it kills the bulk cells because they’re dividing rapidly, but the stem cells, which divide less rapidly, can hide. Killing the stem cells is important because stem cells can divide and produce more cancer cells, as well as create more stem cells.”

Prabhu said the current therapy for CML and AML extends the patient’s life by keeping the number of leukemia cells low, but the drugs fail to completely cure the disease because they do not target leukemia stem cells.

“We were able to show in the cell culture dish and in our mouse models that J3 works quite well at killing both leukemia cells and leukemia stem cells,” he said. “The compound really cures mice of leukemia. It worked for every single mouse we tried it on. And it cured them without any side effects and without relapse.”

Prabhu noted that the lack of side effects is due to the fact that fish oil is nontoxic, though he warns that taking too much of it can be somewhat dangerous as fish oil is known to contain heavy metals, like mercury.

“We were completely surprised by what we found,” he said. “We had no idea that the J3 compound would work so well.”

Craig Jordan, the Philip and Marilyn Wehrheim Professor at the University of Rochester Medical Center who is collaborating with Paulson and Prabhu, also was surprised by the results.

“The J3 compound is a very novel approach to leukemia therapy,” Jordan said, “and the findings in the mouse models were quite impressive.”

 

Cure in Hand—Now What?

So, Prabhu and Paulson have cured leukemia in mice using a compound derived from fish oil. I wonder, “Does this mean that popping a drugstore fish-oil capsule can help protect against leukemia?”

“Yes, it may,” Prabhu says, “depending on whether or not your body produces J3 when it metabolizes fish oil.”

According to Prabhu, there is variation in the human population regarding how people metabolize fish oil. While some people take fish oil and produce J3, others may not be able to synthesize the compound. To avoid this discrepancy in their mice models, the researchers injected the mice with the purified compound rather than with fish oil.

Now that the team knows that J3 cures leukemia in mice when they inject it into the rodents’ abdomens, they want to know if the compound will work if administered orally.

“We are investigating how stable the compound is and whether it will break down in the stomach, so we are trying some experiments using simulated gastric juice,” Prabhu said. “We also want to know if you give it to a mouse in a pill form does enough get in to the right place or do you have to do an intravenous injection?”

In addition, the scientists want to know if the compound will work the same way in humans. Craig Jordan has helped with this part of the project by providing the Penn State team with human leukemia cells. Paulson and Prabhu are growing these cells in culture dishes and then adding J3 to see if it kills them.

After investigating the effects of J3 on human leukemia cells in cell culture dishes, the team plans to grow human leukemia cells in mice that lack an immune system to see if the compound will work in vivo. If it works, they hope to partner with a company set up a clinical trial.

“Both of us know that a lot of people have cured cancer in mice and that most of those cures never made it to the clinic,” said Paulson. “But we’re optimistic that our therapy will translate into humans. If it does and we can help people live even a little bit longer, it would be an incredible thing.”