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Extending Cancer Research in Central Pennsylvania

According to the American Cancer Society, some 245,000 people in the United States have leukemia, with 40,000 new cases added each year and more than 20,000 deaths each year.

Scientists in the College of Agricultural Sciences are conducting research aimed at preventing, treating, and curing one of the region's most prevalent diseases. Professors of Veterinary and Biomedical Sciences Sandeep Prabhu and Robert Paulson have found a safe and effective treatment for two kinds of leukemia: acute myeloid leukemia (AML), which kills 60 percent of patients within five years after diagnosis, and chronic myeloid leukemia (CML), which kills 10 percent of patients within five years after diagnosis. The team is preparing to test its treatment--high doses of fish oil--in human clinical trials in the near future.

Prabhu and Paulson aren't the only scientists in the College of Agricultural Sciences who are researching cancer. "Agriculture is about food, and compounds in certain foods [such as fish oil] are powerful cancer fighters," says Gary Perdew, interim head of the Department of Veterinary and Biomedical Sciences and the John T. and Paige S. Smith Professor in Agricultural Sciences. "Researchers across the college are focused on studying dietary approaches to cancer prevention and treatment with a goal of helping cancer patients in Pennsylvania and beyond."

According to Jeffrey Peters, Distinguished Professor of Molecular Toxicology and Carcinogenesis and deputy director of the Penn State Cancer Institute, more than 21,000 people are diagnosed with cancer in central Pennsylvania each year--with lung, colon, liver, breast, and prostate cancers among the most common. Unfortunately, many of the region's residents live in rural communities without convenient access to cancer hospitals, which can reduce their chances of achieving good treatment outcomes.

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Jeffrey Peters and his colleagues are teasing apart the biochemistry of why oleic acid found in avocados and olive oil, among other foods, is implicated in contributing to cancer prevention. Peters and his colleagues have narrowed their focus to a receptor, called peroxisome proliferator-activated receptor beta/delta, that occurs naturally on the DNA of human cells.

"There is a need in central Pennsylvania for better access to state-of-the-art cancer care," says Peters. "I view it as part of Penn State's land-grant mission to help provide this care to the residents of our Commonwealth."

According to Peters, Penn State aims to improve its cancer research and patient care by applying for designation as a National Cancer Institute (NCI) through the National Institutes of Health. Currently, there are 70 NCI-designated cancer centers in the United States, all aimed at developing and translating scientific knowledge from promising laboratory discoveries into new treatments for cancer patients.

"With numerous experts studying cancer, the College of Agricultural Sciences is playing an important role in Penn State's efforts to become NCI designated," says Peters. "With NCI designation, Penn State would be in a better position to conduct research that is relevant to the people of central Pennsylvania and to increase the number of clinical trials we conduct, which can directly benefit residents' health."

Fish Oil

Sandeep Prabhu and Robert Paulson are playing an important role in helping to position Penn State for NCI designation as they prepare their fish oil study for human clinical trials.

The team's research shows that omega-3 fatty acids from fish oil trigger the body's cells to produce a compound that is showing great promise for killing both leukemia cells and leukemia stem cells.

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Sandeep Prabhu

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Robert Paulson

The drugs currently available to patients with CML eliminate the bulk of leukemia cells, but not stem cells, says Paulson. "If you don't get rid of those stem cells, the cancer will come back," he says.

In collaboration with David Claxton, professor of medicine at the Milton S. Hershey Medical Center, the researchers are preparing to submit an application to the Food and Drug Administration to begin a clinical trial to test the effects of different doses of fish oil in patients with CML.

Specifically, they plan to enroll 30 CML patients who would likely relapse if they were to go off the standard-of-care drug. "We believe if they add fish oil to their treatment, we can accelerate their recovery and they will successfully remain in remission," says Paulson.

In the meantime, the team has submitted a grant proposal to the Leukemia and Lymphoma Society to conduct a second clinical trial focused on AML. "With AML, the standard of care, which is intensive chemotherapy, hasn't changed in almost 40 years," says Paulson.

The researchers are particularly interested in patients over age 60 who have a hard time tolerating intensive chemotherapy. "We're hoping to target that patient population and see if by adding fish oil, we can lower the dose of chemotherapy they receive so they can better tolerate the treatment and have better outcomes," Paulson says.

The Diet-Cancer Link

Besides fish oil, other components of foods are also thought to reduce cancer risk. For example, the oleic acid found in avocados and olive oil, among other foods, is implicated in contributing to cancer prevention. Jeffrey Peters is teasing apart the biochemistry of why this is the case. Peters and his colleagues have narrowed their focus to a receptor, called peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), that occurs naturally on the DNA of human cells.

"We found that fatty acids, like those in oleic acid, bind to PPARβ/δ on cells that are implicated in diseases like inflammatory bowel disease, diabetes, colon cancer, and non-melanoma skin cancer, and possibly work to suppress the cells' growth," says Peters.

To learn more about these receptors, Peters and his colleagues examine their function in human cells and mice. Called knockouts, these models are modified so they do not express PPARβ/δ. "By doing this you can tell if the receptors are required for the effects you see; in our case, suppression of cancer cell growth," he says. "We've discovered that if you activate the PPARβ/δ receptor by allowing it to bind with oleic acids from foods, that you can slow cancer growth."

A recent study, which Peters and his colleagues published in The Toxicologist in 2018, demonstrated the effects of PPARβ/δ on skin cancer. "The onset of tumor formation and tumor multiplicity were significantly decreased in response to receptor activation with both the synthetic and natural PPARβ/δ agonists (chemicals like oleic acid that activate PPARβ/δ)," says Peters.

Just as fish oil targets leukemia stem cells, so too does oleic acid target cancer stem cells. "Deep down in the center of tumors you have these stem cells, and if you don't kill them, you get recurrence of the cancer," says Peters. "The natural and synthetic PPARβ/δ agonists we're working with actually target these cells and make them die."

A Combination Treatment

Another class of compounds, called flavonoids, also helps to prevent cancer and may be useful in combination with chemotherapy drugs in treating cancer. Gary Perdew and his colleagues are examining the effects of flavonoids--which are found in bitter-tasting vegetables such as parsley and kale--and ellagitannins--which are found in pomegranates and walnuts, among other foods--on a cell receptor called the aryl hydrocarbon receptor (AHR). "The AHR promotes cancer when activated by agents such as those found in cigarette smoke," says Perdew. "We have shown that this activity can be blocked by flavonoids and ellagitannins."

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Gary Perdew and his colleagues are examining the effects of flavonoids--which are found in bitter-tasting vegetables such as parsley and kale--and ellagitannins--which are found in pomegranates and walnuts, among other foods--on a cell receptor called the aryl hydrocarbon receptor.

Perdew is studying the activity of the AHR in live cultured cells from patients with head and neck cancer as a result of smoking. "We're treating human tumor cell lines with flavonoids and ellagitannins to see how these antagonists affect the tumor cells," says Perdew. "We're also combining this approach with other chemotherapy drugs to see if they can augment standard chemotherapy. We are showing that these combinations really work."

In addition, Perdew is working with colleagues to combine his antagonist treatment with drugs that modulate immune responses that occur when the immune system responds to the death of so many cancer cells as a result of chemotherapy. "It turns out that once you undergo standard chemotherapy, there is some level of immune response to the cells that are dying, and the AHR may be augmenting this process," he says.

Perdew adds that it's possible that a combined treatment of standard chemotherapy, an immune response therapy, and antagonists to block the activity of the AH receptor can effectively eliminate cancer in the body. "Let's just say you had thousands and thousands of cells and after chemotherapy you're down to 100 cells," he says. "If you treat with our antagonists and possibly an immune response drug, could you get the cell count down to 10? And would these cells then be in such bad shape that they wouldn't grow back? That's what we hope to learn."

Bitter-Taste Sensitivity

The link between food intake and cancer incidence isn't always so clear. Joshua Lambert, associate professor of food science, and his colleagues were interested in determining how sensitivity to bitter-tasting foods might impact food choice and ultimately cancer risk. By examining cancer incidence among people with high bitter-taste sensitivity, the researchers hypothesized that women with higher bitter-taste sensitivity would consume fewer vegetables and have higher incidence of cancer.

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Joshua Lambert and his colleagues thought they could show that compounds in bitter-tasting vegetables, such as Brussels sprouts and broccoli, reduce cancer risk. By examining cancer incidence among people with high bitter-taste sensitivity, they hypothesized that women with higher bitter-taste sensitivity would consume fewer vegetables and have higher incidence of cancer.

But they were only partly right.

The research examined the relationship between the ability to taste the bitter-tasting chemical phenylthiocarbamide, known as PTC, and risk of cancer in a subset of the UK Women's Cohort Study--a study of 35,000 middle-aged British women whose diet, lifestyle, and health has been tracked for about 20 years.

Lambert and his colleagues analyzed the food intake of 5,500 women in the study, using a 217-item food-frequency questionnaire administered when the women joined the cohort in the late 1990s. The researchers hypothesized that women with higher bitter-taste sensitivity would consume fewer vegetables and have higher incidence of cancer.

Although there was no correlation between bitter-taste sensitivity and vegetable intake, the researchers did find that, among older women, bitter-taste sensitivity was associated with greater cancer risk. The findings were published in July in the European Journal of Nutrition.

Lambert notes that depending on the level of sensitivity to bitter tastes, study participants were classified as super-tasters, tasters, or non-tasters. "The difference in cancer incidence between the women with the highest bitter-taste sensitivity and those with the lowest was striking," he says. "'Super-tasters' had about a 58 percent higher risk of cancer incidence compared to 'non-tasters.' Tasters also had a higher risk of developing cancer, compared to women who were classified as 'non-tasters,' but the effect was more modest."

However, in this analysis, high bitter-taste sensitivity didn't yield the expected link to dietary choices that could explain the higher cancer incidence, Lambert points out. "Our hypothesis was that women who had higher bitter-taste sensitivity--either the 'tasters' or 'super-tasters'--would be at higher risk of developing cancer than women who were 'non-tasters.' We thought that would happen because over their lifetime they would have consumed fewer bitter-tasting vegetables, which have been reported to have cancer preventive activities," he says.

"When we looked at the data, we saw that for women over 60, cancer risk was higher among women classified as 'tasters' or 'super-tasters,'" he says. "But we didn't see any differences in bitter-tasting vegetable consumption. Women classified as 'tasters' and 'super-tasters' consumed as many Brussels sprouts and as much broccoli, for instance, as the 'non-tasters.'"

So where does that leave researchers? Anxious to do more studies to unravel the factors that drive the relationship between bitter-taste sensitivity and cancer, says Lambert.

Studying Cancer at Its Source

While some researchers in the college are exploring the link between diet and cancer incidence, others are investigating the molecular underpinnings of the disease.

For example, Adam Glick, professor of veterinary and biomedical sciences, and colleagues are examining a protein, called inositol-requiring enzyme 1 (IRE1), that may serve as a key driver in a series of molecular interactions that can both promote and, paradoxically, inhibit tumors in certain types of cancers, such as non-melanoma skin cancers.

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Adam Glick and colleagues are examining a protein, called inositol-requiring enzyme 1 (IRE1), that may serve as a key driver in a series of molecular interactions that can both promote and, paradoxically, inhibit tumors in certain types of cancers, such as non-melanoma skin cancers.

"We're studying the basic biology of cancer to discover new ways to target the disease," says Glick. "The more we know about the molecular circuitry--and the mutations and genetics of cancer--the more we can design drugs that specifically target cancer cells without harming normal cells."

According to the researchers, IRE1 is regulated by the Ras protein, which is known to be important in human cancer. Ras normally helps manage cell growth and division, but when mutated, it can cause many different types of cancer. "The end result is cells don't continue to proliferate and undergo a process called senescence, or accelerated aging," says Glick. "Basically, they die."

According to Nicholas Blazanin, a former graduate student in Glick's laboratory and a current postdoctoral researcher at the University of Texas at Austin, this is the first time that a connection between Ras and a dual role of IRE1 has been made in cancer.

The researchers, who presented their findings in the journal Proceedings of the National Academy of Sciences in 2017, say the power of both promoting and inhibiting tumors makes IRE1 a promising focus for future anti-cancer research.

"What this says to us is that by manipulating IRE1 we can potentially drive tumor cells to self-terminate," says Glick.

The team hopes future research may shine a light on the mechanism in other forms of cancer as well. "We're starting to test the hypotheses that we generated both on skin cancer and in lung cancer models," says Glick. "Preliminary results from a lung adenocarcinoma model suggest that the IRE1a-XBP1 pathway is very important for development of lung cancer."

An additional project in the Glick lab, funded by the Penn State Cancer Institute and Institutes of Energy and the Environment, involves a collaborative study with Daniel Hayes, associate professor of biomedical engineering. Hayes and his lab group have developed nanoparticles that can deliver gene regulatory nucleic acids to tumors. "We have identified a microRNA sequence that specifically kills skin tumor cells in cell culture, and we hope to test this soon in our in vivo skin tumor model," says Glick.

Joining Forces for Better Cancer Care

Across the college, experts are studying cancer from various angles and at multiple scopes of the disease--from basic research to human clinical trials. Their work is a major contributor to Penn State's efforts to become designated as a National Cancer Institute cancer center.

"There are certain metrics that we have to meet if we want to succeed with our proposal to NIH," says Peters. For, example, he says, the University must demonstrate that it produces relevant, high-impact research related to cancer and that it receives significant support for this work from other funding agencies. In addition, Penn State must provide evidence that it engages in community outreach around cancer. Plans are underway with Penn State Extension to provide part of this required outreach.

"We are doing all of these things every day," he says. "Penn State has some of the world's top experts in cancer research. I'm optimistic that we'll get designated."

By Sara LaJeunesse
Portraits by Michael Houtz