Uprooting cancer to cultivate health

Cancer cells in culture from human connective tissue, illuminated by darkfield amplified contrast, at a magnification of 500x. Photo, by Dr. Cecil Fox, obtained from the National Cancer Institute.

Cancer cells in culture from human connective tissue, at a magnification of 500x. Photo, by Dr. Cecil Fox, obtained from the National Cancer Institute.

Cancer afflicts about four of every ten people at some point in life, according to the National Cancer Institute. Texas A&M AgriLife Research has taken part in the worldwide efforts to eradicate this strikingly common and often deadly disease.

“AgriLife Research has a broad mandate to help address food, fiber, and environmental issues facing Texans,” said Director Craig Nessler. “Our scientists recognize the connection between diet and disease, study the biological underpinnings of cancer, and create new treatments. They have made extraordinary contributions toward battling cancer.”

AgriLife Research scientists are discovering the protective properties of foods, finding new ways to diagnose and treat cancer by studying molecular processes in cells, and testing and designing drug candidates.

Foods

Mangos

A team of scientists from the Texas A&M University System recently completed two studies on how mango polyphenols may affect cancer and non-cancer breast cells. (Photo courtesy Institute for Obesity Research and Program Evaluation, Texas A&M )

Some AgriLife researchers are seeking ways to prevent cancer by focusing on the potential of foods to protect against the disease. Mangos, for example, contain compounds that reduce inflammation in normal cells and are toxic to breast cancer cells, AgriLife researchers have found.

Dr. Susanne Talcott, a nutrition scientist at AgriLife Research, led the studies on polyphenol compounds found in mangos. These compounds suppressed the multiplication of cancer cells and the growth of tumors in mice. The polyphenols work by changing the abundance, in cells, of certain proteins and microRNAs important to cancer cell proliferation. Talcott presented the results at a Federation of American Societies for Experimental Biology meeting in April 2013.

The studies “have moved us closer to determining whether mango polyphenols will have cancer-fighting effects on human beings,” Talcott told an AgriLife Today writer.

Bioactive compounds

Mango polyphenols belong to the ranks of bioactive compounds: substances that affect human health but are not nutrients. Rigorous studies are crucial for evaluating the link between “bioactives” and decreased risk of diseases such as cancer, says Dr. Joanne Lupton, another nutrition scientist with AgriLife Research. Lupton studies the effect of dietary fiber, a bioactive compound, on colon cancer. Her research and her work in public policy helped establish a Dietary Reference Intake Value (DRI) for dietary fiber.

Dr. Joanne Lupton of the nutrition and food sciences department of the College of Agriculture and Life Sciences will be the keynote speaker at an international conference Nov. 1 in Germany. (Texas A&M AgriLife photo)

Dr. Joanne Lupton was the keynote speaker at an international conference Nov. 1, 2013 in Germany. (Texas A&M AgriLife photo)

“Having a DRI-like process to establish efficacy of bioactives would make a significant contribution to human health,” she said in a keynote presentation to the Council for Responsible Nutrition in Taunus, Germany in November 2013.

“Although my research is on fiber and colon cancer, there is a lot of scientific support for other bioactives being important to health,” Lupton says.

Biomarkers

One of Lupton’s research collaborators is Dr. Robert Chapkin, who holds appointments in both nutrition and biochemistry and biophysics at AgriLife Research.

He is also collaborating with researchers at Fred Hutchinson Cancer Research Center in Seattle to study how lignin — a plant-derived polymer — affects the health of study volunteers. In particular, Chapkin aims to understand how lignin in diet influences cancer risk. The research intersects with areas of biochemistry, nutrition, and bioinformatics.

“How do you assess one’s risk of cancer? This takes me into a field called biomarkers,” says Chapkin. “These are indicators, if properly interpreted, of risk. If you can analyze those indicators you can determine whether indeed risk is higher or lower and whether a treatment is effective or ineffective.”

For help investigating potential biomarkers related to cancer, Chapkin and others turn to the Genomics and Bioinformatics Service at AgriLife Research.

Dr. Charlie Johnson, director of the Texas AgriLife Genomics and Bioinformatics Service, next to the next-generation sequencing system on the Texas A&M University campus in College Station. (Texas A&M AgriLife Research photo by Kathleen Phillips)

Dr. Charlie Johnson, director of the Texas AgriLife Genomics and Bioinformatics Service, next to the next-generation sequencing system on the Texas A&M University campus in College Station. (Texas A&M AgriLife Research photo by Kathleen Phillips)

“Looking at gene expression, we are examining networks of genes and their interrelation in cancer,” says Dr. Charles Johnson, director of Genomics and Bioinformatics. “On the DNA side, we are looking for polymorphisms that may be markers of future cancer or may be indications of DNA damage that can lead to cancer, and we are using DNA sequencing of family members to help determine those who are predisposed to cancer.”

Molecular mechanisms

A new biomarker can illuminate cancer cells’ workings at a molecular level, helping AgriLife researchers uncover new paths toward diagnosis, treatment, or prevention.

In breast cancer cells, for example, one indicator of out-of-control cell growth is the improper activity of the enzyme telomerase. AgriLife researchers have found that this runaway enzyme can be slowed down by Arabidopsis, a small plant related to mustard and cabbage. The plant restricts telomerase activity by increasing the abundance of a newly discovered inhibitory RNA molecule. Dr. Dorothy Shippen, an AgriLife Research biochemist, led the study. To further investigate these results, Shippen and collaborator Robin Fuchs-Young at the Texas A&M Health Science Center received a $200,000 grant in November 2013 from the Cancer Prevention and Research Institute of Texas.

“Newly discovered telomerase regulatory RNAs have the potential to serve as novel biomarkers and targets for breast cancer prevention and treatment strategies,” Shippen told a writer at the Texas A&M College of Science.

Treatments

Shippen is one of several AgriLife researchers finding that fundamental processes in cells can point the way toward new treatments.

Dr. Vishal Gohil, Texas A&M AgriLife Research (Photo courtesy of Texas A&M AgriLife Research)

Dr. Vishal Gohil, Texas A&M AgriLife Research (Photo courtesy of Texas A&M AgriLife Research)

Dr. Vishal M. Gohil, an AgriLife Research biochemist who studies cellular respiration and energy production, recently discovered that meclizine, an over-the-counter antihistamine and nausea medication, might help treat some forms of cancer and other diseases. The work appeared in the Journal of Biological Chemistry in October 2013. Gohil and his collaborators discovered this drug’s potential when looking for compounds that reduce mitochondrial respiration.

“We found that a particular enzyme which is inhibited by meclizine has been proposed [in other research] to be a drug target for the treatment of many diseases,” Gohil said to an AgriLife Today writer. “And this pathway has also been proposed to be a critical pathway for the proliferation of cancer cells.”

Treatments for cancers that resist treatment

Gohil’s work on meclizine addresses the fact that some cancer cells evade existing cancer medications. Roughly half-a-million people die from cancer each year in the United States, according to the National Cancer Institute. In practically all these fatal cases, the patients’ tumors are either resistant to medication or become resistant over time. Resistance occurs in many cancers for many treatment regimens.

AgriLife researchers are now directly targeting tumor cell resistance.

photo of Dr. Sacchettini

Dr. Jim Sacchettini. (Photo courtesy of AgriLife Today.)

Dr. Jim Sacchettini, an AgriLife Research biochemist, along with Dr. Steve A. Maxwell at the Texas A&M Health Science Center and others, has found a useful biomarker of resistance and created a series of compounds to address it.

The team found that resistance to cancer medications correlates with low levels of certain oxygen-containing molecules in cancer cells. The researchers then created compounds that increase the levels of these “reactive oxygen species” in the resistant cells. The most promising compound, RTI-79, makes medications more effective at treating resistant cell lines of non-Hodgkin’s lymphoma as well as ovarian, breast, prostate, and pancreatic cancers.

The compound has also shown great success in animals; it did not increase the side effects of medications nor adversely affect healthy cells. The team has filed a patent and started a company to pursue the work into the clinical realm. The researchers are now preparing for clinical trials on patients with ovarian cancer as a first application

Interdisciplinary collaboration

Sacchettini could not have accomplished his work on RTI-79 without collaborators in other fields. Interdisciplinary collaborations bring together disparate resources and expertise, which can reveal creative solutions to entrenched problems.

The multidisciplinary mission of AgriLife Research encourages such collaborations, and the organization actively promotes them. For example, AgriLife Research is working to partner with the Texas A&M University College of Veterinary Medicine & Biomedical Sciences. Together they have access to nationally preeminent veterinary imaging and cancer therapeutic capabilities, including the Diagnostic Imaging and Cancer Treatment Center and the Center for Structural Biology. Cancers in animals often resemble human cancers in cause, appearance, progression, and treatment. Comparative cancer research can help discover new treatments for both humans and animals.

AgriLife Research is also supporting the new Center for Epigenetics & Disease Prevention, established by the Texas A&M Health Science Center Institute of Biosciences and Technology in Houston in September 2013. The center involves collaborations across The Texas A&M University System. Dr. Roderick Dashwood heads the center and holds a joint appointment with AgriLife Research. The work will range from synthesizing derivatives of bioactive compounds to testing their ability to stop or prevent cancer and other diseases in humans.

“While there are many examples of major breakthroughs from individual investigators, there are areas of scientific discovery that require a very large commitment in time and expertise that would not be possible from a single laboratory,” says Sacchettini. “Taking a new vaccine or therapeutic from the laboratory to the patient requires experience and expertise in several different areas of science and technology as well as the drive, determination and finances of several investigators working very closely together.”

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