Feature Health & Medicine Researcher news Slideshows Student researchers

NCI grant funds SMU research into cancer-causing viruses that hide from the immune system

Genes common to both the human T-cell leukemia virus and high-risk human papillomaviruses activate survival mechanisms in cancer cells. An SMU lab, with National Cancer Institute funding, is hunting ways to inhibit those genes to halt the development of cancer.

SMU virologist and cancer researcher Robert L. Harrod has been awarded a $436,500 grant from the National Cancer Institute to further his lab’s research into how certain viruses cause cancers in humans.

Under two previous NCI grants, Harrod’s lab discovered that the human T-cell leukemia virus type-1, HTLV-1, and high-risk subtype human papillomaviruses, HPVs, share a common mechanism that plays a key role in allowing cancers to develop.

Now the lab will search for the biological mechanism — a molecular target — to intervene to block establishment and progression of virus-induced cancers. The hope is to ultimately develop a chemotherapy drug to block the growth of those tumor cells in patients.

“The general theme of our lab is understanding the key molecular events involved in how the viruses allow cancer to develop,” said Harrod, an associate professor in SMU’s Department of Biological Sciences whose research focuses on understanding the molecular basis of viral initiation of cancer formation.

While HTLV-1 and HPV are unrelated transforming viruses and lead to very different types of cancers, they’ve evolved a similar mechanism to cooperate with genes that cause cancer in different cell types. The lab discovered that the two viruses tap a common protein that cooperates with cellular genes to help the viruses hide from the immune system.

That common protein, the p30 protein of HTLV-1, binds to a different protein in the cell, p53, which normally has the job of suppressing cancerous growth or tumor development. Instead, however, p30 manages to subvert p53’s tumor suppressor functions, which in turn activates pro-survival pathways for the virus.

From there, the virus can hide inside the infected cell for two to three decades while evading host immune-surveillance pathways. As the cell divides, the virus divides and replicates. Then ultimately the deregulation of gene expression by viral encoded products causes cancer to develop.

“They are essentially using a similar mechanism, p30, to deregulate those pathways from their normal tumor-suppressing function,” Harrod said.

Tumor suppression, DNA damage-repair pathways, begin to fail with age
About 15 percent to 20 percent of all cancers are virus related. Worldwide, about 10 million people are infected with HTLV-1 and, as with other viral-induced cancers, about 3 percent to 5 percent of those infected go on to develop malignant disease.

Cancer is often associated with the process of normal aging, because our tumor suppression and DNA damage-repair pathways begin to break down and fail, explained Harrod. Our pathways don’t as easily repair genetic mutations, which makes us more susceptible to cancers like adult T-cell leukemia and HPV-associated cervical cancers or head-and-neck carcinomas, he said.

The human T-cell leukemia virus is transmitted through blood and body fluid contact, usually infecting infants and children via breastfeeding from their mother. A tropical infectious disease, it’s endemic to Southeast Asia, primarily Japan, Taiwan, China and Malaysia, as well as certain regions in the Middle East, Northern Africa and islands of the Caribbean. In the United States, Hawaii and Florida have the highest incidence of adult T-cell leukemia. HTLV-1 is highly resistant to most modern anticancer therapies, including radiotherapy and bone marrow or matching donor stem cell transplants. The life expectancy of patients with acute or lymphoma-stage disease is about six months to two years after diagnosis.

In the case of HPV, certain high-risk sub-types aren’t inhibited by today’s available HPV vaccines. It’s considered the high-risk HPVs are sexually transmitted through direct contact with the tissues of the virus-producing papillomas or warts. High-risk HPVs can also cause cervical cancers and head and neck carcinomas, many of which are associated with poor clinical outcomes and have high mortality rates.

How do viruses cause cancer?
For both HTLV-1 and HPV, the virus itself does not cause cancer to develop.

“It’s cooperating with oncogenes — cellular genes that become deregulated and have the potential to cause cancer,” Harrod said. “The role of these viruses, it seems, is to induce the proliferation of the cell affected with cancer. We’re trying to understand some of the molecular events that are associated with these cancers. ”

The lab’s three-year NCI grant runs through 2019. Harrod’s two previous grants awarded by the National Institutes of Health were also three-year-grants, for $435,000 and $162,000. Each one has targeted HTLV-1 and the p30 protein.

The lab’s first NCI grant came after the researchers provided the first demonstration that p30 could cooperate with cellular oncogenes, which have the potential to cause cancer, to cause deregulated cell growth leading to normal cells transforming into cancer cells. That original discovery was reported in 2005 in the article “A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions,” in the high-profile journal Molecular and Cellular Biology.

“We find that the p30 protein is involved in maintaining the latency of these viruses. These viruses have to persist in the body for 20 to 40 years before a person develops disease. To do that they have to hide from the immune response,” Harrod explained. “So p30 plays a role in silencing the viral genome so that the affected cells can hide, but at the same time it induces replication of the affected cells. So when the cell divides, the virus divides. We call that pro-viral replication.”

The term “latency maintenance factor” in reference to p30 originated with Harrod’s lab and has gained traction in the HTLV-1 field.

Under the lab’s second NCI grant, the researchers figured out how to block pro-survival pathways to kill tumor cells.

In the current grant proposal, Harrod’s lab demonstrated that by inhibiting specific downstream targets of p53 — essentially blocking pathways regulated by the p53 protein — they could cause infected tumor cells to collapse on themselves and undergo cell death.

“We do that independent of chemotherapy,” Harrod said. “So that was a big find for us.”

Goal is to eliminate cancer cells by inhibiting pathway
Each grant project builds upon the one before it, and the third grant extends the work, to now include high-risk HPVs.

“Now that we’ve shown we can block one or two of these factors to cause cell death, we’re starting to get an eye really on how we can inhibit these cancer cells and what potentially down the road may lead to a therapeutic,” Harrod said. “That’s the ultimate goal.”

One of the biggest challenges will be to inhibit the pathways in the tumor cells without targeting normal cells, he said. The lab’s recent findings indicate the researchers may soon be within reach of identifying a new strategy to eliminate cancer cells by inhibiting pathways key to their survival.

Harrod’s lab collaborates on the research with: Lawrence Banks, Tumor Virology Group Leader, International Centre for Genetic Engineering and Biotechnology, Trieste, Italy; Brenda Hernandez, Associate Director, Hawaii Tumor Registry, University of Hawaii Cancer Center, Honolulu; and Patrick Green, Director, Center for Retrovirus Research, The Ohio State University. — Margaret Allen, SMU

Health & Medicine

Blocking enzyme may prove novel way to thwart HIV

In 1996 the introduction of “triple cocktail” drug therapy transformed AIDS from a death sentence into a manageable chronic disease. The drug regimen, also known as HAART for highly active antiretroviral treatment, involved treating patients with three or more classes of antiviral medicines.

But the virus fought back. It mutates easily, and the mutations caused resistance to first one and then another drug making up the cocktail. Unsettling reports of newly infected patients with the drug-resistant virus meant researchers needed to find new ways to fight HIV infection.

That could be what is happening in the Dedman Life Sciences Building at SMU, where a young assistant professor of biological sciences is conducting research that may lead to a novel way of combating HIV-1.

In his office in Dedman College’s Department of Biological Sciences, Assistant Professor Robert Harrod talks about an exciting discovery his research team made last year. The discovery involves the way viruses replicate and the disease Werner syndrome, a rare genetic disorder that causes premature aging.

The HIV-1 virus infects white cells involved in fighting infection, inserting itself into the genetic material of the cells, commonly known as T-cells, to cause AIDS. Once the virus is integrated into the host cell, Harrod explains, it is dependent on “human cellular transcription factors” to replicate. The researchers have shown that the Werner syndrome enzyme is an essential factor in that transcription process. They reasoned if they could inhibit the enzyme function, they could block the transcription.

Using cells developed by researchers at the University of Washington who are studying Werner syndrome, the SMU researchers were able to insert the enzyme defect that causes Werner syndrome into HIV-infected T-cells, blocking 95 percent of retroviral transcription. If the HIV/AIDS virus can’t be transcribed, it can’t replicate.

The one in 1,000 people in Japan who are Werner syndrome carriers (without developing the syndrome) have not been observed to develop AIDS, Harrod points out, suggesting that affecting the functioning of the enzyme that causes Werner syndrome is a plausible way to fight HIV/AIDS.

The beauty of the Werner syndrome-enzyme approach to HIV/AIDS treatment is that the virus can’t mutate to defeat treatment, Harrod says.

The HIV-inhibition research was published in the April 20, 2007 issue of “The Journal of Biological Chemistry.”

Harrod’s research group, which includes Master’s degree student Madhu Sukumar and three biological sciences undergraduates, now is searching for molecules that will inhibit the function of the Werner syndrome enzyme, and thus, viral replication.

Harrod’s work also is an example of the international collaboration that is occurring to find solutions to global health issues. He is collaborating on the research with Antonito Panganiban from the University of New Mexico-Health Sciences Center, Carine Van Lint from the Universite Libre de Bruxelles and two clinical researchers, Dennis Burns and Daniel Skiest, from UT Southwestern Medical Center at Dallas.

According to the World Health Organization, 33 million people are living with HIV/AIDS worldwide. That is why Professor William Orr, chair of Biological Sciences at SMU, calls Harrod’s research exciting.

“It’s going to provide an alternative way in which one might be able to deactivate or slow down this scourge,” Orr says.

Harrod joined SMU in 2002 and teaches undergraduate and graduate students. He earned his Ph.D. at the University of Maryland in 1996, and received postdoctoral training at the National Institutes of Health and the Naval Medical Center. — Cathy Frisinger

Related links:
Robert Harrod
Antonito Panganiban
Carine Van Lint
Dennis Burns
Pegasus News: Novel HIV inhibitor
SMU Research 2003: Biological Building Blocks
Biological Sciences Department
Dedman College of Humanities and Sciences

Energy & Matter Health & Medicine Plants & Animals Student researchers

Aids, cancer targeted by biology researchers

In his third-floor laboratory in Dedman Life Sciences Building, biologist Robert Harrod and his team are zeroing in on a new way to inhibit the virus that causes AIDS. They already have shown that their approach, which involves the rare genetic disorder Werner syndrome, works when the disorder’s enzyme defect is introduced into cells.

Now they are trying to find practical ways to use this pathway to inhibit the AIDS virus. The beauty of this approach is that the AIDS virus will not be able to mutate in a way that can defeat this treatment, says Harrod, associate professor in the Biological Sciences Department of Dedman College.


Down the hall from Harrod’s lab, Assistant Professor of Biological Sciences Jim Waddle is preparing to file for a patent on a tiny “worm” that is expected to be highly useful in drug-testing, producing results far more quickly than tests run on larger lab creatures.

Meanwhile, their colleagues, Associate Professor Pia Vogel and her husband, John Wise, a lecturer in the Biological Sciences Department, are conducting work that may have implications for cancer treatment.

In university laboratories throughout the world, enormous strides have been made in biology research in recent years, including the mapping of the human genome. With young faculty members like Harrod, Waddle and Vogel working on cutting-edge conundrums, and a recent $3.6 million gift to Biological Sciences, SMU’s department is poised to play a high-profile role in biology advances in coming years, says William Orr, chair and professor of biological sciences.

The gift from philanthropist and SMU Board of Trustees member Caren Prothro and the Perkins-Prothro Foundation includes $2 million for an endowed chair, $1 million for an endowed research fund, $500,000 for a graduate fellowship fund and $100,000 for an undergraduate scholarship fund.

The endowment will enable the University to attract a biologist with a national reputation in research to join a faculty that is strong in cellular and molecular biology and biochemistry and is doing research that could have practical applications in medicine, Orr says.


For example, Vogel and Wise are looking for a way to improve the long-term efficacy of chemotherapy treatments. Wise uses a nautical metaphor to explain their work: “Picture a cancer cell as a ship on a sea and the chemotherapy being dumped into the ship, there’s a mechanism like a sump pump that will dump that chemical back overboard,” he says.

That cellular “sump pump” is important to normal cell health because it keeps toxins out.

“Of course, with cancer cells that are targeted for destruction by chemotherapeutics, you’d like to be able to turn off that mechanism,” Wise adds.

John Wise

Vogel explains that many cancer cells respond to treatment by pumping out more and more of the toxins as time goes on, so that a cancer treatment that works well initially might not work as well in later stages.

“Switching chemotherapy drugs doesn’t help because the cancer cells just pump out everything, resulting in multi-drug resistance,” she says.


Using Electron Spin Resonance Spectroscopy, a biophysical technique that obtains structural information about the cellular pump, Vogel’s research group is trying to find a way to shut off the ATP energy usage by this cellular sump pump.

“If you can knock out the pump, you can sink the cancer ship,” she says.

Harrod, who studies retroviruses that infect humans and who is focusing on transcriptional gene regulation, is working on a mechanism that might sidestep a more specific type of multidrug resistance — of the virus that causes AIDS to the conventional HAART (highly active antiretroviral treatment) drug regimen.

Pia Vogel

His approach is related to a rare genetic disorder called Werner syndrome, which causes premature aging in those who have the disease. Researchers have noted that individuals who are carriers for Werner syndrome do not develop AIDS. Harrod hypothesized that the enzyme involved in Werner syndrome is necessary for transcription of the retrovirus.


Using cells that had the Werner syndrome defect inserted into them, his lab was able to confirm this link, and last year he and co-researchers published the findings in “The Journal of Biological Chemistry.” Now his group is looking for molecules that might be used to block this transcription-necessary enzyme. Included among the researchers cited in the journal article were several biological sciences students. Both graduate and undergraduate students assisted Harrod in his lab work on retroviral transcription.

Ask Assistant Professor Jim Waddle about the contributions made by students, and he’ll talk about the weird “worm” discovered by one of his graduate students. Waddle, whose Ph.D. work was in molecular genetics, has been studying the nematode Caenorhabditis elegans as a model for food absorption in the human gut.

Fingerlike projections called microvilli, which are necessary for the absorption of nutrients, line the human gut; nematodes have microvilli on every gut cell.


As part of their research, Waddle’s lab doused the nematodes in mutation-causing chemicals and examined them via a fluorescent protein.

Ph.D. candidate Christina Paulson looked at 20,000 nematodes in this manner and came up with one that had a nematode version of diverticulosis, with outpouchings all along the gut.

Disappointingly, the mutated worm turned out to be normal in terms of lifespan, reproduction and absorption of nutrients. But, Waddle says, “we threw our heads together and thought about conditions the nematode might encounter in the wild” versus the laboratory setting. He wondered if the worm might have trouble eliminating toxins. It did.

Jim Waddle

Normal nematodes eliminate toxins too quickly for the worms to be useful in drug testing, but toxins stay in the weird worms long enough to have an effect on them. And that means the millimeter-long creature likely will be highly useful in drug-testing situations, because a nematode’s life cycle is so much shorter than that of the larger animals, such as mice, that generally are used to test drugs.


The student who identified the worm is one of 18 graduate students in the Department of Biological Sciences. Nine are working on Master’s degrees, nine on Ph.Ds. With 126 undergraduates, the department enrolls the largest segment of undergraduate majors in the natural sciences at SMU. Undergraduate students who intend to go into biological research can apply for the BRITE (Biomedical Researchers in Training Experience) program, a collaboration between SMU and the University of Texas Southwestern Medical Center that leads to acceptance into a UT Southwestern Ph.D. program.

Orr believes the department is poised for a leap forward in size and stature. Administrative support to boost research has come from Provost Paul Ludden, whose background is in biochemistry. Current research projects are supported by $4.3 million from agencies that include the National Institutes of Health and the National Science Foundation.
Christina Paulson

Orr’s dream for the department is to double the current tenured and tenure-track faculty to 18 members. Of the nine, seven conduct ongoing research projects, five of which are funded by federal agencies. The department will add an assistant professor in spring 2009. Later that year, a national search will be conducted to fill the new Distinguished Chair of Biological Sciences.

william.jpgAlthough the department is small, a synergy has developed from building a faculty that is focused on cellular and molecular biochemistry, Orr says.

Researchers can work together on projects, brainstorming ideas for new areas of investigation. More grants can be applied for, which means more grants awarded.

“We have a strong group that is focused on certain areas. By adding new faculty we will be able to boost the overall stature of the department,” Orr says. “If we increase the academic stature and the amount of research, we can provide more opportunities for graduate students and for undergraduates. It all works together.” — Cathy Frisinger

William Orr

Related links:
Robert Harrod
Jim Waddle
Pia Vogel
John Wise
William Orr
Biological Sciences Department
Dedman College of Humanities and Sciences