Palladin, the travels continue

Our second Hard Science blogpost “Have Palladin, Will Travel,” on January 19, 2009, introduced the work of UNC cell and molecular physiologist Carol Otey and the protein she discovered a decade or so ago that plays an important role in cell motility, adhesion and structure.

Study first author Silvia Goicoechea, PhD and, on the right, Carol Otey, PhD in the Otey Lab at UNC

Also mentioned was Otey’s most recent work in which  palladin was found mutated in an inherited form of pancreas cancer and was also produced in large amounts — “upregulated” — in a number of sporadic pancreas tumors.

Now it appears that the protein with the fancy name may prove to be a molecular marker of pancreatic cancer , one that might help spot the disease at its earliest stages, when it can be treated more successfully with surgery.

In a finding published April 26, 2010, in the online journal PLoS One, the researcher and her colleagues  showed that a specific form of a protein called palladin is produced in large amounts in the “tumor nest,” the cells that surround a pancreatic tumor. 

The blue cells in the middle, surrounding the “space” in the center of a pancreatic duct, are the tumor cells, and the brown cells around them are the tumor-associated fibroblasts (stained for palladin).

Measuring the levels of this form of palladin in patient samples could provide an improved way to screen for the deadly cancer, possibly catching it earlier than ever before, said senior study author Carol Otey, Ph.D., associate professor of cell and molecular physiology at UNC.

“The problem with pancreas cancer is it is almost never caught at an early stage,” said Otey. “By the time a person develops suspicious symptoms, the disease has typically progressed too far. But if you can diagnose it early, it can be treated very effectively with surgery.” 

Otey and her colleagues decided to see if the upregulation of palladin in the tumor nest could provide a useful diagnostic tool for identifying the disease at earlier stages. They knew that the single palladin gene message can actually be cut and pasted together in a manner that produces at least seven different palladin protein products. Turns out only a couple of these forms of palladin – called isoforms – appear in pancreatic tissue. 

The researchers found that the longer of these two isoforms was upregulated in the cells surrounding the tumor — called tumor-associated fibroblasts — when compared to normal pancreas. Their findings were consistent, regardless of whether they were looking in cultured cell lines, patient samples, or tumors from a mouse model. 

Otey thinks that the upregulation of this form of palladin in tumor-associated fibroblasts could help them become contractile and stiff — more like muscle than connective tissue — in order to generate channels through neighboring tissue so the cancer can metastasize and spread.  

“The interactions between these tumor-associated fibroblasts and tumor cells are really important and are probably what is causing pancreas cancer to be so deadly,invasive and resistant to current therapies,” said Otey.

And that is why raising public awareness and enhancing our abilities to diagnose the disease early is so critical, says Hong Jin Kim, associate professor of surgery at UNC, who along with Otey is senior author of the study.

“It appears that the upregulation of palladin in the tumor-associated fibroblasts is an early event in the neoplastic process,” said Kim. “We may be able to take advantage of these findings, since pathologic confirmation of pancreatic adenocarcinoma in the preoperative setting is often difficult, requiring an invasive procedure directed by endoscopic ultrasound.  If we can enhance the diagnostic efficiency of these studies by staining for palladin, it would be clinically helpful for interventional gastroenterologists and pathologists.”

For palladin, the travels continue….

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Chemo drug awakens virus in cancer cells

Viruses and cancers interact in ways that were previously unknown  to science.  A new study led by UNC researchers shows that a common cancer drug can activate a viral infection that, paradoxically, can help anti-viral medications eradicate virus-associated cancer.  

The cooperative study, conducted by a team of UNC School of Medicine scientists and the UNC Project in Malawi, demonstrated for the first time in humans that a common drug used to treat Burkitt lymphoma can activate infection by the Epstein-Barr virus (EBV), a virus which typically lies latent inside the tumor cells of affected patients.

The finding paves the way for a future study using both a cancer drug and an antiviral agent to eradicate both the active virus infection and the tumor.  The study is reported in the April 1 issue of the journal Clinical Cancer Research.

Margaret L. Gulley, MD, professor of pathology and laboratory medicine, said,  “What we have learned from this work is a potential means of capitalizing on presence of viral genomes within tumor cells to alter those tumor cells in a way that makes them more susceptible to treatment. Our findings have implications for other EBV- related malignancies that, overall, are among the most common cancers worldwide.” Gulley is a member of UNC Lineberger Comprehensive Cancer Center. 

Weihua Tang, MD, PhD, the study's first author and research fellow with Margaret L. Gulley, MD

 EBV infects more than 90 percent of the world’s population and is associated with diseases ranging from infectious mononucleosis to lymphomas, gastric cancer and cancer of the nose and throat. 

Burkitt lymphoma, which is associated with EBV, is rare in most parts of the world, but is endemic in sub-Saharan Africa. Burkitt lymphoma is an aggressive, fast-growing type of non-Hodgkin lymphoma that often occurs in children. The disease may affect the jaw, bowel, lymph nodes, or other organs. 

The study demonstrated that initiating treatment with the anti-cancer drug  cyclophosphamide in children with Burkitt lymphoma simultaneously triggered an active EBV infection. The increased replication of EBV in cancer tissue makes these cells more susceptible to the antiviral drugs that kill cells containing replicating virus. Antiviral agents such as ganciclovir and valacyclovir are already in routine clinical use for treating active viral infections. 

Researchers enrolled 21 patients with a confirmed diagnosis of EBV-related Burkitt lymphoma. The patients ranged in age from 5-15 and were under treatment with cyclophosphamide for their cancer.  Through laboratory analysis of biopsy samples, researchers found that cyclophosphamide seems to induce the phase of viral infection most susceptible to antiviral therapy. 

Gulley points out that cyclophosphamide “is fairly efficacious, but it and even more expensive chemotherapeutic agents may be hard to come by in developing nations.”

Moreover, she says clinical trial data are needed to determine if chemotherapy and antiviral therapy synergize in managing Burkitt lymphoma.  

 “Our work provides scientific data to justify moving forward with a clinical trial.  Generic versions of several pertinent antiviral agents are available and are relatively inexpensive.”

Plans for such a trial are already underway under the leadership of Carol Shores, MD, PhD, associate professor of surgery in UNC’s Otolaryngology/Head and Neck Surgery Department and senior author of the study.  Shores says she is currently working to get approval for a Phase I/II clinical trial of the antiviral drug valacyclovir with cyclophosphamide in Malawi. “Valacyclovir recently went off patent, and a relatively generic form is available.  It is an oral drug approved in the US for children as young 3 years of age.

Sweet call on gene patents

Clinton Colmenares in our news office wrote this …

 Jim Evans is a self-proclaimed science geek whose intellect and wit move at warp speed. He rides a bike to work and wears neck ties fashioned with DNA patterns. In our popular Santa video he proclaimed that the jolly old elf is “clearly a mutant.” 

He’s also an expert in gene patenting and genetics policy. He led a program to educate federal judges about the intricacies of genetics and genetic policy. He chaired a Federal task force, part of the Secretary of Health and Human Services Advisory Committee on Genetics, Health and Society that recently made formal recommendations to the HHS secretary regarding the role of gene patents in medical diagnostics.  

James P. Evans, MD, PhD

When news broke that United States District Court Judge Robert Sweet ruled on March 29 that seven patents related to the BRCA 1 and BRCA 2 genes were invalid — genes cannot be patented, basically — we contacted Jim. So did reporters from The New York Times, the Wall Street Journal and the CBS Evening News (they decided not to run a story). 

Jim had the last quote in The Times:  

James P. Evans, a professor of genetics at the University of North Carolina, said that would not necessarily be the case. There is thriving competition in areas like testing for mutations that cause cystic fibrosis or Huntington’s disease, even though no company has exclusivity.  

“It’s quite demonstrable that in the diagnostic area, one does not need gene patents in order to see robust development of these tests,” he said.  The ruling “came as a surprise to everybody. It’s really quite unusual for plaintiffs to get a summary judgment.”

In the WSJ he said:  

“If this decision is upheld, it in the end is a win for patients and providers,” said Dr. Evans, also a medical geneticist at the University of North Carolina, Chapel Hill. 

Here are some of the comments he shared with me yesterday: 

“I think that the judge showed an impressive understanding of genetics and some of the nuances involved. I agree with him.  

“The essence of DNA is that it is an embodiment of biological information. As such it is distinct from other chemical compounds in nature. It is this informational content that makes it special and the act of isolating it therefore is less relevant to patent considerations than for other biological molecules. A gene still does the same thing (i.e. confer information) in the test tube as it does in the cell. Thus, Judge Sweet correctly noted that a gene is qualitatively different from other biological molecules such as adrenaline, which can be patented when isolated.  

“It’s a very important case, but its immediate impact shouldn’t be overestimated. It will be appealed to the Court of Appeals for the Federal Circuit, the court to which all patent cases are appealed. Then it will almost certainly be appealed to the Supreme Court, though who knows if they will agree to hear it. 

“There will be arguments about whether this ruling will be good for patients; I would say yes. The broad area of diagnostic testing is unduly hampered by gene patents and they are not necessary for the development of diagnostic genetic tests. This ruling, if upheld, will open the field of genetic diagnostics in time for the benefits of robust analytic techniques like whole genome sequencing to be applied for patient benefit.  

“While one can argue that the patent incentive may serve a more useful purpose in the realm of therapeutics, most useful therapeutic patents are considerably “downstream” of the genes themselves so I doubt that one will see any significant deleterious effect of such a ruling on therapeutics either. In broad terms I think this is a win for both patients and their providers. 

“The issue of gene patenting has been controversial since the United States Patent and Trademark Office first granted them. Such controversy and furor have arisen in part because people tend to perceive genes as different from other biological entities.  

“They are something we all share and they encode information that is unique to each of us as individuals. Thus it is difficult at one basic level to defend the patenting of genes. The idea that we would be prevented from having considerable latitude in analyzing our own genes is something that strikes people as a bit absurd on the face of it.”