DNA

Predicting oral cancer

Source: www.dailyrx.com

Oral cancers can occur anywhere in the mouth. As with any cancer, the sooner it’s found, the better. A new tool helps doctors know when oral cancer may be in a patient’s future.

A recent study finds that a set of molecular markers can help judge which lesions in the mouth are most likely to turn into oral cancer.

The Oral Cancer Prediction Longitudinal Study was conducted in Canada at the Oral Cancer Prevention Program at the BC Cancer Agency in Vancouver.

“The results of our study should help to build awareness that not everyone with a low-grade oral premalignant lesion will progress to cancer,” said Program Director, Miriam Rosin, PhD. “However, they should also begin to give clinicians a better idea of which patients need closer follow-up.”

Every year, cancer shows up in the mouths of nearly 300,000 people around the globe. Some of these start as spots – or lesions – in the mouth that have not yet become cancerous.

It’s always been difficult to tell which of these pre-malignant lesions will progress to full blown cancer.

In an earlier study, Rosin’s team had analyzed the DNA of tissue that eventually turned into oral cancer. This research provided a method for grouping patients according to risk.

For this study, researchers examined pre-cancerous tissue from nearly 300 patients, who were followed over a period of years. These patients were placed into either low-, intermediate- or high-risk groups.

Two additional DNA markers were used to zero in on a patient’s oral cancer risk factors.

“Compared with the low-risk group, [the] intermediate-risk patients had an 11-fold increased risk for progression, and the high-risk group had a 52-fold increase in risk for progression,” Dr. Rosin said.

Only about 3 percent of the people in the low-risk group developed cancer within five years.For those in the intermediate-risk, just over 16 percent saw the disease progress to cancer, while about 63 percent of high-risk patients developed oral cancer within five years.

To translate, this means that two out of every three high-risk lesions are progressing toward cancer, Dr. Rosin says.

“Identifying which early lesions are more likely to progress may give clinicians a chance to intervene in high-risk cases, and may help to prevent unnecessary treatment in low-risk cases,” Dr. Rosin said.

This study was published August 21 in Cancer Prevention Research, a journal of the American Association for Cancer Research. No financial information was available.

September, 2012|Oral Cancer News|

Molecular markers help predict oral cancer progression

Source: DrBicuspid.com

August 21, 2012 — A group of molecular markers has been identified that can help clinicians determine which patients with low-grade oral premalignant lesions are at high risk for progression to oral cancer, according to data from the Oral Cancer Prediction Longitudinal Study published in Cancer Prevention Research (August 21, 2012).

“The results of our study should help to build awareness that not everyone with a low-grade oral premalignant lesion will progress to cancer,” said Miriam Rosin, PhD, director of the Oral Cancer Prevention Program at the British Columbia (BC) Cancer Agency, in a press release issued by the American Association of Cancer Research, which publishes the journal. “However, they should also begin to give clinicians a better idea of which patients need closer follow-up.”

In 2000, Rosin and colleagues used samples of oral premalignant lesions in which progression to cancer was known to have subsequently occurred to develop a method for grouping patients into low- or high-risk categories based on differences in their DNA.

In their current population-based study, the researchers confirmed that this approach was able to correctly categorize patients as less or more likely to progress to cancer. They analyzed samples from 296 patients with mild or moderate oral dysplasia identified and followed over years by the BC Oral Biopsy Service, which receives biopsies from dentists and ear, nose, and throat surgeons across the province. Patients classified as high-risk had an almost 23-fold increased risk for progression.

Next, the researchers added two additional DNA molecular risk markers related to loss of heterozygosity to the analysis in an attempt to better differentiate patients’ risks. They used the disease samples from the prospective study and categorized patients into low-, intermediate-, and high-risk groups.

“Compared with the low-risk group, intermediate-risk patients had an 11-fold increased risk for progression and the high-risk group had a 52-fold increase in risk for progression,” Rosin said.

Of patients categorized as low-risk, only 3.1% had disease that progressed to cancer within five years. In contrast, intermediate-risk patients had a 16.3% five-year progression rate and high-risk patients had a 63.1% five-year progression rate.

“That means that two out of every three high-risk cases are progressing,” Rosin said. “Identifying which early lesions are more likely to progress may give clinicians a chance to intervene in high-risk cases and may help to prevent unnecessary treatment in low-risk cases.”

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

August, 2012|Oral Cancer News|

Demystifying the immortality of cancer cells

Source: http://medicalxpress.com/
Author:

In cancer cells, normal mechanisms governing the cellular life cycle have gone haywire. Cancer cells continue to divide indefinitely, without ever dying off, thus creating rapidly growing tumors. Swiss scientists have discovered a protein complex involved this deregulated process, and hope to be able to exploit it to stop tumor formation in its tracks.

The telomeres can be seen as white dots on these chromosomes © National Institute of Health

All our cells come equipped with an automatic self-destruct mechanism; they are programmed to die after a certain number of divisions. This internal clock is of great interest to cancer researchers, because most forms of cancer exhibit a defect in this innate timing mechanism. Cancer cells continue to divide indefinitely, long past the moment at which a normal cell would self-destruct. A team of researchers from professor Joachim Lingner’s laboratory at EPFL has learned how this defect is regulated in a tumor. Post-doctoral researcher Liuh-Yow Chen led the team in publishing an article appearing in the journal Nature on the 4th of July 2012. Their hope is that the discovery will provide new targets for drug therapies to combat the deadly disease.

Cellular immortality, which is responsible for cancer formation, hearkens back to a critical function of the cells of the developing embryo. At the ends of every chromosome there is a special sequence of DNA known as a telomere, whose length is governed by the telomerase enzyme. This sequence represents the lifespan of the cell. Every time the cell divides, it is shortened, and when the telomere finally runs out, the cell dies. This reserve allows most cells to divide about 60 times – sufficient for the cell to play its given role in the organism, without succumbing to inevitable genetic mutation.

Cellular immortality, cancer’s common denominator
Normally, once the embryonic stage is completed, our cells stop producing telomerase – with the notable exception of somatic stem cells. But occasionally, a cell will mutate and reactivate production of the enzyme, so that when the cell divides, the telomere gets longer instead of shorter. This is what gives cancer cells their immortality.

“This mutation, on its own, is not enough to cause cancer,” explains Joachim Lingner, co-author and head of the lab. “But cellular immortality is a critical element in tumor formation in 90% of known cancers.” Researchers the world over hope to be able to stop the runaway growth of cancer cells by targeting this mechanism with drug therapy.

But interestingly enough, even in a cancer cell the telomere doesn’t grow indefinitely long. With each cell division it loses some 60 nucleotides, like most cells, but then the activated telomerase causes it to gain just as many back. The internal clock is reset to zero, and the cell becomes immortal. But there’s one interesting question here: What is stopping the telomere from getting indefinitely long?

Stopping the clock with three proteins
The EPFL team was able to provide an answer to this question; they identified three proteins that join together and then attach themselves to the telomere. A bit like a lid on a pot, this protein complex prevents telomerase from acting on the telomere. But in the cancer cell, their timing is off – their involvement takes place too late.

“If we could cause these proteins to act earlier, or if we could recreate a similar mechanism, the cancer cell would no longer be immortal,” explains Ligner. The cancer cells would die a normal death. Clinical applications are still a long way off, however, he insists. “Our discovery may allow us to identify potential targets – for example, a secondary protein to which these three proteins also attach. But right now our work is still in the basic research stages.”

Source: Cancer July 5, 2012

Genes May Link Disparate Diseases

Source: The Wall Street Journal

Diseases that strike different parts of the body—and that don’t seem to resemble each other at all—may actually have a lot in common.

Scientists have identified the genetic basis for many separate diseases. Now, some researchers are looking at how the genes interact with each other. They are finding that a genetic abnormality behind one illness may also cause other, seemingly unrelated disorders. Sometimes diseases are tangentially linked, having just one gene in common. But the greater the number of shared genetic underpinnings a group of diseases has, the greater the likelihood a patient with one of the illnesses will contract another.

Researchers have found evidence, for example, that there is a close genetic relationship between Crohn’s disease, a gastrointestinal condition, and Type 2 diabetes, despite the fact the two conditions affect the body in very distinct ways. Other illnesses with apparently close genetic links are rheumatoid arthritis and Type 1 diabetes, the form of the disease that usually starts in childhood, says Joseph Loscalzo, chairman of the department of medicine at Brigham and Women’s Hospital in Boston.

This network approach, known among scientists as systems biology, could change the way medical specialists view and treat disease, according to some researchers. Rather than only looking to repair the parts of the body that are directly affected by illness, “we should be looking at what the wiring diagram [inside of cells] looks like,” says Albert-László Barabási, a physicist at Northeastern University’s Center for Complex Network Research in Boston.

Research work in the field is being done by geneticists, biologists and physicists at several universities and drug makers. The aim is to map how genes and the proteins they produce interact within cells in order to gain a better understanding of what goes wrong in the body to cause disease.

The information could help better predict a person’s risk of developing diseases, researchers say. It also could aid drug development. By figuring out which proteins are most critical to the normal functioning of the body, pharmaceutical companies could target those key proteins to treat disease. In some cases, drug companies may want to avoid interfering with key proteins to avoid too many unintended side effects, says Marc Vidal, director of the Center for Cancer Systems Biology at Dana-Farber Cancer Institute in Boston.

Since all the DNA in the human body was first sequenced in 2000, some 4,000 diseases with a known genetic basis have been identified, according to the National Institutes of Health. But only about 250 of those diseases have treatments, leaving many genetic puzzles left to untangle.

Scientists have long known that proteins and other molecules in the body don’t act alone. In order for the body to operate efficiently, biological substances must bind to or pass chemical messages to each other to start and stop working. The system is complex: Each gene is thought to produce, on average, five separate substances, mostly proteins, and these products interact with each other. When a protein, or group of proteins, malfunctions, it appears to give rise to a variety of distinct illnesses.

Dr. Barabási and his colleagues set out to see which diseases shared genetic underpinnings. They used information from a vast database at Johns Hopkins University in Baltimore that pulled together research from around the world on diseases and genes they were linked to. The scientists then mapped out a network indicating which diseases were seemingly connected to each other through common genes.

Of the 1,284 diseases mapped, nearly 900 had genetic links to at least one other disease. And 516 of these formed a so-called disease cluster, in which illnesses, mainly cancers, were linked to each other through multiple genetic connections.

Among the findings: Deafness shared at least one of 41 genes with over 20 other diseases, suggesting that it sits centrally in a cluster of other diseases. These include cardiomyopathy, a condition in which the heart muscle deteriorates; and ectodermal dysplasia, an abnormal development of the skin, hair, nails or teeth. Colon cancer shared at least one of 34 genes with 50 other diseases. Also in the cancer cluster were squamous cell carcinoma, a type of skin cancer, and throat cancer, but these had fewer genetic links between them. The work was published in the Proceedings of the National Academy of Sciences in 2007.

Because the diseases in the cluster were linked at the level of the cellular network, “the breakdown of one gene can lead to many apparently unrelated diseases,” says Dr. Barabási.

Another study by Dr. Barabási’s team aimed to see if their database analysis of genetically linked diseases was borne out in real life. The researchers analyzed more than 32 million Medicare hospital claims.

When patients developed multiple conditions, they were more likely to get illnesses that had close genetic links to their original disease than they were to get other disorders.

The study, published in 2009 in one of the journals of the Public Library of Science, PLoS Computational Biology, also showed that patients who developed diseases that tend to coincide with many others were more likely to die sooner than people whose diseases were more tangentially connected.

Using the data, the researchers estimated people’s likelihood of getting a second disease. A patient with ischemic heart disease, for example, has a 60% greater risk of getting Type 2 diabetes than an average healthy person.

Other biological processes also link seemingly unrelated diseases. In work published in 2008 in the Proceedings of the National Academy of Sciences, Dr. Barabási’s team identified a cluster of diseases, including diabetes and anemia, or coronary heart disease and hypertension, that appear to share common metabolic pathways, such as how chemicals are broken down or used in the body.

Dr. Vidal is currently working with Dr. Barabási and other researchers to map out all the possible protein interactions within a human cell. Dr. Vidal says about 20% of the project is finished, making it already the most complete map of the human protein network. The researchers also are developing protein-network maps for other organisms, including a yeast cell and Caenorhabditis elegans, a tiny worm with some 19,000 genes, about the same number as humans.

To test the role played by key proteins, or hubs, the researchers selectively deleted proteins or genes in the organisms and observed what happened. In the yeast cell, they found only about a quarter of the genes and proteins appeared to be essential, in that they connected to large numbers of other proteins and substances. The organism died when these hubs were removed, Dr. Vidal says.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

May, 2012|Oral Cancer News|

HPV DNA, E6?I-mRNA expression and p16(INK4A) immunohistochemistry in head and neck cancer – how valid is p16(INK4A) as surrogate marker?

Source: HighWire- Stanford University

It has been proposed that p16(INK4A) qualifies as a surrogate marker for viral oncogene activity in head and neck cancer (HNSCC). By analyzing 78 HNSCC we sought to validate the accuracy of p16(INK4A) as a reliable marker of active HPV infections in HNSCC. To this end we determined HPV DNA (HPVD) and E6?I mRNA (HPVR) expression status and correlated these results with p16(INK4A) staining. In tonsillar SCC 12/20 were HPVD+ and 12/12 of these showed active HPV infections whereas in non-tonsillar SCC 10/58 were HPVD+ and 5/10 showed active HPV infections. Thus, we prove about 8% of non-tonsillar SCC to be also correlated with HPV-associated carcinogenesis. Strikingly, 3/14 (21.4%) of tonsillar and non-tonsillar HPVD+/HPVR+ cases did not show p16(INK4A) overexpression and these cases would have been missed when applying initial p16(INK4A) staining only. However, in 13 cases negative for HPV, DNA p16(INK4A) was overexpressed. In conclusion, our data confirm tonsillar SCC to be predominantly but not only associated with active HPV infections. Furthermore, our data show that p16(INK4A) overexpression is not evident in a subgroup of HNSCC with active HPV infection. Definitive HPV data should therefore be utilised in diagnostics and treatment modalities of HPV positive and HPV negative HNSCC patients, resulting in a paradigm shift regarding these obviously different tumour entities.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

April, 2012|Oral Cancer News|

Oral HPV infection affects 7% of the US population

Source: www.onclive.com
Author: Ben Leach

Approximately 7% of Americans are infected with oral human papillomavirus (HPV), and men are 3 times as likely to be infected as women, according to an analysis that helps define a leading factor in the rise of oropharyngeal cancer.

The findings of the HPV prevalence study were presented at the Multidisciplinary Head and Neck Symposium in Phoenix, Arizona, in January and concurrently published in the Journal of the American Medical Association.1

The cross-sectional study was based on samples taken from 5579 men and women between the ages of 14 to 69 years that were obtained at mobile examination centers as part of the National Health And Nutrition Examination Survey (NHANES) 2009-2010. The samples were obtained through an oral rinse and gargle, with subsequent DNA samples used to determine HPV type. Demographic data were obtained using standardized interviews.

Human Papillomavirus (HPV)

HPV prevalence in the overall study population was 6.9% (95% confidence interval [CI], 5.7%-8.3%). HPV type 16, which accounts for 90% of HPVpositive oropharyngeal squamous cell carcinomas, was the most common form, affecting 1.0% of the study population (95% CI, 0.7%-1.3%).

Prevalence of HPV was significantly higher in men versus women (10.1% [95% CI, 8.3%- 12.3%] for men compared with 3.6% [95% CI, 2.6%- 5.0%] for women; P < .001]). Sexual contact was identified as a major factor in the rate of infection, with 7.5% of those who had experienced any form of sexual contact (95% CI, 6.1%-9.1%) infected, compared with 0.9% (95% CI, 0.4%-1.8%; P < .001) of those without a history of any form of sexual contact.

“This study of oral HPV infection is the critical first step toward developing potential oropharyngeal cancer prevention strategies,” Maura Gillison, MD, PhD, lead author of the study, said during a press conference at the symposium. “This is clearly important because HPV-positive oropharyngeal cancer is poised to overtake cervical cancer as the leading type of HPV-caused cancers in the US. We currently do not have another means to prevent or detect these cancers early.”

Prevalence of HPV Infection
in the US Population, 2009-20101

Characteristic Number in Study
(With Infection)
HPV Prevalence
(%)
Sex
Male 2748 (295) 10.1
Female 2753 (113) 3.6
Age
14-17 656 (16) 1.7
18-24 792 (45) 5.6
25-29 463 (32) 7.1
30-34 436 (39) 7.3
35-39 461 (31) 5.4
40-44 495 (30) 6.3
45-49 482 (37) 7.3
50-54 474 (50) 8.3
55-59 381 (47) 11.2
60-64 498 (55) 11.4
65-69 363 (26) 4.2

Further analysis identified risk factors for infection: HPV prevalence in men and women who had more than 20 sexual partners in their lifetime was 20.5% (95% CI, 17.4%-23.9%); among those who smoked more than 20 cigarettes a day, HPV prevalence was 20.7% (95% CI, 12.6%-32.0%).

Although cigarette and alcohol use have classically been associated with the disease, Gillison said that this study suggests that oral HPV is predominantly sexually transmitted. As to why men had a higher overall rate of HPV prevalence than women, the study authors suggested factors such as sexual behavior (ie, does a higher probability of transmitting HPV through oral sex on women compared to men exist?) and hormonal differences affecting the duration of infection.

Overall, the incidence of HPV-positive oropharyngeal cancers increased by 225% between 1988 and 2004, according to National Cancer Institute research. There were an estimated 6700 cases of HPV-positive oropharyngeal cancers in 2010, up from 4000 to 4500 in 2004.

Gillison said that the study was not necessarily designed to be used to advocate for vaccinating boys and girls before they become sexually active. However, Gillison said that large, prospective studies on the effectiveness of HPV vaccinations should be the next step in determining whether the vaccinations should be made mandatory at a national or global level.

“It’s difficult to make public policy recommendations based on a hope or a speculation,” Gillison said.

Notes:
1. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012; 307(7):published online ahead of print January 26, 2012. doi:10.1001/jama.2012.101

March, 2012|Oral Cancer News|

Computer scientists may have what it takes to help cure cancer

Source: nytimes.com
Author: David Patterson

The war against cancer is increasingly moving into cyberspace. Computer scientists may have the best skills to fight cancer in the next decade — and they should be signing up in droves.

One reason to enlist: Cancer is so pervasive. In his Pulitzer Prize-winning book, “The Emperor of All Maladies,” the oncologist Siddhartha Mukherjee writes that cancer is a disease of frightening fractions: One-fourth of deaths in the United States are caused by cancer; one-third of women will face cancer in their lifetimes; and so will half of men.

As he wrote, “The question is not if we will get this immortal disease, but when.”

Dr. Mukherjee noted that surprisingly recently, researchers discovered that cancer is a genetic disease, caused primarily by mutations in our DNA. As well as providing the molecular drivers of cancer, changes to the DNA also cause the diversity within a cancer tumor that makes it so hard to eradicate completely.

The hope is that by sequencing the genome of a cancer tumor, doctors will soon be able to prescribe a personalized, targeted therapy to stop a cancer’s growth or to cure it.

According to Walter Isaacson’s new biography “Steve Jobs,” a team of medical researchers sequenced the Apple executive’s pancreatic cancer tumor and used that information to decide which drug therapies to use. Since Mr. Jobs’s cancer had already spread, this effort was even more challenging. Each sequencing cost $100,000.

Fortunately for the rest of us, the cost of turning pieces of DNA into digital information has improved: The costs dropped a hundredfold in the last three years. The tipping point before widespread use is believed to be $1,000 per individual genome, which is a reason for the major investment in reducing its cost. Given such dramatic improvement, we could soon afford to sequence the genomes of the millions of cancer patients, which only billionaires could afford a few years ago.

How can computer scientists help?

First, as recently reported in this newspaper, the cost of millions of short reads of one cell by a gene sequencing machine is dwarfed by the data processing costs to turn them into a single usable three-billion-base-pair digital representation of a genome. To make personalized medicine affordable for everyone, we need to drive down the information processing costs.

Second, we need to collect cancer genomes in a repository and make them available to scientists and health professionals. The computer scientist David Haussler of the University of California, Santa Cruz, for example, is creating one. Plans are that this five-petabyte (5,000,000,000,000,000 bytes) store will house more than 20,000 genomes.

Third, finding a personalized, targeted therapy for each tumor among myriad possible combinations of drugs is like finding a very small needle in a very large haystack. Researchers are exploring the engagement of people when traditional hardware and software are not up to the task.

An inspirational example is the Foldit game — developed by the computer scientist Zoran Popovic at the University of Washington — that recently attracted thousands of volunteers to uncover the structure of an enzyme important to H.I.V. research.

Cancer tumor genomics is just one example of the Big Data challenge in computer science. Big Data is unstructured, uncurated and inconsistent, and housing it often requires a thousand-fold increase in size over traditional databases. It is not pristine data that can be neatly stored in rows and columns. YouTube alone holds nearly one exabyte of videos, which is one trillion megabytes, or 1,000,000,000,000,000,000 bytes.

The Big Data research challenge is to develop technology that can obtain timely and cost-effective answers to Big Data questions. A Berkeley team of eight faculty members and 40 Ph.D. students is rising to that challenge via three initiatives: inventing algorithms based on statistical machine learning; harnessing many machines in the cloud; and developing crowd-sourcing techniques to get people to help answer questions that prove too hard for our algorithms and machines.

Algorithms, machines and people gave our new lab its name: the AMP Lab.

AMP technology could help the war on cancer. It needs new algorithms to find those needles in haystacks. To process genome data faster and more cheaply, the war needs new infrastructure to use many machines in the cloud simultaneously. And it needs to be able to engage the wisdom of the crowd when the problems of cancer genome discovery and diagnosis are beyond our algorithms and machines.

It may have been true once that expertise in computer science was needed only by computer scientists. But Big Data has shown us that’s no longer the case. It is entirely possible that we have the skill sets needed now to fight cancer and to advance sciences in myriad other ways.

The night after we made that argument, I awoke in the middle of the night with this question etched into my mind: Given that millions of people do have and will get cancer, if there is a chance that computer scientists may have the best skill set to fight cancer today, as moral people aren’t we obligated to try?

December, 2011|Oral Cancer News|

Lab at Hershey Medical Center identifies a virus that could kill cancer

Source: www.pennlive.com
Author: Nick Malawskey, The Patriot-News

This is not the kind of lab we picture when we think of world-changing science. It’s not the clean, spotless modern laboratories of television or movies. It’s a cluttered, workaday environment, where plastic test tubes rub shoulders with petri dishes and tubs of chemicals on busy shelves.

The white board isn’t covered with the scrawl of complex mathematical formulas, but reminders of whose turn it is to buy the doughnuts. But it is here, on the fifth floor of the Penn State Milton S. Hershey Medical Center, where Dr. Craig Meyers and his team might have conducted a miracle.

What he and his lab claim discovery of is breathtaking in its simplicity.

A common virus, omnipresent in the world. When it infects humans, it does no harm. But introduce it into certain kinds of tumors and the virus appears to go wild, liquefying every cancer cell it comes into contact with.

It’s the type of discovery that could change the world. And like all great stories of scientific discovery, it begins with a moment of sublime serendipity, not unlike Isaac Newton nodding off beneath an apple tree.

A Tiny Virus

It’s one of the smallest, simplest viruses and yet adeno-associated virus type 2, or AAV2, could be among the most important agents in modern medicine. That’s because it’s almost perfectly imperfect. For whatever reason, through its evolution, AAV2 developed what would, in most cases, be a dead end — it cannot easily reproduce.

Viruses live and reproduce through asexual replication. In the simplest terms, they infect an organism and attack living cells, inserting viral genes inside healthy cells. The viral genes then hijack the cell, using it to reproduce and create more viruses. The new viruses are released into the environment, where they begin infecting other healthy cells.

AAV2 doesn’t work that way.

At the University of Florida in Gainsville, Nicholas Muzyczka has made a career studying AAV2 and he knows the virus about as well as anyone.

“And the deal with [AAV2] is that it will go into the cells in your body — and do nothing,” Muzyczka said. “It’ll just sit there.” By itself, the virus is harmless and, in some cases, won’t even replicate. Instead, it relies on a “helper” virus to poke it along. One of its helper viruses is believed to be the human papillomavirus, or HPV, which is widely believed to be one of the major causes of cervical cancer.

There has also been evidence that not only does HPV impact AAV2, but AAV2 might have some form of impact on HPV — and alter the chances of someone developing cervical cancer.

Which is exactly what Meyers’ lab at Penn State was studying when the lab had its Newton-under-the-apple-tree moment five years ago.

What happened involves a cervical cancer sample, some AAV2 and a few extra days in an incubator.

‘We Thought Something Had Gone Wrong’

Meyers has spent the last 18 years at Penn State, most of it studying HPV. He was one of the first scientists to grow the virus in a laboratory setting, and today his lab is one of the major suppliers of HPV for scientific studies. A few years ago, he was continuing his research into HPV, cervical cancer and the relationship with AAV2.

Other studies indicated that women with cervical cancer don’t have AAV2 and women with AAV2 don’t have cervical cancer. Meyers and his lab were trying to figure out why. Their method was simple: Infect groups of cervical cancer cells with AAV2 and harvest the cells after 24, 48 or 72 hours to note any changes taking place.

On a whim, Meyers told one of his research assistants to infect a cancer cell culture and let it sit for awhile — say, a week.

A week later, she walked into his office and said something strange had happened. That culture of cancer cells they had infected a week ago? They were all dead.

“We thought something had gone wrong,” Meyers said. “My first reaction was: ‘The incubator. I’ll have to get the incubator fixed.’”

The lab repeated the process five, 10, a dozen times. Each time, it had the same result. A week after being infected with AAV2, the cervical cancer cells were dead.

The lab began to spread out its research, collecting other types of cancer samples from other labs to infect with AAV2, including breast cancer. Each time, they had the same results: Infect the cancer cells, wait a week and the cells die. By replicating the experiment, the laboratory was able to gain some understanding of the mechanics of what was happening.

“What the virus seems to be doing is turning on [a gene in] all these cancer cells that causes them to die, to turn on themselves and commit suicide,” Meyers said. Even more encouraging, when his lab infected mice that had human breast cancer tumors with AAV2 earlier this year, they found the tumors had liquefied — a reassuring result because that isn’t always true.

“A lot of times in science, you tend to plan out your experiments and you have a goal, your hypothesis of what you’re trying to prove,” Meyers said. “But sometimes you see bits of data or someone else’s work and you get an idea … a lot of times some of the best things come from those little ideas.”

We’ve Been Here Before

The Penn State lab isn’t the first to announce what could be a major breakthrough using viruses to combat cancer.

Twenty years-ago, researchers at the University of California thought they found the silver bullet — a modified cold virus that killed about 60 percent of human tumors grown in laboratory mice.

News of the research caused The New York Times to ask: “Can the common cold cure cancer?” Headlines in The Los Angles Times and The Pittsburgh Post-Gazette proclaimed the research to be “a cancer-killer.” It didn’t turn out that way. During clinical testing in humans, the modified virus fizzled. But the research, which centered around a gene named P53 did rejuvenate an entire field of study — oncolytic virology.

The link between viruses and cancer isn’t anything new. For close to a century, scientists have believed there is some connection between the two. In 1904, doctors first noticed that leukemia patients occasionally went through periods where they appeared to get better — and those periods corresponded with outbreaks of the flu. The 1950s saw a flurry of activity, when several viruses — including hepatitis B and West Nile — were used in human trials in an attempt to treat cancer. While both viruses caused some tumor regression, the side effects, namely contracting hepatitis and West Nile, outweighed the benefits.

The study of viruses as anti-cancer agents petered out under the weight of a basic catch-22: Researchers needed something tough enough to survive the human immune system, but also a virus that wouldn’t adversely affect normal human cells.

When then-President Richard Nixon went before the nation in 1971 to declare a crusade against cancer, it was widely believed that cancer was caused by viruses altering the DNA of healthy cells. While that’s true in some cases, in others cases, cancer’s runaway growth of cells is caused by faulty genetics or cell mutation due to environmental conditions. It wasn’t until decades later that technology and basic scientific understanding — of cancer and virology — caught up to the idea of using viruses or “oncolytic viruses” to deliver anti-cancer treatments.

Since the first studies in the mid-1990s with the mutated cold virus, there have been a number of advances in the field, and numerous modified viruses are currently being tested around the world.

Five years ago in China, the first oncolytic virus, H101, was approved for clinical use, ironically a variant of the modified cold virus studied in the mid-’90s in California. The Chinese — their testing standards are a bit more lax than ours — use H101 in conjunction with chemotherapy to reduce or eliminate tumor growth in patients with head and neck cancers.

In the U.S., a Massachusetts-based biotechnology firm named BioVex is testing a modified version of herpes in patients with stages III and IV of melanoma. An earlier study by BioVex showed eight of the 50 patients treated with the virus recovered completely and a majority of the patients showed improvement.

The treatment holds enough promise that Amgen, one of the world’s largest biotechnology companies offered $1 billion to acquire BioVex earlier this year.

Bench To Bedside

The common cold viral study two decades ago highlights some of the major hurdles in moving a virus-based treatment from the laboratory to the bedside. There’s a world of biological complexity between mice and humans, and the vast majority of drugs, somewhere around 90 percent, never bridge that gap.

In the case of the modified cold virus, researchers didn’t account for the fact that most people, at one time or another, suffer from the cold and build biological defenses against it. So when they introduced the engineered virus, the body attacked and killed it, reducing its effectiveness in treating patients. Then they ran into their second major hurdle — discouraged, their industry partner, Pfizer, pulled its funding from the project.

The American Cancer Society, which funds cancer research, estimates it takes about 10 to 12 years to fully develop a drug or therapy from the laboratory to bedside use.

“There’s just tremendous challenges,” cancer society spokeswoman Lynne Ayres said.

Drugs have to go through a series of tests prior to their use on humans, then at least three levels of human testing. All of which requires time and money — roughly $2 billion annually. The American Cancer Society and the National Institute of Health are only able to pay for about 10 percent of the grant requests they receive.

That means a lot of research could be stalled in the pipeline. Even Meyers’ research wasn’t able to secure national funding for his preliminary testing of the AAV2 virus. His most recent research was funded through a roughly $35,000 grant from the Pennsylvania Breast Cancer Coalition.

Even once a drug or therapy passes through the FDA approval process, there’s one final step before it makes it to the general public — production and distribution.

“You’ve got to get funding to bring it to the market, which involves getting [pharmaceutical industry] support,” Ayres said.

And, she asked, what is the industry going to spend development costs on?

“Something they can make money on,” she said. “These are the realities.”

Human Trials are Years Away

Meyers’ research — and the resulting publicity — have made him something of a public figure overnight. Every day, he gets emails from people congratulating him on his findings. And every day, he receives just as many from people begging for a cure. It’s a request he simply cannot fulfill yet. Yes, the virus appears to work in a laboratory setting and has destroyed tumors in mice. But his research still has a long road ahead of it before it makes its way to hospitals.

His next step will be to push toward clinical trials in people. But first he has to complete pre-clinical testing before he can apply to the Food and Drug Administration for human testing. Bottom line: Even with unlimited funding, it could be another two to four years before Meyers injects AAV2 into the first patients. Until then, he’ll continue to receive the emails from desperate people, begging him for a cure.

“It’s a very emotional topic. Everyone has somebody they know who has one type of cancer or another,” Meyers said. “And cancer’s not like one day you’re alive and the next day you’re dead. It’s a long, debilitating, chronic problem.

“You need to be reminded sometimes that the research you’re doing could have an affect on people out there.”

In the meantime, Meyers isn’t the only one looking at AAV2. Remember Muzyczka at the University of Florida? He’s among the many researchers looking at AAV2 for its use as a transportation device for genes. Because the virus is so simple, it’s relatively easy for scientists to remove its small amount of genes and replace them with human ones.

The idea is to introduce the carrier virus into the body of a person who might be suffering from a genetic disorder due to a problem in their own body’s DNA structure.

AAV2 virus, carrying the human genes, enters the patient’s cells and inserts its DNA fragment into our genes, repairing or replacing the broken sequence. Because the virus is small, simple and doesn’t easily replicate, it reduces the chances of something going wrong.

“In a lot of different ways, it’s proving to be the safest way to deliver genes,” Muzyczka said. “And a lot of people are getting kind of excited about this because it does seem innocuous.”

It’s already being tested to treat hemophilia in England, where researchers used it to introduce healthy genes into people with the condition.

AAV2 then could be the key to one of the medical holy of holies — real, systemic gene therapy.

Not only could it kill cancer cells, but it could be the vehicle to treat other genetic conditions, such as Alzheimer’s disease, Parkinson’s disease and cystic fibrosis.

“No one’s at the point where the Food and Drug Administration has approved it,” Muzyczka said. “But it is getting to the point where people think it’s going to work.”

Steps to FDA approval
Source: Federal Food and Drug Administration
It’s a long, long road from the laboratory to the bedside, governed by the Food and Drug Administration. The vast majority of all drugs and therapies developed don’t make it. The American Cancer Society estimates it takes about 10 to 12 years to fully develop a drug or therapy from the laboratory to bedside use. Steps include:
1. Preclinical (animal) testing. This is where Dr. Meyers team is in the process.
2. Phase 1 studies (typically involve 20 to 80 people).
3. Phase 2 studies (typically involve a few dozen to about 300 people).
4. Phase 3 studies (typically involve several hundred to about 3,000 people).
5. Submission of a new drug application is the formal step asking the FDA to consider a drug for marketing approval.
6. After an application is received, the FDA has to decide whether to file it so it can be reviewed.
7. Review of the application resulting in application approval or the issue of a response letter.

 

November, 2011|Oral Cancer News|

CU Med School prof seeing red over wine benefit study

Source: www.aurorasentinel.com
Author: Sara Castellanos

There’s a reason Robert Sclafani always chooses red wine over white wine, and it’s not just because he thinks it tastes better.

Sclafani, a professor of biochemistry and molecular genetics at the University of Colorado’s School of Medicine, prefers the darker of the two wines because of its health benefits.

Red wine contains much more of a compound called resveratrol, found in the skin of grapes and also in peanuts and leeks.

Sclafani and his colleagues are currently testing the effects of resveratrol on mice, and this month he received encouraging news from overseas that resveratrol can have health benefits for obese humans.

“There are a number of studies in animals where you can take an animal like a mouse and give it cancer by treating it with carcinogens or manipulating the genes in mice so they’ll get cancer,” Sclafani said. “If you treat the animal with resveratrol, it blunts the effect; they either get less cancers, cancers never develop or they never go anywhere.”

Here’s how it works: resveratrol causes damage to the DNA in cancer cells, he said.

“We think that’s the Achilles heel,” he said.

The compound has been known to have positive effects for more than a decade, but on Nov. 2, a group of scientists in the Netherlands showed for the first time that it can have health benefits in obese humans.

Eleven obese but healthy men had taken a relatively low dose of the compound daily for a month, which lowered their metabolic rate, cut the accumulation of fat in the liver, reduced blood sugar, blood pressure, triglycerides and inflammation, and boosted the efficiency of muscles, according to the Washington Post.

That news solidified Sclafani’s research on resveratrol.

“We’ve shown in our studies that moderate amounts of resveratrol, much lower than they’re using in these individuals, can have anti-cancer effects in mice and cell-culture studies,” he said.

The researchers in the Netherlands did say, however, that a person would have to drink at least 2 gallons of red wine a day to get the equivalent amount of resveratrol as the dosage used in the study, according to the Post.

But their research and Sclafani’s could help explain the “French paradox.”

Sclafani said French people eat fatty diets (foie gras, steak and fries) and drink a lot of red wine but have much less cancer and heart disease than one would expect.

“It’s still not understood, but that’s always been the idea, that there must be something in red wine that allows them to have this unhealthy diet and still have reduced disease,” he said.

Sclafani and, Rajesh Agarwal, a professor in the Department of Pharmaceutical Studies at the School of Medicine, also found recently that resveratrol is successful in preventing a specific type of cancer in mice.

“As recently as last month, we are in the position that we can have more convincing data in the mice showing that … resveratrol is extremely effective in preventing the appearance of oral cancer,” he said.

In a couple of years, they hope to test the effects of resveratrol in humans with oral cancer, which is a common affliction among people in countries like India. Agarwal said high quantities of concentrated resveratrol could be given to patients with oral cancer in the form of a mouth wash or a gel.

And the best part, he said, is there are no known side effects to resveratrol.

But just because the compound is found in red wine doesn’t mean that Agarwal encourages people to drink as much as they want, as often as they want, in hopes of living a cancer-free life.

“Anything in excess is not good,” he said. “People will say, ‘OK, so resveratrol is good, and it’s in the red wine’ so they’ll start drinking more red wine. But before they die of cancer, they’ll die of liver failure. It’s kind of a fine balance, and that needs to be taken into account.”

But consuming moderate amounts of foods that contain resveratrol certainly can’t hurt, he said.

“As my good friend Bob Sclafani says, he eats a lot of Thai food and drinks red wine so he can be healthier for a longer time,” Agarwal said.

November, 2011|Oral Cancer News|

Evaluation of Human Papilloma Virus Diagnostic Testing in Oropharyngeal Squamous Cell Carcinoma: Sensitivity, Specificity, and Prognostic Discrimination

Source: Clinical Cancer Research

Abstract

Purpose: Human papillomavirus-16 (HPV16) is the causative agent in a biologically distinct subset of oropharyngeal squamous cell carcinoma (OPSCC) with highly favorable prognosis. In clinical trials, HPV16 status is an essential inclusion or stratification parameter, highlighting the importance of accurate testing.

Experimental Design: Fixed and fresh-frozen tissue from 108 OPSCC cases were subject to eight possible assay/assay combinations: p16 immunohistochemistry (p16 IHC); in situ hybridization for high-risk HPV (HR HPV ISH); quantitative PCR (qPCR) for both viral E6 RNA (RNA qPCR) and DNA (DNA qPCR); and combinations of the above.

Results: HPV16-positive OPSCC presented in younger patients (mean 7.5 years younger, P = 0.003) who smoked less than HPV-negative patients (P = 0.007). The proportion of HPV16-positive cases increased from 15% to 57% (P = 0.001) between 1988 and 2009. A combination of p16 IHC/DNA qPCR showed acceptable sensitivity (97%) and specificity (94%) compared with the RNA qPCR “gold standard”, as well as being the best discriminator of favorable outcome (overall survival P = 0.002). p16 IHC/HR HPV ISH also had acceptable specificity (90%) but the substantial reduction in its sensitivity (88%) impacted upon its prognostic value (P = 0.02). p16 IHC, HR HPV ISH, or DNA qPCR was not sufficiently specific to recommend in clinical trials when used in isolation.

Conclusions: Caution must be exercised in applying HPV16 diagnostic tests because of significant disparities in accuracy and prognostic value in previously published techniques.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

October, 2011|Oral Cancer News|