Oral Cancer News

Genome sequencing of head and neck cancers may quickly—and soon—spur new therapies. There are 20 tumor types being studied by the massive, $100 million Cancer Genome Atlas (TCGA) project. Head and neck squamous cell carcinoma (HNSCC) is the eighth to be unveiled. The first, glioblastoma, has been cited in a whopping 2000-plus manuscripts.

“That’s an enormous number of citations,” said University of North Carolina medical oncologist David Hayes at the recent American Association for Cancer Research (AACR) meeting. Yet, “the squamous cell carcinoma of the head and neck dataset is much, much bigger.

“This is a very big project.”

Much clinically relevant HNSCC data was released at AACR, and more will be released at the May American Society of Clinical Oncology meeting, Hayes said in an email. Hayes is national co-chair of TCGA’s Data Analysis Subgroup. The frequently fatal HNSCC is the fifth most common cancer globally; sixth in the US. It is overwhelmingly associated with smoking (80% attributable risk). The rest is linked to an epidemic of the Human Papilloma Virus (HPV).

Conducting an exhaustive series of genomic tests on tumor samples from 279 patients, the overarching find made by Hayes’ hundreds-strong TCGA group was that HNSCCs fall into four clinically relevant subtypes: basal, mesenchymal, atypical, and classical.

Furthermore, there are surprising, major similarities between lung cancer and non-HPV (smoking) related HNSCCs, and between cervical cancer and HPV-related HNSCCs.

For instance, in non-HPV-driven cancers, the group located more than 30 sites of significant “somatic copy number alteration,” or sites of major alteration in gene copy numbers, most of which were identical to those of lung squamous cell carcinoma.

Much of this was unknown. It suggests we can look at cancers like HNSCC as “molecular patterns that can be leveraged and understood,” Hayes said. Drugs for one cancer can be “easily transferred” to cancers once thought different, but are suddenly unveiled as genetically alike.

The findings the HNSCC group is making, as with other cancers exhaustively sequenced for the government-sponsored TCGA, are overwhelming in number. They will keep researchers busy for years. But TCGA groups are also producing data with more immediate clinical potential.

The HNSCC group isolated for the first time the 18 most-mutated HNSCC genes, the “most important genes in this cancer…the driving genes,” Hayes said. Many are potential targets.

Yet their absence can lead to targets, too. The group noted that HPV-driven HNSCCs “almost never have a TP53 mutation.” This isn’t “therapeutically actionable,” as it is not a druggable mutation. But the group saw that those HPV-negative patients who don’t possess the TP53 mutation do tend to have a mutation in a “very druggable gene: H-Ras,” Hayes said. (About 5% of samples possessed this mutation.)

Existing drugs may indeed successfully target H-Ras mutations, the way they can’t other Ras oncogenes, says Frank McCormick, outgoing AACR president, and director of the University of California San Francisco Comprehensive Cancer Center.

“H-Ras is likely to be druggable through inhibition of farnensylation,” McCormick said in a recent email. “Farensyl transferase inhibitors (FTIs) are thought to have failed because K-Ras and N-Ras have a back-up system. Mutations in K-Ras and N-Ras are far more common than H-Ras, as we now know, so most of the tumors on which FTIs were tested didn’t respond. However, tumors driven by H-Ras, though rare, are likely to respond to FTIs. Now that patient selection is feasible (which it wasn’t 20 years ago when FTIs were being tested), it should be possible to select H-Ras-driven cancers up-front, then treat with FTIs.”

Translation: oncologists could start treating that new subset of HNSCC patients with promising drugs—soon.

The HNSCC group has identified at least two other immediate “candidate therapeutic targets,” Hayes said. First, they found that a certain mutation in the gene PIK3CA occurs in almost 40% of HPV-driven tumors. “So that is a very near-term actionable observation.” Drugs inhibiting PIK3CA are in the pipeline for cancers of the breast, among others.

And in HPV-negative samples, the group confirmed there is a large number of high-frequency mutations in genes, including epidermal growth factor receptor (EGFR) and cyclin D1 (CCND1), that could be clinically addressed in the “relative short term,” he said.

Still, not every patient has a druggable mutation, he cautioned. The new data have “complicated” things. Yet they also let researchers “recognize patterns and simplify things.”

In a PLOS One paper, the group explained further: “The differences in the expression patterns found in the (four new) subtypes are clinically relevant.”¹ They discovered the gene Np63 is overexpressed in the “basal” subtype. Earlier, another group found exposure to the widely used cancer drug cisplatin led to decreased levels of Np63.² “So this treatment may be particularly effective for patients in (the “basal” subgroup).”

The group has also found conflicting data arousing “great interest,” says Hayes. EGFR-targeting drugs have been given to all kinds of HNSCC patients ever since other researchers found EGFR is over-amplified in many.³ Indeed, the FDA approved an EGFR-inhibitor for metastatic HPV-positive HNSCC. But Hayes’ group found EGFR expression is low in the new “atypical” subtype, and in those very same HPV-positive cancers. Work is ongoing to “figure out” that one.

The group also revealed in PLOS that P13 Kinase inhibitors may be an attractive option for patients with both the “atypical” and “classical” subtypes. And SOX2 and ALDH1—putative cancer stem cell markers—were found to be highly expressed in the “atypical” and “classical” HNSCCs: two possible future targets.¹

The 279 tumor samples have yielded the largest genomic dataset for each typical HNSCC site (e.g., oral cavity, larynx, hypopharynx, oropharynx) by a factor of at least two.

But the landslide of data is far from over. By year’s end, says Hayes, the group will announce analysis results from 200 additional HNSCC samples.

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

Source: www.alberniportal.ca
Author: Leatitia Michael

A survey reveals that the general public, including those who smoke, do not know very much about oral, head, and neck cancer (OHNC).

There were nearly 40,000 new cases of oral, head and neck cancer diagnosed last year in the USA, of which 85 per cent could be linked to tobacco use and heavy alcohol consumption. Yet, according to a survey from the Medical University of South Carolina, the public remains largely unaware of the risks.

In the study, over 1,000 members of the public were telephoned and 62 per cent said they were not knowledgeable about OHNC. Among smokers, the lack of awareness ran at 58 per cent. Under half of non-smokers and smokers knew that smoking was a risk factor. Hoarseness was correctly identified as a symptom by only one per cent of smokers and two per cent overall. But 17 per cent of the sample incorrectly named headache as a symptom.

People can spot the signs and symptoms of OHNC themselves, but 94 per cent had not been told to look for problems like mouth sores that do not heal. And only 26 per cent had been check for this by a doctor. Clearly there is some way to go in raising awareness among the public of OHNC.

Source: www.nydailynews.com
Author: Corky Siemaszko

Michael Douglas said the tumor at the back of his tongue was the size of a walnut, but it still took doctors nine months to figure out it was throat cancer.

“I knew something was wrong,” he said. “My tooth was really sore, and I thought I had an infection.”

But the ear-nose-and-throat doctors and periodontists he consulted kept giving him antibiotics.

“And then more antibiotics, but I still had pain,” he said.

Finally, in 2010, a doctor in Montreal figured out that thing on his tongue was tumor.

“Two days later, after the biopsy, the doctor called and said I had to come in,” Douglas recalled in a wide-ranging interview with New York magazine. “He told it me it was stage-four cancer. I said, ‘Stage four. Jesus.’

“And that was that. After complaining for nine months and them not finding anything, and then they told me I was stage four? That was a big day.”

Douglas not only talked about his brush with mortality, he also chatted about his Hollywood comeback. He plays flamboyant piano tickler Liberace in an HBO biopic, “Behind the Candelabra,” that airs May 26.

“Liberace loved sex,” he said.

But the “Wall Street” star’s revelation that he had cancer sent a scare through Hollywood, where the words “stage four” were looked at as a death sentence. And for a time, Douglas looked like hell — losing 45 pounds as he subsisted on mostly on matzo ball soup as he healed.

Weakened by chemotherapy and radiation treatments, Douglas said he spent hours lying on a couch. Douglas looked like hell while recovering from cancer — losing 45 pounds as he subsisted on mostly on matzo ball soup.

“I watched a lot of sports, anything where I didn’t know the ending,” he said.

But Douglas was lucky to have a curable kind of cancer and now he’s back at work feeling a “new rejuvenation.”

Douglas said he believe his illness was “karmic retribution” for his decades of success, including two Academy Awards and four Golden Globes.

“That’s life,” said Douglas, 68. “I was ready for some karmic retribution.”

Douglas may be on the mend, but he’s hit other bumps in the road. His glamorous wife, actress Catherine Zeta-Jones, remains in rehab, where she has been fighting depression.

His troubled 34-year-old son by his first wife is doing time for distributing crystal meth — and recently had nearly five years added to his sentence after he was caught doing drugs in prison.

“I have gone from being a very disappointed but loving father who felt his son got what was due him to realizing that Lady Justice’s blindfold is really slipping,” he said. “I’m not defending Cameron as a drug dealer or drug addict, but I believe, because of his last name, he’s been made an example.”

Douglas, who has two kids with Jones, has expressed regrets in the past about being a lousy dad to Cameron. And he has spoken about growing up in the shadow of his famous father, actor Kirk Douglas.

“Success is expected, and yet the track record of the second generation is not great,” he said. “Only a small group of us, like Jane Fonda, have succeeded.” Fonda’s dad was actor Henry Fonda.

“The good and the bad of being second generation is: There are no illusions,” he said. “I always knew that this was a business. It can be wonderful, but it is a business.”

Source: www.drbicuspid.com
Author: DrBicuspid Staff

High-risk types of human papillomavirus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). However, HPV-positive OPSCC is highly curable, and patients with HPV have better survival compared with HPV-negative patients, whose cancers are usually associated with alcohol and tobacco use.

To better understand the molecular mechanisms underlying these differences, Jochen Hess, PhD, and colleagues at University Hospital Heidelberg monitored changes in DNA modifications in HPV-positive and HPV-negative OPSCCs (Journal of Clinical Investigation, May 1, 2013).

They applied an array-based approach to monitor global changes in CpG island hypermethylation between HPV-negative and HPV-positive OPSCCs, and identified a specific pattern of differentially methylated regions that critically depends on the presence of viral transcripts. This DNA modification pattern was significantly correlated with improved survival in three separate groups of OPSCC patients, the researchers noted.

“Our study highlights specific alterations in global gene promoter methylation in HPV-driven OPSCCs and identifies a signature that predicts the clinical outcome in OPSCCs,” they concluded.

Researchers have discovered a new mechanism by which the human papilloma virus (HPV) causes head and neck cancer, and they have designed a drug to block that mechanism. Though further research is needed, the new agent might offer a safer treatment for these tumors when combined with a tapered dose of standard chemotherapy.

HPV-positive head and neck cancer has become three times more common since the 1970s, and it could reach epidemic levels in the future, say researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) who led the study.

“We believe these findings will help meet the real need for more effective and safer therapy for a growing number of HPV-positive head and neck cancer patients,” says principal investigator Dr. Quintin Pan, associate professor of otolaryngology at the OSUCCC – James.

The study was published in the journal Oncogene.

The research, which mainly used head and neck cancer cells, shows that a protein produced by the virus blocks a protein made by the host cell. The cell protein, called p300, regulates a gene called p53. This gene both controls cell division and protects the body against cancer by causing cells to die before they become malignant.

By blocking the cell protein, HPV forces the host cell to live instead of die and to proliferate and form tumors.

The prospective new drug, called CH1iB, prevents the viral protein from binding with the cell protein. This restores the function of the p53 “tumor-suppressor” gene and triggers the death of the cancer cells.

“Our study revealed a new mechanism for p53 inactivation in HPV-positive head and neck cancer, and this allowed us to develop an agent that disrupts that interaction and reactivates p53 in HPV-positive head and neck cancer,” Pan says. “Our pre-clinical studies show CH1iB can reactivate p53 and eliminate HPV-positive head and neck cancer cells.”

Pan notes that the standard of care for HPV-positive head and neck cancer uses high-dose cis-platinum, a chemotherapy drug that causes serious side effects that are difficult for patients to tolerate. The drug’s toxicity raises the need for safer therapy, and, although further testing is necessary, combining CH1iB with a low dose of cis-platinum might one day provide an alternative.

For this study, Pan and his colleagues used high-risk HPV-positive head and neck squamous cell carcinoma cells. Key technical findings include:

• The small-molecule inhibitor CH1iB inhibits the binding of the HPV E6 protein with the p300 cell protein;
• The binding of the CH1iB inhibitor with p300 reactivated p53 and dramatically potentiated the efficacy of cis-platinum in HPV-positive head and neck cancer cells;
• The combination of CH1iB and cis-platinum eliminated 91 percent of HPV16-positive head and neck cancer cells; it also increased apoptosis by 984 percent and 443 percent compared with CH1iB and cis-platinum respectively alone.

“These results suggest that fewer cycles or a tapered dose of cis-platinum, along with a CH1 inhibitor, might be sufficient to effectively manage HPV-positive head and neck cancer patients and offer a better toxicity profile,” Pan says.

“Taken together, our data suggest that we’ve discovered a novel approach for reactivating the p53 gene in HPV-positive head and neck cancer that may translate to other HPV-positive carcinomas.”

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

A common virus known to cause cervical and head and neck cancers may also trigger some cases of lung cancer, according to new research presented by Fox Chase Cancer Center at the AACR Annual Meeting 2013.

Examining tissue samples from lung cancer patients, the researchers found that nearly 6% showed signs they may have been driven by a strain of human papillomavirus (HPV) known to cause cancer.

If HPV indeed plays a role in lung cancer in some patients, the next step is to better understand those tumors so they can be treated more effectively. “The ultimate goal,” says study author Ranee Mehra, MD, attending physician in medical oncology at Fox Chase, “is to determine if we can target our therapies to the specific characteristics of these tumors.”

Studies from Asia have shown that lung tumors are frequently infected with HPV. The pattern makes sense, explains Mehra – the lungs are located very near the head and neck, which are known to be at risk of tumors upon exposure to some strains of HPV.

To investigate, she and her colleagues examined 36 tissue samples from people diagnosed with non-small cell lung cancer who had never smoked, part of the Fox Chase Cancer Center Biosample Repository. The reason they chose non-smokers, Mehra explains, is that smoking is a major cause of lung cancer – but in non-smokers, the explanation is often less obvious.

The researchers found that 4 out of 36 samples had signs of infection from two strains of HPV known to cause cancer, 16 and 18. Looking more closely at the two samples infected by HPV 16, Mehra and her team saw signs the virus had integrated into the tumor’s DNA – which is even more suggestive that the infection caused the tumor. They presented their findings at the annual meeting of the American Association for Cancer Research.

Although this suggests that HPV drives lung cancer in less than 6% of non-smoker patients, making it a relatively rare occurrence, lung cancer is very common, Mehra notes – killing more than 1 million people every year. Approximately 10 percent of cases occur in non-smokers. “Given how many patients develop lung cancer, if even a small percentage of those tumors stem from HPV, that ends up being a large number of patients,” she says.

It’s not clear how HPV reaches the lung, she says; patients may simply breathe it in. And just because these patients have evidence of an HPV infection that does not necessarily mean the infection caused their tumors, Mehra cautions. “It could simply be a coincidence that they had both lung cancer and HPV,” she notes. “But the presence of both simultaneously, and the integration of the virus into the tumor’s DNA, fuels the hypothesis that they are related.”

Although the majority of people are exposed to HPV, these results are largely not cause for concern, assures Mehra. “In my practice, I treat many people with head and neck cancers who are infected with HPV. Some fear that they are ‘contagious’, and could somehow pass the cancer onto their families,” she says. “Mostly, I reassure them – even though most people have been exposed to HPV, it’s rare for someone to develop cancer as a result.”

And people who have lung cancer but never smoked need not rush to their doctors to determine if they also have HPV, since doctors don’t know yet if they should treat these tumors differently, or if the presence of the virus has any impact on prognosis. “These results are very preliminary and not a reason to run to your doctor to find out if you are infected, or panic if you are,” she states.

As such, researchers need to investigate what factors drive some people to develop cancer after exposure to HPV, so they can better treat those types of tumors, says Mehra. “Hopefully, this research will fuel some discussion or further studies,” she notes. “What we need is a better understanding of why does cancer develop in some patients and not in others.”

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

New discoveries by a team of scientists at LSU Health Sciences Center New Orleans for the first time reveal the inner workings of a master regulator that controls functions as diverse as the ability of nerve cells to “rewire” themselves in response to external stimuli and the mechanism by which certain viruses hijack normal cellular processes to facilitate their replication that can ultimately lead to cancer. The research was published in the Journal of Biological Chemistry.

The complex genetic programs controlling the function of cells and the organs, nerves, and tissues that they form are expressed through the concerted contributions of some 30,000 unique proteins that constitute the human genome. Coordination of these proteins is controlled by a small set of master regulators that sense the environment of the cell and alter subtle features of the genetic programs to maintain metabolic balance, called cellular homeostasis. More radical alterations in the genetic programs due to gene mutation or in response to viral or bacterial infection frequently lead to conditions that can result in cancer or developmental defects.

Lead investigator Dr. Virginia Ronchi, a postdoctoral fellow, and research associate Jennifer Klein, working in the laboratory of Dr. Arthur Haas, Professor and Head of Biochemistry and Molecular Biology at the LSU Health Sciences Center New Orleans School of Medicine, focused on the E6AP enzyme. This enzyme regulates the functions of several dozen different proteins involved in key homoeostatic processes. The E6AP protein belongs to a class of enzymes known as ubiquitin ligases. E6AP controls its target protein functions by attaching a smaller protein called ubiquitin to them that serves as a molecular flag to signal removal of the target by a large cellular nanomachine called the 26S proteasome.

Inherited mutations in the E6AP gene that block its activity result in Angelman’s syndrome, a developmental condition characterized by severe mental retardation in children because the brain is unable to “learn” by adapting its nerve connections to outside stimuli. Other mutations that cause a duplication of the E6AP gene and increased activity are thought to cause some forms of inherited Autism Spectrum Disorder. In other tissues, the genetic program of the Human Papillomavirus produces an E6 viral protein following infection that hijacks the E6AP enzyme to target a different set of cells, not only ensuring the ability of the virus to replicate but causing uncontrolled growth resulting in benign skin tags, warts, or cervical cancer, depending on the site of infection. The Hepatitis C virus exploits a similar strategy to ensure its replication in the liver by expressing a different protein that redirects the function of E6AP, resulting in cirrhosis and liver cancer in the chronically infected.

The LSUHSC investigators used the ability of E6AP to form chains of ubiquitin as a window into the molecular function of the enzyme. The studies provide a description of the mechanism for the enzyme at the molecular level which provides potential strategies for designing drugs to block E6AP function in the case of the Human Papillomavirus and Hepatitis C virus. Because E6AP is similar to a larger family of related master regulators that control other cell functions, knowledge about it may also apply to future drug design for enzymes involved in many other diseases.

“The current work by Ronchi and Klein marks a major advance in our understanding of this important class of cell regulators and redefines more than 15 years of work in the field by other investigators,” notes Dr. Haas.

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

Source: www.bizjournals.com
Author: James Ritchie

Dr. Keith Wilson finds robotic surgery to be a good approach for removing tumors growing deep in the throat, as I recently reported. As it turns out, such tumors are often part of an alarming trend. They’re often caused by the sexually transmitted human papillomavirus, also known as HPV.

In decades gone by, oral cancer was almost always associated with tobacco and alcohol use. It was typically a disease of old men. No more. Many of Wilson’s patients are nonsmokers and very light drinkers.

“I can’t tell you how surprised people get,” said Wilson, who is chief of staff at University of Cincinnati Medical Center. “We’re seeing younger, more affluent and more highly educated patients.”

High-risk HPVs cause virtually all cervical cancers. They have in recent years been implicated in oropharyngeal cancers. The oropharynx is the middle part of the throat, including the soft palate, the base of the tongue and the tonsils.

About 63 percent of oropharyngeal cancers, or 11,000 cases per year, are associated with HPV infection, according to the American Dental Association. They’re frequently under age 50.

Fortunately for such patients, HPV-associated oropharyngeal cancers have a better prognosis than those with other causes. Wilson said that cure rates can approach 90 percent.

The da Vinci surgical robot is an effective tool for removing them, he said, because its long, joined arms can go where a surgeon’s hands can’t. But the machines, made by Sunnyvale, Calif.-based Intuitive Surgical Inc., are gaining some criticism. The robotic surgery system is facing safety questions from the U.S. Food and Drug Administration after a string of complaints across the country – as many as 500 since January 2012.