Monthly Archives: May 2001

Gene-Therapy Fights Oral Cancer

  • 5/16/2001
  • San Francisco, CA
  • Daniel Q. Haney
  • Associated Press

A gene-therapy mouthwash shows promise of warding off oral cancer by killing ominous growths before they turn malignant.

The idea is to attack these pre-malignant patches by unleashing viruses programmed to kill cells with cancer-causing genes.

The first study of this approach is still under way, but doctors said yesterday that it appears to work in at least some patients, making ominous patches in their mouths disappear completely. In the past 20 years, scientists have learned that all cancer arises from genetic defects that accumulate during a lifetime, causing cells to grow rampantly and spread in the body.

With this insight came the belief that it might be possible to target these bad genes to stop cancer. This was once one of the hottest ideas in cancer research. But enthusiasm cooled as scientists hit roadblocks. One was reaching and killing every cancer cell. Even reaching 80 percent of the cells is not good enough, because the rest keep growing.

So researchers decided that the mouth might be an excellent target for gene therapy, since the problem can be so easily reached. “The advantage is that it’s where we can see it,” said Dr. Ezra Cohen of the University of Chicago. “We can get to it, and the therapy does not get absorbed into the body.”

White or red patches in the mouth, so-called dysplastic lesions, frequently are a forerunner of malignancy and are common in smokers and heavy drinkers. These cells usually contain mutant genes, and one of the most common is a broken p53 gene. This tumor-suppressor gene ordinarily kills cells that contain dangerous mutations. Without a working copy of this gene, growths can become cancerous.

The treatment consists of adenovirus, a kind of cold virus, that lacks a working copy of one gene that ordinarily allows the virus to infect cells with good p53 genes. Without this gene, it should infect only cells with damaged p53 genes. In theory, the crippled virus will enter these precancerous cells and kill them.

May, 2001|Archive|

Predicting Oral Cancer

  • 5/13/2001
  • Janet McConnaughey
  • AP

A simple genetic test can help doctors accurately predict whether people with common white patches inside their mouths are likely to develop deadly oral cancer.

The technique developed at the University of Oslo could help physicians assess patients with the patches, called oral leukoplakia, so they can be treated early if cancer appears likely. “I think there is a message to physicians: Beware of white patches,” said Dr. Jon Sudbo, whose study was published in Thursday’s issue of the New England Journal of Medicine. “There is a message to consumers and patients: Beware of white patches. And get them investigated.”

The key is the number of chromosomes in the cells that make up those patches. If it’s the normal 46, cancer is unlikely. If the number is doubled, cancer is more likely. And it becomes very likely if the number cannot be divided evenly by 23, the number of chromosomes received from each parent.

More than 300,000 people around the world, including about 30,000 in the United States, are diagnosed each year with oral cancer, making it the nation’s No. 11 cancer and the ninth most common worldwide. More than half of those people die within five years, largely because the cancers are hard to diagnose early. The death rate hasn’t changed in more than 20 years.

Because there is no way to know which white patches will develop into cancer, doctors often remove them as a precaution. But there is also no good way to tell whether they have removed enough. Sudbo and his colleagues kept a long watch, averaging 8 1/2 years, on 150 patients with white patches where cells showed abnormal formation and organization, a further indication that cancer might develop. Out of 103 patients with leukoplakia made up of cells with 46 chromosomes, only three developed cancer. Twelve of 20 patients with 92-chromosome patches developed cancer. But cancer developed in 21 of the 27 patients with “aneuploid” lesions, those in which the chromosomes did not divide evenly by 23. Two of the six non-cancerous patients started with 46-chromosome lesions which later turned aneuploid.

“This gives us the opportunity to treat these patients with chemopreventive agents, which much likely has a much better effect than waiting until it becomes cancer,” Sudbo said. No drugs have yet been proved to prevent oral cancer, but many are being tested, said Dr. Scott Lippman, chairman of clinical cancer prevention at the M.D. Anderson Cancer Center in Houston. He said Sudbo’s study was very compelling, but no single test can find every likely cancer because so many different changes can turn cells to cancer.

Thirty to 50 percent of all oral cancers have the normal 46 chromosomes. The test is unlikely to predict those cancers, said Lippman and Dawn Willis, scientific program director for the American Cancer Society. However, they said, several other studies published within the past year have found other genetic markers for oral cancer. For instance, there’s also a risk of cancer if cells from the white patches have lost one gene from any of a number of specific pairs. The risk increases with the number of such missing genes. Many mouth cancers could be prevented by avoiding tobacco and alcohol, she said.

Further studies should develop guidelines for analyzing the results for several different markers at once, Lippman said. “That’s much more predictive than any one marker.” Other studies could also give doctors a much better idea of how far outside the edges of the white patches they need to go to cut out all pre-cancerous cells, he said. Genetic tests will let doctors check on whether they got all changed cells, without a biopsy.

May, 2001|Archive|

Cancer Patients’ Mouth Sores Relieved in Studies

  • 5/12/2001
  • San Francisco
  • Deena Beasley
  • Reuters

An experimental drug that stimulates cell growth can reduce the duration of severe mouth sores in cancer patients undergoing toxic treatments like chemotherapy, researchers said on Saturday.

“Currently, there are no approved or consistently effective treatments for severe mucositis. This is a potential breakthrough,” said Dr. Ricardo Spielberger, a staff physician at the City of Hope National Medical Center in Duarte, California, and lead investigator in a midstage clinical trial of the recombinant human keratinocyte growth factor, or KGF. KGF, a human protein shown to protect certain tissues from damage, is being developed by Amgen Inc., which sponsored the studies of the drug.

Mucositis, or severe inflammation of mucous membranes in the mouth and throat, is a serious and painful side effect of cancer therapy. Patients who develop the condition have difficulty swallowing, eating, drinking and talking. The mouth sores cause pain and lower the quality of life for patients but also make them more susceptible to infection, the researchers said. “Mucous membranes are affected by toxic cancer therapies because they are fast-dividing cells — like tumor cells,” explained Dr. Patrick Stiff of Loyola University in Chicago, a co-author of the study. He said mouth sores were the No. 1 complaint of lymphoma patients who could be successfully treated with intense doses of radiation therapy followed by stem cell transplants.

PROBLEM HALVED

In a trial of 129 of these patients, those who received injections of KGF, both before and after undergoing cancer therapy, experienced an average of four days of severe oral mucositis, compared with 7.7 days for patients who received a placebo, the investigators said. Patients who received a single dose of the drug before cancer treatment suffered mucositis for an average of five days. “We are able to provide these patients with a curative therapy, but there are lots of side effects. Now we are trying to alleviate some of those,” Stiff said.

In a separate Phase II trial, 64 patients with colorectal cancer were given either KGF or placebo in concert with two cycles of chemotherapy. The group receiving placebo had a 78 percent mucositis rate, compared with 32 percent in the KGF-treated group. The colorectal cancer study also found a reduction in the duration of oral mucositis — 10.2 days for the placebo vs. 3.4 days for KGF-treated patients.

Patients in both trials reported less pain and used less pain medication. They also needed less intravenous nutrition than other patients, the investigators said. In both studies, KGF was well tolerated. Minor side effects included skin rashes, flushing and swelling, and reversible increases in blood serum levels.

“Patients’ mouths become dry as the membrane thickens up, but that’s something we want to have happen,” Stiff said.

Amgen is currently conducting a pivotal-stage trial of KGF in lymphoma patients, and trials of the drug in other types of cancer, such as head-and-neck, are planned.

May, 2001|Archive|

Cervical Cancer Virus Linked to Some Head and Neck Cancer

  • 5/10/2001
  • Journal of the National Cancer Institute

The virus that causes most cases of cervical cancer has been linked to some head and neck cancers, particularly to cancer of the tonsils, according to an article published this month in the Journal of the National Cancer Institute (JNCI, Vol. 92, No. 9). The findings are providing hope for treating a type of cancer that has not seen improvements in survival rates for the past three decades. The research by Maura Gillison, MD, and colleagues at Johns Hopkins Oncology Center, suggests some of the cancers that tested positive for the presence of the human papillomavirus (HPV) represent a distinct class of disease with a more favorable prognosis.”We found that HPV-positive HNSCC [head and neck squamous cell carcinomas] had significantly improved disease-specific survival when compared with patients with HPV-negative tumors, even after adjustment for age, lymph node status and heavy alcohol consumption,” the researchers wrote.

What the Researchers Found

Dr. Gillison and her colleagues tested tumor tissues from 253 patients with head and neck cancers and found 25 percent of the cases were HPV-positive. In 90 percent of those HPV-positive tumors, HPV16 – the type of the virus most often associated with cervical cancer – was present.Earlier research suggested a link between HPV and cancers of the tongue, tonsils and pharynx. This new study confirms a strong link between HPV and those cancers – particularly in cancer of the tonsils. “These findings are exciting because, in addition to providing a solid etiologic link between high-risk HPV infection and a subgroup of HNSCC, they promise improvements in diagnosis and also possibly treatment,” wrote David T.W. Wong, MD, and Karl Munger, MD, of Harvard Medical School, in an editorial accompanying the study. “These are pressing issues, given that the incidence and survival associated with oral cancer have essentially remained unchanged over the last 30 years.” In 1995, the International Agency for Research on Cancer concluded that high-risk HPV types 16 and 18 are carcinogenic, or cancer-causing, for humans, according to the editorial. Those types of HPV have been linked to penile, anal and vulvar cancers in addition to cervical cancer. The link between HPV and head and neck cancers had been less strong before this new study.

HPV is Sexually Transmitted

“One reason this article has elicited so much interest is undoubtedly because HPV is a sexually transmitted infection, and this new link with oral cancers suggests a link with oral sex – although questions about sexual practices were not asked of the patients in the study,” says Dawn Willis, PhD, MPH, director of research promotion and communication for the American Cancer Society.An estimated 60 percent of today’s young Americans are infected with one or more forms of HPV in young adulthood, according to Dr. Willis. “At the time of the initial infection, there is sometimes, but not always, an eruption of genital warts in either sex that later disappear,” she says. “The virus may remain latent for many years, and only a few of the infected individuals go on to develop cervical – or oral – cancers later in life. This in itself is an interesting observation, which implies that other genetic and/or environmental factors are involved.”Dr. Willis calls this new research “an excellent example of epidemiological detection work.””The authors have clearly established the association of HPV with oral cancers that have a better prognosis than those that are associated with heavy alcohol and tobacco use. And, HPV-positive oral cancers are excellent candidates for treatment with one of the therapeutic HPV vaccines that are now in clinical trials for cervical cancer,” she says.

The Promise of Vaccines

At Johns Hopkins, researchers are planning to test HPV vaccines in patients with oropharyngeal cancers – including cancers of the tonsils, the soft palate, posterior pharynx and base of the tongue, according to a news article published in JNCI. “If any of the current crop of investigational HPV vaccines prove successful, they should be available to the general public within five years,” Dr. Willis says. “Of even greater importance, there are a number of prevention trials testing a prophylactic [preventive] HPV vaccine. Such an inoculation would be invaluable in reducing the incidence and mortality of these cancers, particularly among populations where early detection is not affordable or culturally acceptable.”

May, 2001|Archive|