4 replies to this topic

[kevin]

Link: http://www.eurekaler...i-srp090203.php
Date: 09-03-03
Author: -
Title: Study raises prospect of practical vaccine for metastatic melanoma

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Public release date: 2-Sep-2003
Contact: Bill Schaller
william_schaller@dfci.harvard.edu
617-632-5357
Dana-Farber Cancer Institute

Study raises prospect of practical vaccine for metastatic melanoma

BOSTON--In a step toward a practical vaccine for advanced melanoma, a notoriously difficult-to-treat form of cancer, researchers at Dana-Farber Cancer Institute have demonstrated the effectiveness of a vaccine that is safer and easier to produce than earlier versions.

Writing in the Sept. 1 issue of the Journal of Clinical Oncology, investigators led by Dana-Farber's Glenn Dranoff, M.D., report that the vaccine, made by inserting a key gene into a patient's own melanoma cells, prompted a powerful immune system attack on melanoma tumors in several patients who received it in a clinical trial. More than three years after the trial began, 10 of the 35 patients who initially enrolled were still alive, and four of them had no signs of disease.

These results, which are comparable to those obtained by Dranoff and his colleagues in earlier studies of similar, but harder-to-work-with vaccines, suggest the technique holds real promise as a useful treatment for metastatic (spreading) melanoma.

"Our findings show that an antitumor immune response to melanoma can be created using a vaccine that is safe and relatively easy to make," says Dranoff, the study's senior author. "The survival of 10 patients for more than three years is especially encouraging and raises the possibility that vaccination might be effective in combination with other, existing therapies."

Like all vaccines, the one developed by Dranoff and his colleagues seeks to intensify the body's normal immune-system attack on diseased cells. It is based on the idea that melanoma cells, which are normally camouflaged from the immune system, can be made to betray their presence in the body, sparking an especially vigorous immune response.

The vaccine is made by removing a portion of a patient's tumor and mixing it with specially equipped viruses, which carry a gene for a substance called granulocyte-macrophage colony-stimulating factor (GM-CSF). The viruses invade the melanoma cells and deposit the gene there, causing the cells to begin pumping out GM-CSF. The cells are then re-injected into the patient.

GM-CSF acts like a magnet for agents of the immune system, drawing an attack on melanoma cells throughout the body, not just those that contain the GM-CSF gene. When tumor samples from vaccinated patients are viewed under a microscope, cancer-fighting cells are often found swarming around the melanoma cells – evidence of a potent immune response.

When the technique was first tested in melanoma patients, Dranoff and his colleagues used a retrovirus (whose genetic programming is written in RNA rather than DNA) as the delivery vehicle for GM-CSF. While the results were encouraging, the process of preparing the vaccine was both lengthy and cumbersome. The retrovirus enters only cells that are actively dividing and could itself increase the risk of cancer. Vaccines prepared in this fashion therefore require extensive safety testing before being injected into patients.

The vaccine used in the new study, by contrast, was made with a weakened cold virus, known as an adenovirus, as the gene-ferrying agent. Adenoviruses are capable of entering resting cells and produce fewer complications than retroviruses.

The study, a Phase I trial undertaken to assess the vaccine's safety and potential effectiveness, involved 35 patients with metastatic melanoma, a type of cancer that begins in the skin but which, if spread to other parts of the body, carries a high death rate. Vaccines were successfully made for all but one of the patients. Eight patients had to withdraw from the study because their disease progressed rapidly. Side effects of the treatment were generally minimal, usually amounting to no more than irritation around the injection site.

Researchers removed tumor samples from 16 patients following vaccination to gauge the extent of the tumor response. In 10 of those cases, they found a large influx of immune system cells and substantial numbers of dead melanoma cells. Plus, ten of patients – 29 percent of the original group – were alive three years after receiving the treatment.

The results have encouraged Dranoff and his colleagues to undertake a larger, Phase II study of the vaccine and to test whether it can be effective in patients whose melanoma has not yet spread systematically.

"We plan to explore alternative techniques for producing the vaccine, as well as determining which patients can benefit from it the most," Dranoff remarks. "This will help us determine its proper place in the arsenal of melanoma treatments."

Co-authors of the study include Dana-Farber researchers Robert Soiffer, M.D., and Stephen Hodi, M.D.; Frank Haluska, MD, PhD, and Martin Mihm, MD, of Massachusetts General Hospital; and colleagues at Brigham and Women's Hospital, Harvard Medical School, Beth Israel Deaconess Medical Center, Children's Hospital Boston, and Cell Genesys of Foster City, Calif.


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The study was funded in part by the National Institutes of Health, the Cancer Research Institute, the Leukemia and Lymphoma Society, and Cell Genesys.

Dana-Farber Cancer Institute is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
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[chubtoad]

http://www.scienceda...31127075134.htm
Source: BioMed Central
Date: 2003-11-27


Skin Cancer Breakthrough: Gene Explains Why Men Are At Higher Risk Of Malignant Melanoma

Researchers from Germany have identified a gene that is associated with an increased risk of suffering from skin cancer. The research, published this month in Journal of Carcinogenesis, could also explain why men are more likely to suffer from malignant melanoma than women.

Although most people associate melanoma with exposure to UV light, through excessive sunbathing for example, the disease can be inherited – indicating that faulty genes are also partly to blame. Genetic risk factors also affect the likelihood of individuals suffering from non-inherited, or sporadic, melanoma.

To identify these risk factors, researchers from the University Hospital in Tuebingen took blood samples from 450 healthy volunteers, and 500 people who had been diagnosed with malignant melanoma, from which they could extract DNA. In collaboration with Genefinder Technologies Ltd., Munich, Germany and Sequenom Inc., San Diego, USA, the researchers studied the DNA samples, looking for slight differences in the genes between people with melanoma skin cancer and people with no cancers at all. To do this they screened more than 25,000 sites across the whole genome, which are known to vary naturally between different people.

The researchers identified a gene called BRAF that contains several sites of natural variation. Some variants were more likely to be found in people who suffered from melanoma than in those that did not. But, when the data was separated by sex, it appeared that the variants only conferred a higher risk of suffering from melanoma on men who carried them.

At present, men have a 1 in 58 chance, and women a 1 in 82 chance of developing the disease in their lifetime. The researchers write: "BRAF may be one explanation of why males have an increased lifetime incidence of melanoma compared to females".

Until now, the best-known risk factor for melanoma was if you had a mutated copy of the gene CDKN2A. This gene could explain about 25% of the inherited cases of melanoma, which equates to about 1% of the total number of cases.

The risk associated with BRAF is much more significant. The researchers write: "We estimate that BRAF could account for an attributable risk of developing melanoma of approximately 4% in the German population. This risk estimate is much higher than that attributed to CDKN2A."

Dr. Peter Meyer, the managing researcher of this study, said: "It will be exciting to learn more about whether BRAF is also associated with melanoma-risk in other populations with higher melanoma incidences like Australians."

The BRAF gene encodes a protein that activates the growth and multiplication of cells. Recent studies have shown that mutations in BRAF, which cause the protein to become more active, are commonly found in melanomas and moles. The variants that have been identified in this study do not have any effects on the activity of the protein – how they increase the risk of suffering from melanoma is currently unknown.

Professor Claus Garbe, the principal investigator of the project said: "Moles are a major risk factor for the development of malignant melanoma. BRAF mutations occur in the majority of melanomas but also in moles. We are therefore interested in addressing the question of whether carrying certain variants of the BRAF gene could predispose people to having or developing more moles, and thus to an increased risk of developing melanoma"

Dr. Goppala Kovvali, the Editor-in-chief of Journal of Carcinogenesis said: "This article is an important contribution to the field of carcinogenesis. I anticipate that several studies will be undertaken to investigate the BRAF gene in connection with melanoma, especially in the United States and Australia where skin cancer is one of the common cancers."

The incidence of malignant melanoma has rapidly increased in recent years. It is the leading cause of death from skin disease, as once the cancer has spread it is resistant to most available treatments.

[chubtoad]

http://www.eurekaler...ct/medicine.php

Jefferson scientists encouraged by trial results of next-generation vaccine for melanoma

A vaccine for advanced melanoma created from a patient's own tumor cells has shown some early signs of causing immune responses in recipients. The vaccine is a second-generation version that aims to improve on the earlier successes of a vaccine created by David Berd, M.D., professor of medicine at Jefferson Medical College of Thomas Jefferson University in Philadelphia and at Jefferson's Kimmel Cancer Center.
While it's still in the initial stages of testing, Dr. Berd and his co-workers are encouraged by the first results and hopeful they bode well for the vaccine's future use. Dr. Berd presents his team's results June 7 at the annual meeting of the American Society of Clinical Oncology in New Orleans.

[chubtoad]

http://www.eurekaler...t/chemistry.php

Scientists identify molecular link driving spread of skin cancer

Finding holds promise for inhibition of metastasis with targeted, synthetic peptides
An international team of scientists has identified an important molecular link involved in the spread – or metastasis – of melanoma to other organs such as the lungs.
By introducing a synthetic peptide that mimics one component of this link, the researchers blocked this cellular interaction, significantly deterring the migration of cancer cells beyond the original tumor site. Blocking this protein linkage also was shown to inhibit angiogenesis--the creation of blood vessels that nourish new, secondary tumors--and spur cell death or apoptosis.

The results, published in the July issue of the journal Cancer Research, open the door to the prospect of targeted therapeutics capable of preventing or limiting the metastasis of skin cancer.

"The ability of these synthetic peptides to reduce tumor cell metastasis and angiogenesis and increase apoptosis may be important in the development of therapeutics for malignancy," said Hynda Kleinman, Ph.D., chief, cell biology section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Md.

[Mind]

Gene therapy reduces skin cancer to sunburn in mouse model

DALLAS - Dec. 10, 2004 - Researchers at UT Southwestern Medical Center at Dallas have successfully tested the first gene therapy for skin cancer, using a mouse model for the disease xeroderma pigmentosum, or XP.

Their results, available online and to be published in an upcoming issue of the Proceedings of the National Academy of Sciences, show promise for similar gene therapy to be pursued in children suffering from this rare disorder.

Dr. Errol Friedberg's research into gene therapy for xeroderma pigmentosum and DNA repair may someday help children with this disease.

XP is a debilitating disease in which patients must avoid the sun and all other sources of ultraviolet (UV) light.  Exposure to UV light increases the risk for all cancers, but exposed skin is most prone to the disease.  With a 10,000-fold increase in cancer risk, many XP sufferers eventually succumb to tumors at an early age.

Mice with mutations in the gene Xpa suffer from XP and develop cancerous lesions on their skin within three weeks after UV light exposure. Dr. Errol Friedberg, professor and chair of pathology at UT Southwestern, in collaboration with Dr. Carlos F.M. Menck of the Institutes of Biomedical Sciences in Sao Paulo, Brazil injected the normal gene into mice suffering from XP. After treatment with the normal gene, the mice were free from disease.

"Gene therapy for XP has the potential to completely prevent cancer in a group of patients who otherwise may suffer no other ill effects from their genetic defect," Dr. Friedberg said.

When the body is exposed to UV light, the DNA in dividing cells can become damaged. Normally, the body enlists a group of proteins whose job it is to repair the sites of UV-induced damage. But in children with XP, mistakes in DNA caused by UV light cannot be fixed because of mutations in the genes for the repair proteins. DNA damage goes uncorrected, and as cells divide they accumulate numerous mutations. When these mutations occur in genes that normally suppress cancer, cells develop abnormally and cancer ensues.

A mutation in any one of seven human genes involved in DNA repair is sufficient to cause XP. One of these genes is XPA.  Humans with mutations in XPA are one the largest groups of XP patients.

In their gene therapy study, Dr. Friedberg and colleagues injected the normal version of mouse Xpa into the mutant mice, using a disabled virus that infects multiple cells. They then exposed the mice to UV light for a few hours over several days. Five months after the last exposure - long after Xpa mutant mice would normally develop skin lesions - the treated mice merely had sunburn.

The skin cells surrounding the site of the injection in the treated Xpa mutant mice were nearly identical to those of normal animals, indicating that the DNA repair mechanism had been restored by the addition of the normal Xpa gene, Dr. Friedberg said.