RxPG News : Melanoma

Compounds extracted from vegetables help to inhibit melanoma

Sun, 01 Mar 2009 08:59:56 PST

( from http://www.rxpgnews.com ) Compounds extracted from green vegetables such as broccoli and cabbage could be a potent drug against melanoma, according to cancer researchers. Tests on mice suggest that these compounds, when combined with selenium, target tumors more safely and effectively than conventional therapy.

"There are currently no drugs to target the proteins that trigger melanoma," said Gavin Robertson, associate professor of pharmacology, pathology and dermatology, Penn State College of Medicine. "We have developed drugs from naturally occurring compounds that can inhibit the growth of tumors in mice by 50 to 60 percent with a very low dose."

Robertson and his colleagues previously showed the therapeutic potential of targeting the Akt3 protein in inhibiting the development of melanoma. The search for a drug to block the protein led them to a class of compounds called isothiocyanates.

These naturally occurring chemicals found in cruciferous vegetables are known to have certain cancer-fighting properties. However, the potency of these compounds is so low that a successful drug would require large impractical amounts of these compounds.

Instead, the Penn State researchers rewired the compounds by replacing their sulfur bonds with selenium. The result, they believe, is a more potent drug that can be delivered intravenously in low doses.

"Selenium deficiency is common in cancer patients, including those diagnosed with metastatic melanoma," explained Robertson, whose findings appear in the March edition of Clinical Cancer Research. "Besides, selenium is known to destabilize Akt proteins in prostate cancer cells."

To study the effectiveness of the new drug -- isoselenocyanate -- researchers injected mice with 10 million cancer cells. Six days later, when the animals developed large tumors, they were divided into two groups and treated separately with either the vegetable compounds or the compounds supplemented with selenium.

"We found that the selenium-enhanced compounds significantly reduced the production of Akt3 protein and shut down its signaling network," explained Robertson, who is also associate director of translational research and leader of the experimental therapeutics program at Penn State Hershey Cancer Institute. The modified compounds also reduced the growth of tumors by 60 percent, compared to the vegetable-based compounds alone.

When the researchers exposed three different human melanoma cell lines to the two compounds, the selenium-enhanced drug worked better on some cell lines than others. The efficiency was from 30 to 70 percent depending on the cell line.

The exact mechanism of how selenium inhibits cancer remains unclear. However Robertson, who has a filed provisional patent on the discovery, is convinced that the use of naturally occurring compounds that target cancer-causing proteins could lead to more effective ways of treating melanoma.

"We have harnessed something found in nature to target melanoma," said Robertson. "And since we only need tiny amounts to kill the cancer cells, it means even less toxic side-effects for the patient."

Human trials of the new drug are still some years away, but the Penn State researcher envisions a drug that could be delivered either intravenously to treat melanoma, or added to sunscreen lotion to prevent the disease.

MicroRNA responsible for aggressiveness of metastatic melanoma cell lines

Mon, 09 Feb 2009 12:10:02 PST

( from http://www.rxpgnews.com ) Scientists have long wondered how melanoma cells travel from primary tumors on the surface of the skin to the brain, liver and lungs, where they become more aggressive, resistant to therapy, and deadly. Now, scientists from NYU Langone Medical Center have identified the possible culprit—a short strand of RNA called microRNA (miRNA) that is over-expressed in metastatic melanoma cell lines and tissues.

The new findings, published online this week and in the February 10, 2009 print edition of the Proceedings of the National Academy of Sciences (PNAS), suggest that miRNA silencing to counteract or attack this mechanism may be an effective therapeutic strategy for metastatic melanoma, according to Eva Hernando, Ph.D., assistant professor in the Department of Pathology at NYU School of Medicine, and the lead author of the study. Dr. Hernando is also a member of the NYU Cancer Institute at NYU Langone Medical Center.

The highly aggressive character of melanoma, says Dr. Hernando, makes it an excellent model to probe the mechanisms underlying metastasis, the process by which cancer cells travel from the primary tumor to distant sites in the body. Though other researchers have found that altered miRNAs contribute to breast cancer metastasis, this is the first study to examine the role of miRNA in metastatic melanoma.

"Melanoma becomes deadly after the cells leave the primary tumor through the blood and metastasize in other organs where they are resistant to therapy," says Dr. Hernando, who notes that the average survival for patients after melanoma metastasis occurs is only nine months. "Normal cells are unable to travel and survive in alien locations, so we are very interested in understanding the invasive, adaptive, and resistant traits of the very aggressive melanoma cell." miRNAs are short pieces of RNA that block the expression of proteins that are encoded by messenger RNAs. They serve as regulators of protein expression, acting like the volume control on a radio. In recent years, miRNAs have been linked to the over- or under-expression of a variety of genes linked to cancer and other diseases.

Dr. Hernando's lab found a miRNA is over-expressed in metastatic melanoma cell lines and tissues. The lab found that the elevated expression of miRNA 182 turns it into an oncogene (a gene involved in cancer tumor initiation or progression), by increasing the invasive capacity of melanoma cells in vitro and stimulating the cell's metastatic potential in a mouse model.

In addition, the NYU scientists found that miRNA 182 also represses the expression of two tumor suppressors called FOXO3 and MITF, which normally prevent cells from becoming malignant. By repressing the suppressors, miRNA 182 permits melanoma cells to migrate and survive independently, two properties necessary for metastasis.

MiRNA 182 also belongs to a cluster located in a genomic region, chromosome 7q, that is frequently amplified in melanoma and contains two other oncogenes; BRAF and C-MET. The study found a correlation between genomic amplification and miRNA over expression, though it is unclear whether other molecular mechanisms play a role in this effect, according to Dr. Hernando.

Finally, the scientists observed that in a significant fraction of metastatic melanomas, high miRNA 182 levels correlate with low levels of FOXO3 and MITF, supporting the relevance of this mechanism in human melanoma.

The study suggests that miRNA 182 is a novel therapeutic target. When it is inhibited, it impairs the invasive potential of melanoma cells and induces cell death. In theory, the administration of anti-miRNA 182 could block the growth or expansion of the primary melanoma tumor. Several academic laboratories and pharmaceutical companies are working to improve the delivery of anti-miRNAs by using chemical modification and nano particles to increase their stability, specificity, and ability to reach tumors in sufficient doses with low toxicity.

The NYU Cancer Institute is currently studying whether anti-miRNA will work on miRNA 182 to inhibit the growth or spread of primary melanoma in mice. Dr. Hernando says that even if the anti-miRNA cannot do this on its own, it might work in combination with conventional chemotherapy or novel targeted therapies.

This study is the result of an extensive collaboration between members of NYU's Interdisciplinary Melanoma Cooperative Group, led by Iman Osman, M.D. , one of the study's co-authors, which has a large biospecimen bank comprising human tissue, blood and patient clinico-pathological information.

"The existence of this bank permits us to validate our laboratory findings using human tissue," says Dr. Hernando. "In this study, we began looking at cell lines and then at melanoma tissue. Now that the mechanism has been proven using cell lines and mice, the next step will be to perform in-vitro studies with cell lines to assess the effect of anti-miRNA on cell death in both normal and melanoma cells. Once that study is completed, we can use this model for studies in mice to block the growth of the primary melanoma tumor or the metastasis by using anti-miRNA. All these steps will determine if this approach could be eventually applied to humans."

A novel designer molecule to fight malignant melanoma

Sun, 02 Nov 2008 16:05:00 PST

( from http://www.rxpgnews.com ) By playing it safe and using a two-pronged attack, a novel designer molecule fights malignant melanoma. It was created and tested by an international team of researchers led by the University of Bonn. On the one hand, the substance is similar to components of viruses and in this way alerts the immune system. The body's own defences are also strengthened against cancer cells in this process. At the same time, the novel molecule also puts pressure on the tumour in a different way. It switches off a specific gene in the malignant cells, thus driving them to suicide. With mice suffering from cancer, the researchers have thus been able to fight metastases in the lung. In Nature Medicine's November issue they report about this promising strategy. This article is available online from November 2nd.

For their research project, the scientists drew on the latest insights into biology's box of tricks. A close relative of the nuclear DNA, known as RNA, served them as therapy. It has only been known for a few years that small RNA molecules can basically be used to target certain genes and switch them off. This effect is called RNA interference; the Americans Craig Mellow and Andrew Fire were awarded the Nobel Prize in 2006 for its discovery.

'We used this method in order to drive the tumour cells to suicide,' the Bonn dermatology researcher Professor Thomas Tüting explains. Every single body cell is equipped with a corresponding suicide programme. It is activated, for example, if the cell becomes malignant. It dies before it can do any more harm. 'But in tumours a gene is active that suppresses this suicide programme,' Professor Tüting, who is head of the Experimental Dermatology Laboratory, explains. 'We have pinpointed this gene and switched it off by using RNA interference.'

At the same time the researchers also crept up on cancer by another route: 'We basically "disguised" our RNA,' Professor Gunther Hartmann, director of the Institute of Clinical Chemistry and Pharmacology says. 'That is why the immune system took it for the genetic makeup of a virus.' Many viruses actually do use RNA to store information. So if the body discovers RNA fragments which it takes to be the genetic makeup of a virus, it mounts an attack on them. By means of this trick the body's defences were prompted to tackle the tumour cells far more aggressively than normal.

RNA is also present in the body's own cells. For a long time it was not known how the immune system distinguishes between 'harmful' and 'harmless' RNA. Only two years ago, Professor Hartmann was able to shed light on the problem in a sensational article in the journal 'Science'. The scientists used this knowledge in order to modify the RNA substance in such a way that it was able to alert the immune system.

'The beauty of this method is that we can attack the cancer with one designer molecule along two completely different routes,' Professor Hartmann says. 'This way the tumour is deprived of opportunities of sidestepping the attack that make successful therapy so difficult in other cases.' Initial experiments in mouse models have shown that growth of metastases in the lungs is inhibited significantly by the new molecule. The therapy even led to the secondary tumours becoming smaller or even disappearing entirely.

Despite this, the research team warns against excessive optimism: 'What works in mice does not necessarily prove successful in humans as well,' Professor Tüting warns. 'Apart from that, many issues need to be addressed before a trial with cancer patients can even be thought of.' Still, the approach appears very promising, especially as the therapeutic RNA molecule can be easily customised to suit different kinds of cancer.

Listening to the sound of skin cancer

Tue, 17 Oct 2006 02:05:37 PST

( from http://www.rxpgnews.com ) Researchers at the University of Missouri-Columbia can now detect the spread of skin cancer cells through the blood by literally listening to their sound. The unprecedented, minimally invasive technique causes melanoma cells to emit noise, and could let oncologists spot early signs of metastases -- as few as 10 cancer cells in a blood sample -- before they even settle in other organs.

The team's method, called photoacoustic detection, combines laser techniques from optics and ultrasound techniques from acoustics, using a laser to make cells vibrate and then picking up the characteristic sound of melanoma cells. In a clinical test, doctors would take a patient's blood sample and separate the red blood cells and the plasma. In a healthy person, the remaining cells would be white blood cells, but in a melanoma patient the sample may contain cancer cells. To find out, doctors would put the sample in saline solution and expose it to rapid-fire sequences of brief but intense blue-laser pulses, each lasting just five billionths of a second.

In lab tests, the Missouri-Columbia team was able to detect melanoma cells obtained from actual patients, showing that the method can spot as few as 10 cells in saline solution. The dark, microscopic granules of melanin contained in the cancer cells absorb the energy bursts from the blue-laser light, going through rapid cycles of expanding as they heat up and shrinking as they cool down. These sudden changes generate loud cracks -- relative to the granules' size -- which propagate in the solution like tiny tsunamis.

The sound waves produced by melanin are high-frequency ultrasounds, meaning that they cannot be heard by the human ear, even if amplified. However, researchers can pick them up with special microphones and analyze them with a computer. Other human cells do not contain pigments with the same color as melanin, so the melanin signature is easy to tell apart from other noises, said John Viator, a biomedical engineer at Missouri-Columbia and a coauthor of the Optics Letters paper. And the presence of melanin granules in the blood is an unmistakable sign. "The only reason there could be melanin in the human blood is that there would be melanoma cells," he said.

This new blood test would allow for a much more timely diagnosis of metastasis and with early diagnosis comes early treatment and increased likelihood for survival. As one of the most aggressive forms of cancer, if a melanoma is not removed at its earliest stages, it will penetrate into the deep layers of the skin. From there its cells can break off and pass into the circulatory and lymphatic systems, spreading to other organs and creating metastases even after the original melanoma has been surgically removed.

An earlier metastasis warning, as this blood test provides, could alert oncologists to the cancer when it's at its earliest stages in other parts of the body and help them to begin a quicker counterattack, for example by administering chemotherapy, said Viator. "Our method can help doctors plan treatment to battle the spread of the disease," he said.

Current techniques to monitor the disease spread and recurrence have proven to be inaccurate, time-consuming and painful, according to the researchers. This new blood test would enable physicians to have a more accurate method of monitoring for metastasis.

In fact, the blood-test procedure could be performed regularly such as in screenings for high-risk patients, requiring just a small sample of blood, and its results would be almost immediate. "It could take just 30 minutes to find out if there are any circulating cancer cells," Viator said.

Other labs have used photoacoustic detection for scanning mouse brains and for mapping port-wine stains (birthmarks), but this would be its first application to oncology, Viator said. The team is now planning a pilot study on actual blood samples from patients, and larger clinical studies will need to be done, but the test shows great promise for early detection of the spread of this disease, according to Viator.

The team is also working with other Missouri-Columbia scientists in the veterinary college and the department of surgery to extend the reach of its technique to other types of cancer. Because of melanin, melanoma is the only type of cancer whose cells will strongly absorb all wavelengths of light, emitting ultrasounds that stand out from those of other cells. But artificial materials could also be introduced, to act as light absorbers -- and as noise makers. "We're looking for methods to attach other kinds of absorbers to cancer cells," Viator said. For example, he said, gold nanoparticles -- particles only a few millionths of a millimeter wide -- could be attached to the cells using proteins that bind to special receptors on the cells' membranes. With their own photoacoustic signature, the gold particles would then signal the presence of cancer cells.

Malignant melanoma cells secrete a potent embryonic growth factor

Mon, 31 Jul 2006 11:32:37 PST

( from http://www.rxpgnews.com ) A Northwestern University research group has discovered that aggressive melanoma cells secrete Nodal, a protein that is critical to proper embryo formation.

The researchers identified the potent and highly unstable embryonic growth factor by injecting aggressive melanoma cells into developing zebrafish embryos, which were used as "biosensors" for tumor cell-derived signals, and were consequently able to induce ectopic (abnormal) embryonic skull and backbone (axes) formation.

"This finding highlights the convergence of tumorigenic and embryonic signaling pathways. From a translational perspective, Nodal signaling provides a novel target for treatment of aggressive cancers such as melanomas," said Mary J. C. Hendrix, the corresponding author, of Children's Memorial Research Center where the discovery was made.

Hendrix is president and scientific director of the Children's Memorial Research Center, professor of pediatrics at Northwestern University Feinberg School of Medicine and a member of the executive committee of The Robert H. Lurie Comprehensive Cancer Center of Northwestern University. Jolanta M. Topczewska and Lynne-Marie Postovit, from Children's Memorial Research Center, co-led the study. Working with Brian Nickoloff of the Cardinal Bernardin Cancer Center at Loyola University Stritch School of Medicine, the investigators found that Nodal protein was present in 60 percent of cutaneous (skin) metastatic melanoma tumors but is absent in normal skin.

They also found that blocking Nodal signaling reduced melanoma cell invasiveness, as well as cancer cell colony formation and tumor-forming ability. Strikingly, nodal inhibition promoted the reversion of these cells toward a normal skin cell type. Like embryonic stem cells, malignant tumor cells similarly receive and send molecular cues during development that promote tumor growth and metastasis, or cancer spread.

The Northwestern study takes advantage of these similarities by using the developing zebrafish to "detect" tumor-derived chemical signals.

In addition, one of the hallmarks of aggressive cancer cells, including malignant melanoma, is their unspecified, "plastic" nature, which is similar to that of embryonic stem cells, expressing genes characteristic of multiple cell types, including endothelial, neural and stem cells.

The Hendrix lab has long hypothesized that the plastic nature of malignant melanoma cells serves as an advantage by enhancing the cells' ability to migrate, invade and metastasize virtually undetected by the immune system.

In this study, the researchers showed that aggressive tumor cells, particularly melanoma, are capable of responding to microenvironmental factors as well as influencing other cells via epigenetic (other than genetic) mechanisms, a quality known as bi-directional cellular communication. Bi-directional cellular communication is integral to both cancer progression and embryological development.

The significance of the research team's finding is profound in that it implies that through secretion of Nodal, aggressive melanoma cells maintain their plasticity and modulate the microenvironment, as exemplified by their ability to direct the formation of zebrafish tissues.

These results also highlight the propensity of tumor cells to communicate bi-directionally and survive within an embryonic microenvironment. Further, the findings illuminate the remarkable plasticity of melanoma cells and the utility of the developing zebrafish as a model for studying the epigenetic modulation of tumor cells.

Melanoma is one of the deadliest forms of cancer. The five-year survival rate for melanoma patients with widespread disease is between 7 percent and 19 percent.

New mouse model technology in Melanoma vaccine tool-box

Tue, 28 Mar 2006 19:43:37 PST

( from http://www.rxpgnews.com ) Cancer vaccines are being investigated in early-phase clinical trials around the world, with many of those trials recruiting patients with melanoma. Although tumor regressions have been seen in 10% to 20% of patients with metastatic melanoma, the great promise of cancer vaccines - controlling tumor growth and cancer spread without serious side-effects - remains as yet unrealized. This could be set to change with the publication of a new mouse model technology in Cancer Research, the journal of the American Association of Cancer Research, from a multi-national team led by investigators at the Brussels Branch of the international Ludwig Institute for Cancer Research (LICR).

Melanoma has been a focus of cancer vaccine development because many melanoma-specific vaccine targets, so-called cancer antigens, have been defined, says the studys senior author, LICRs Dr. Benoit Van den Eynde. However, we have a limited understanding of how most, but not all, melanomas evade an immune system that has been primed to detect and destroy cancer cells carrying one of these defined cancer antigens.

According to Dr. Van den Eynde, this is due in part to the lack of appropriate animal models in which detailed immunological analyses can be performed before and after vaccination. The models we use to investigate cancer vaccines at the preclinical level either have a defined cancer antigen in a transplanted tumor, or they have an original tumor that doesnt have a defined antigen. However, in human clinical studies, we have original tumors with defined antigens. So there has been a need for a mouse model that more closely follows the human model.

Thus the Institute that first cloned mouse and human cancer antigens, allowing the rational design of cancer vaccines, has developed a model in which melanoma with a defined cancer antigen can be induced. The model has been engineered to have several mutations found to occur together in human melanoma, and so closely mimics the genetic profile of cancers treated in the clinic. The team, which is comprised of investigators from Belgium, France and The Netherlands, has already begun characterizing a cancer antigen-specific immune reaction observed before the mice were even vaccinated, which they hope will lead to a further understanding of spontaneous melanoma regressions.

Dr. Jill ODonnell-Tormey, Executive-Director of New Yorks Cancer Research Institute, which was founded in 1953 specifically to foster cancer immunology research, believes that this model may yield information crucial for cancer vaccines for other tumor types and not just melanoma. We have clinical trials for cancer antigens for sarcoma, for melanoma, and for breast, prostate, lung and ovarian cancers. Were learning a lot from these trials, but we could learn a lot more if we have a model like this, which selectively expresses each of our target antigens. Just one example might be the analysis of the immune response to cancer antigens during the early stages of cancer onset and progression, which might indicate if there is an optimum time for vaccination.

Malignant melanoma cells reprogrammed !

Tue, 28 Feb 2006 17:44:37 PST

( from http://www.rxpgnews.com ) Scientists at Northwestern University and the Stowers Institute for Medical Research have reprogrammed malignant melanoma cells to become normal melanocytes, or pigment cells, a development that may hold promise in treating of one of the deadliest forms of cancer.

A report describing the group's research was published in the Feb. 27 online edition of the Proceedings of the National Academy of Sciences that will appear in the March 7 issue of the journal.

The experiments were conducted as a collaboration involving the laboratories of Mary J. C. Hendrix, president and scientific director of the Children's Memorial Research Center, Northwestern University Feinberg School of Medicine, and Paul M. Kulesa, director of Imaging at the Stowers Institute for Medical Research in Kansas City, Mo.

Hendrix is professor of pediatrics at the Feinberg School and a member of the executive committees of The Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

The study demonstrated the ability of malignant melanoma cells to respond to embryonic environmental cues in a chick model -- in a manner similar to neural crest cells, the cell type from which melanocytes originate -- inducing malignant cells express genes associated with a normal melanocyte.

The researchers also showed that the malignant melanoma cells lost their tumor-causing ability as they became reprogrammed by the embryonic microenvironment to assume a more normal melanocyte-like cell type.

"Using this innovative approach, further investigation of the cellular and molecular interactions within the tumor cell embryonic chick microenviroment should allow us to identify and test potential candidate molecules to control and reprogram metastatic melanoma cells," Hendrix said.

Neural crest cells give rise to pigment cells as well as bone and cartilage, neurons and other cells of the nervous system. During embryonic development, neural crest cells display "invasive" behavior, similar to metastatic cancer cells, migrating from the neural tube (which becomes the brain and spinal cord) to form tissues along specific pathways.

Kulesa's laboratory transplanted adult human metastatic melanoma cells, isolated and characterized by the Hendrix laboratory group, into the neural tube of chick embryos.

The transplanted melanoma cells did not form tumors.

Rather, like neural crest cells, the melanoma cells invaded surrounding chick tissues in a programmed manner, distributing along the neural-crest-cell migratory pathways throughout the chick embryo.

The investigators found that a subpopulation of the invading melanoma cells produced markers indicative of skin cells and neurons that had not been present at the time of transplantation.

Taken together, results of this study suggest that human metastatic melanoma cells respond to and are influenced by the chick embryonic neural-crest-rich microenvironment, which may hold promise for the development of new therapeutic strategies, the researchers said.

"This idea was pioneered 30 years ago by scientists who thought that the complex signals within an embryonic field may reprogram an adult metastatic cancer cell introduced into such an environment and cause it to contribute in a positive way to an embryonic structure," Kulesa said.

"Today, we have advanced imaging and molecular techniques that allow us to pose the same questions within an intact chick embryo and directly study the molecular signals involved in the reprogramming. The ancestral relationship between melanoma and the neural crest provides a wonderful bridge between developmental and cancer biology," Kulesa said.

One of the hallmarks of aggressive cancer cells, including malignant melanoma, is their unspecified, plastic nature, which is similar to that of embryonic stem cells.

The Hendrix lab has shown that the unspecified or poorly differentiated cell type serves as an advantage to cancer cells by enhancing their ability to migrate, invade and metastasize virtually undetected by the immune system.

Also collaborating on this research were Jennifer C. Kasemeier and Jessica Teddy, Stowers Institute; and Naira V. Margaryan; Elisabeth A. Seftor; and Richard E. B. Seftor, Children's Memorial Research Center.

New option for patients with metastatic melanoma

Wed, 04 Jan 2006 05:46:37 PST

( from http://www.rxpgnews.com ) Patients with metastatic melanoma (MM) have new hope, says a recently published study by Mayo Clinic Cancer Center. The study, which shows the combination of paclitaxel and carboplatin (PC) appears to be effective for MM when traditional treatments have failed, is in this month's issue of Cancer.
"Melanoma is unfortunately one of the few cancers that has become more common over the last few decades, and when it becomes metastatic, there are very few treatment options," says Ravi Rao, M.B.B.S., Mayo Clinic oncologist and lead investigator of the study. "This is a good step towards better treating this cancer. We hope to continue to find treatment options that extend and improve life expectancy for patients." This study appears to have found one such option, with nearly half of the patients that received PC experiencing a clinical benefit of stable disease (19 percent) or tumor size reduction (26 percent).

The National Cancer Institute reports a 2.4 percent increase in the incidence of melanoma between 1992 and 2002. New cases are diagnosed in about 60,000 people each year in the United States, and almost 8,000 die because of metastasized melanoma. Because they know that most therapies provide palliative as opposed to curative options, researchers at Mayo Clinic Cancer Center consider developing more effective curative treatment options to be a priority.

Dr. Rao and his co-investigators examined the records of 31 MM patients at Mayo Clinic who were treated with the PC combination between March 2003 and January 2005. These patients had previously received (and failed) an average of two treatments, including vaccine/immunotherapy. Interestingly, the researchers found that this combination benefited even those patients in whom temozolomide (currently the most commonly used chemotherapy drug for melanoma) failed.

Because the data was collected from the records of patients treated previously and was not part of a set treatment regimen, the schedule and dosage of PC varied. However, the researchers believe that using the drugs weekly (compared to once every three weeks) makes the combination more tolerable, and the researchers prefer that option.

"Other recent studies in the U.S. and Germany looking at combinations that included PC, indicated that there is some clinical benefit from this combination," says Dr. Rao. "Combined with our results, we believe that the PC combination truly has a beneficial role, especially for patients who've had poor results from other treatment options.

"However, this study is retrospective in nature, and further studies are needed to fully understand the impact of this combination on the survival of patients with metastatic melanoma," he says. Dr. Rao also notes that several additional trials using this drug combination are being planned, including some at the Mayo Clinic Cancer Center.

Others involved in the study included Shernan Holtan, M.D.; James Ingle, M.D.; Gary Croghan, M.D., Ph.D.; Lisa Kottschade; Edward Creagan, M.D.; Judith Kaur, M.D.; Henry Pitot, M.D.; and Svetomir Markovic, M.D., Ph.D.

Positive family history increases risk of multiple primary melanomas

Thu, 06 Oct 2005 20:46:38 PST

( from http://www.rxpgnews.com ) Patients with a family history of multiple melanoma skin cancer are at increased risk of multiple primary melanomas, according to a study in the October 5 issue of JAMA.

In 2005, there will be an estimated 62,000 new cases of invasive melanoma and an estimated 7,600 deaths due to melanoma in the United States, according to background information in the article. Melanoma is the fifth leading cancer in men and the sixth leading cancer in women in the United States. The incidence of melanoma continues to rise at about 3 percent per year in the United States, with an estimated lifetime risk for an individual of 1.4 percent. This increasing incidence puts a larger portion of the population at risk not only for one primary melanoma but also for subsequent primary melanomas.

Cristina R. Ferrone, M.D., and colleagues from Memorial Sloan-Kettering Cancer Center, New York, conducted a study to identify the incidence and characteristics of patients at risk of developing multiple primary melanomas (MPM). The study included 4,484 patients diagnosed with a first primary melanoma between January 1, 1996, and December 31, 2002.

The researchers found that 385 patients (8.6 percent) had 2 or more primary melanomas, with an average of 2.3 melanomas per MPM patient. Seventy-eight percent had 2 primary melanomas. For 74 percent of patients, the initial melanoma was the thickest tumor. Fifty-nine percent presented with their second primary tumor within 1 year. Twenty-one percent of MPM patients had a positive family history of melanoma compared with only 12 percent of patients with a single primary melanoma (SPM). Thirty-eight percent of MPM patients had dysplastic nevi (DN; atypical moles) compared with 18 percent of SPM patients.

The estimated cumulative 5-year risk of a second primary tumor for the entire cohort was 11.4 percent, with almost half of that risk occurring within the first year. For patients with a positive family history or dysplastic nevi, the estimated 5-year risk of MPM was significantly higher at 19.1 percent and 23.7 percent, respectively. The most striking increase in incidence for the MPM population was seen for development of a third primary melanoma from the time of second primary melanoma, which was 15.6 percent at 1 year and 30.9 percent at 5 years.

"Patients with a positive family history or a history of DN are at significantly greater risk of developing MPM and should be enrolled in more intensive dermatologic surveillance programs. This high-risk subset of patients should also be further characterized genetically to further elucidate the biology and etiology of melanoma," the authors conclude.

Role of Slug Gene in Melanoma Metastasis Identified

Tue, 06 Sep 2005 06:35:38 PST

( from http://www.rxpgnews.com ) About 60,000 Americans will be diagnosed with melanoma this year, says the American Cancer Society, and 10,000 of those cases will be fatal. If not caught in the early stages, melanoma can be a particularly virulent form of cancer, spreading through the body with an efficiency that few tumors possess. Now, researchers at Whitehead Institute for Biomedical Research have discovered one of the reasons why this particular skin tumor is so ruthless. Unlike other cancers, melanoma is born with its metastatic engines fully revved.

"Other cancers need to learn how to spread, but not melanoma," says Whitehead Member Robert Weinberg, senior author of the paper that will be published September 4 in the early online edition of the journal Nature Genetics. "Now, for the first time, we understand the genetic mechanism responsible for this."

Metastasis (the spread of disease to an unconnected body part) is a highly inefficient, multi-step process that requires cancer cells to jump through many hoops. The cells first must invade a nearby tissue, then make their way into the blood or lymphatic vessels. Next they must migrate through the bloodstream to a distant site, exit the bloodstream, and establish new colonies. Researchers have wondered why melanoma in particular is able to do this not only more efficiently than other cancers, but at a far earlier stage. This new study shows that as melanocytes--cells that protect the skin from sun damage by producing pigmentation--morph into cancer cells, they immediately reawaken a dormant cellular process that lets them travel swiftly throughout the body.

Central to this reawakened process is a gene called Slug (named after the bizarre embryo shape that its mutated form can cause in fruit flies). Slug is active in the neural crest, an early embryonic cluster of cells that eventually gives rise to a variety of cell types in the adult, including dermal melanocytes. In this early embryonic stage, Slug enables the neural crest cells to travel, and then settle, throughout the developing embryo.

"Slug is a key component of the neural crest's ability to migrate," says Piyush Gupta, a MIT graduate student in Weinberg's lab and first author on the paper. "Following its activation during embryonic development, Slug is shut off in adult tissues." But when skin cells in, say, an individual's mole, become malignant, they readily reactivate Slug and gain the ability to spread--something that other cancers can spend decades trying to do.

Weinberg's team demonstrated this through a number of experiments. In the first, they created models of various cancer types by introducing cancer-causing genes into normal human cells and then injecting the tumor cells underneath the skin of mice. Mice injected with breast cancer cells or with fibroblast (connective tissue) cancer cells developed tumors, but the tumors didn't spread. Those injected with melanoma cells immediately developed invasive tumors throughout their body, spreading everywhere from the lungs to the spleen. This strongly supported the suspicion that melanoma is so metastatic in part due to properties intrinsic to melanocytes themselves, and not simply because it is external and thus uniquely exposed to environmental stresses.

For the second experiment, the team used microarray technology (chips covered with fragments of DNA that can measure gene levels) and found that Slug was expressed in human melanoma. "Really, this isn't that surprising," says Gupta, "when you consider that melanocytes in the skin are direct descendants of the neural crest." In fact, Gupta points out that occasionally physicians discover that perfectly benign melanocytes will sometimes manage to migrate through a patient's body into, say, the lymph nodes. This phenomenon isn't related to cancer, but rather demonstrates the latent ability of melanocytes to travel

Finally, the research team found that when Slug was knocked out in melanoma cells, the cancer was unable to metastasize when placed into a mouse.

"This work is yet another demonstration of the notion that certain embryonic genes normally involved in transferring cells from one part of the body to another are also involved in enabling cancer cells to spread," says Weinberg, who is also a professor of biology at MIT.

Incidence Of Nonmelanoma Skin Cancer On The Rise Among Young Adults

Wed, 10 Aug 2005 22:48:38 PST

( from http://www.rxpgnews.com ) A new study from Minnesota finds the incidence of nonmelanoma skin cancer increasing among men and women under the age of 40, according to an article in the August 10 issue of JAMA.

The overall incidence of nonmelanoma skin cancer, consisting of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), is increasing, according to background information in the article. This increasing incidence is most likely due to a combination of factors, including increased exposure to UV light, ozone depletion, and increased surveillance. Long-term exposure to the sun resulting in photodamage is perhaps the biggest risk factor for nonmelanoma skin cancer. In the United States, approximately 800,000 new cases of BCC and 200,000 new cases of SCC were diagnosed in 2000. Nonmelanoma skin cancer generally occurs in persons older than 50 years, and in this age group, its incidence is increasing rapidly. However, little is known about its incidence in persons younger than 40 years.

Leslie J. Christenson, M.D., of Mayo Clinic, Rochester, Minn., and colleagues conducted a study to estimate the sex- and age-specific incidence of BCC and SCC in Olmsted County, Minnesota, in a young population (less than 40 years old) from the beginning of 1976 through 2003. The patients in this study have comprehensive medical records captured through the Rochester Epidemiology Project.

During the study period, 451 incident basal cell carcinomas were diagnosed in 417 patients, and 70 incident squamous cell carcinomas were diagnosed in 68 patients. Overall, the age-adjusted incidence of basal cell carcinoma per 100,000 persons was 25.9 for women and 20.9 for men. The incidence of basal cell carcinoma increased significantly during the study period among women but not among men. Nodular basal cell carcinoma was the most common histologic subtype; 43.0 percent of tumors were solely nodular basal cell carcinoma and 11.0 percent had a mixed composition, including the nodular subtype. The incidence of squamous cell carcinoma was similar in men and women, with an average age- and sex-adjusted incidence of 3.9 per 100,000 persons; the incidence of squamous cell carcinoma increased significantly over the study period among both women and men.

Comparing the change in incidence rates for basal cell carcinoma, per 100,000 persons the rate for 1976-1979 for women was 13.4; for men, 22.9, and for both sexes, 18.2. For 2000-2003, the rate for women was 31.6; for men, 26.7; and for both sexes, 29.1.

For squamous cell carcinoma, per 100,000 persons the rate for 1976-1979 for women was 0.6; for men, 1.3, and for both sexes, 0.9. For 2000-2003, the rate for women was 4.1; for men, 4.2; and for both sexes, 4.1.

"This increase [in nonmelanoma skin cancer in young adults] may lead to an exponential increase in the overall occurrence of nonmelanoma skin cancer over time as the population ages. This may mean even greater demands for health care related to nonmelanoma skin cancer. Our results also emphasize the need to focus on the prevention of skin cancer in the very young so that the increasing incidence of a potentially preventable cancer can be halted," the authors conclude.

Curcumin - Potent turmeric spice blocks growth of melanoma

Tue, 12 Jul 2005 13:12:38 PST

( from http://www.rxpgnews.com ) Curcumin, the pungent yellow spice found in both turmeric and curry powders, blocks a key biological pathway needed for development of melanoma and other cancers, say researchers from The University of Texas M. D. Anderson Cancer Center.

The study, to be published in the August 15, 2005 issue of the journal Cancer, but available on line at 12:01 a.m. (EDT) on Monday, July 11, demonstrates how curcumin stops laboratory strains of melanoma from proliferating and pushes the cancer cells to commit suicide.

It does this, researchers say, by shutting down nuclear factor-kappa B (NF-kB), a powerful protein known to promote an abnormal inflammatory response that leads to a variety of disorders, including arthritis and cancer.

The study is the latest to suggest that curcumin has potent anticancer powers, say the researchers.

"The antioxidant, anti-inflammatory and anti-carcinogenic properties of curcumin derived from turmeric are undergoing intense research here and at other places worldwide," says one of the study's authors, Bharat B. Aggarwal, Ph.D., professor of cancer medicine in the Department of Experimental Therapeutics.

At M. D. Anderson, for example, dramatic results from laboratory studies have led to two ongoing Phase I human clinical trials, testing the ability of daily capsules of curcumin powder to retard growth of pancreatic cancer and multiple myeloma. Another Phase I trial is planned for patients with breast cancer, and given this news of curcumin's activity in melanoma, animal studies will soon begin, Aggarwal says.

Ground from the root of the Curcuma longa plant, curcumin is a member of the ginger family. It has long been utilized in India and other Asian nations for multiple uses: as a food-preservative, a coloring agent, a folk medicine to cleanse the body, and as a spice to flavor food (two to five percent of turmeric is curcumin, for example).

While researchers had thought curcumin primarily has anti-inflammatory properties, the growing realization that cancer can result from inflammation has spurred mounting interest in the spice as an anti-cancer agent, Aggarwal says. He adds that another fact has generated further excitement: "The incidence of the top four cancers in the U.S. - colon, breast, prostate, and lung - is ten times lower in India," he says.

This work is just the latest by M. D. Anderson researchers to show how curcumin can inhibit cancer growth. "Curcumin affects virtually every tumor biomarker that we have tried," says Aggarwal. "It works through a variety of mechanisms related to cancer development. We, and others, previously found that curcumin down regulates EGFR activity that mediates tumor cell proliferation, and VEGF that is involved in angiogenesis. Besides inhibiting NF-kB, curcumin was also found to suppress STAT3 pathway that is also involved in tumorigenesis. Both these pathways play a central role in cell survival and proliferation."

He said that an ability to suppress numerous biological routes to cancer development is important if an agent is to be effective. "Cells look at everything in a global way, and inhibiting just one pathway will not be effective," says Aggarwal.

In this study, the researchers treated three different melanoma cell lines with curcumin and assessed the activity of NF-kB, as well the protein, known as "IKK" that switches NF-kB "on." The spice kept both proteins from being activated, so worked to stop growth of the melanoma, and it also induced "apoptosis," or programmed death, in the cells.

Surprisingly, it didn't matter how much curcumin was used, says the researchers. "The NF-kB machinery is suppressed by both short exposures to high concentrations of curcumin as well as by longer exposure to lower concentrations of curcumin," they say in their study. Given that other studies have shown curcumin is non-toxic, these results should be followed by a test of the spice in both animal models of melanoma and in human trials, they say.

MITF master regulator is the target of gene amplification in melanoma

Sun, 10 Jul 2005 15:55:38 PST

( from http://www.rxpgnews.com ) Researchers have pinpointed specific gene and protein over-production in metastatic melanoma, pointing the way to a possible new drug target, according to a study published in Nature July 7.

Gene amplification is a process that often happens in cancer cells when the normal DNA replication process is altered, causing many copies of the gene to be produced instead of a single copy of a region of a chromosome.

The researchers found that the MITF (microphthalmia-associated transcription factor) master regulator is the target of gene amplification in melanoma. MITF amplification also was more prevalent in metastatic disease and was correlated with decreased overall patient survival.

Collaborators at Yale, using the technology AQUA (Automated Quantitative Analysis) to quantitatively measure protein expression in melanoma tissue microarrays, also found an over-expression of the protein.

"According to the study, these data suggest that MITF represents a distinct class of 'lineage survival' or 'lineage addiction' oncogenes required for both tissue-specific development and tumor progression," said David Rimm, M.D., an author on the study and associate professor in the Department of Pathology at Yale School of Medicine.

Another Yale author on the study was Aaron Berger, a student in Rimm's laboratory. The corresponding author was William Sellers of Dana-Farber Cancer Institute in Boston. Co-authors included researchers at Brigham and Women's Hospital, Harvard, the Massachusetts Institute of Technology, Massachusetts General Hospital, and the Medical University of Vienna.

The AQUA technology is the property of HistoRx, Inc., a New Haven-based bioscience company offering novel digital technologies for in situ diagnostics developed at Yale School of Medicine. It enables researchers to localize and quantify proteins in tissue while maintaining spatial relationships--a process that was previously impossible with conventional methods of pathology analysis and which vastly increases the quality and amount of information for analysis.

Human Anti-CTLA-4 Antibody in Combination with a gp100 Melanoma Vaccine Shows Significant Benefit in Treating Metastatic Melanoma

Mon, 25 Apr 2005 08:05:38 PST

( from http://www.rxpgnews.com ) Medarex, Inc. ( Nasdaq: MEDX ) and Bristol-Myers Squibb Company ( NYSE: BMY ) announced today that complete or partial responses in seven of 56 patients with metastatic melanoma showed durability ranging from four months to the longest still ongoing at over 34 months, with five of the seven responses ongoing for more than two years.

These patients were treated in a Phase II clinical study with the investigational fully human anti-CTLA-4 antibody, MDX-010, in combination with MDX-1379, a gp100 melanoma vaccine. The Phase II clinical trial was conducted by Steven A. Rosenberg, M.D., Ph.D., chief of Surgery at the National Cancer Institute, under a Cooperative Research and Development Agreement with Medarex. Results from the clinical trial were presented at the 96th Annual Meeting of the American Association of Cancer Research, April 16-20, 2005, in Anaheim, California.

The Phase II clinical trial evaluated two dose regimens of MDX-010 in combination with MDX-1379 in a total of 56 patients with metastatic melanoma. All patients had stage IV disease, Karnofsky performance status greater than or equal to 60, no previous MDX-010 treatment or gp100 vaccination, no evidence of autoimmune or immunodeficiency, and three weeks had elapsed since any previous systemic cancer therapy. Of the 56 patients, 29 patients ( cohort 1 ) received 3.0 mg/kg intravenously over 90 minutes of MDX-010 and MDX-1379 every three weeks, and 27 patients ( cohort 2 ) received an initial dose of 3.0 mg/kg intravenously over 90 minutes of MDX-010 and MDX-1379, followed by subsequent doses of 1.0 mg/kg of MDX-010 every three weeks.

Data on the initial 14 patients in cohort 1 and the initial 24 patients in cohort 2 were previously presented at the 2003 annual meeting of the American Society of Clinical Oncology.

Four of the 29 patients treated in cohort 1 experienced complete or partial responses. Two patients experienced complete responses that are ongoing at over 30 and 31 months, respectively, and two additional patients experienced partial responses, with one response lasting four months and the other ongoing at over 34 months. In cohort 2, three of 27 patients experienced partial responses, with one partial response ongoing to six months and two partial responses ongoing at 25 and 26 months, respectively.

Grade III/IV adverse events were reported in nine of 29 patients in cohort 1 and five of 27 patients in cohort 2, with colitis ( seven patients ) and dermatitis ( four patients ) being the most frequently reported.

All of the Grade III/IV events were normalized or managed with medical treatment involving hospitalization, intravenous hydration, steroids, or other medical management. The management of immune-mediated toxicities required strict attention to patient complaints and prompt diagnosis, as they could require surgery or potentially be lethal if not vigorously treated. Of the seven patients who experienced complete or partial responses in the Phase II clinical trial, Grade III/IV events were reported in all five patients with ongoing duration of response greater than or equal to 25 months; no Grade III/IV events were reported in the two patients who experienced partial responses of four and six months duration.

"We are encouraged by the duration of responses in this metastatic melanoma patient population and look forward to the results of the Phase III clinical trial and other trials that investigate the ability of MDX-010 to offer a new approach to treating cancer," said Donald L. Drakeman, president & CEO of Medarex.

About MDX-010

MDX-010 is a fully human antibody against human CTLA-4, a molecule on T cells that is believed to be responsible for suppressing the immune response.

MDX-010 is in clinical studies to investigate its potential to enable the immune systems of cancer patients to fight tumors. MDX-010 is currently in a Phase III clinical trial for metastatic melanoma and in multiple Phase II clinical trials to investigate the product's potential activity in other tumor types.

The potential use of MDX-010 outside oncology is also being explored. Further information regarding Medarex's and Bristol-Myers Squibb's MDX-010 program can be found in Medarex's public disclosure filings with the U.S. Securities and Exchange Commission ( SEC ).

CR011: An Antibody-Drug Conjugate Shows Durable Effects in Animal Models of Melanoma

Mon, 18 Apr 2005 09:09:38 PST

( from http://www.rxpgnews.com ) CuraGen Corporation (Nasdaq: CRGN - News) announced today that new preclinical data on CR011, one of the oncology products being developed by the Company, were presented at the 96th Annual Meeting of the American Association for Cancer Research in Anaheim, CA. Preclinical data on CR011, an antibody-drug conjugate (ADC) that is expected to enter clinical trials in the first half of 2006, demonstrated that it caused tumor regression in animal xenograft models of melanoma.

In a poster, entitled "CR011, a potent fully-human monoclonal antibody- monomethylauristatin E conjugated pro-drug targeting melanoma," it was reported that CR011 selectively binds to GPNMB, a protein highly expressed on the surface of melanoma cells.

Furthermore, in xenograft models of melanoma, treatment with CR011 caused significant improvements in survival, including complete and durable tumor regression, without any notable toxicity or weight loss. This data will be further explored in clinical trials, which are expected to begin during the first half of 2006.

"Antibody-drug conjugates represent a novel approach to utilize potent chemotherapeutic agents and deliver them directly to cancer cells," stated Mario Sznol, M.D., Head of the Melanoma Program at the Yale University School of Medicine. "The activity of CR011 against melanoma in preclinical studies is compelling. Metastatic melanoma is an aggressive disease and the current treatments are inadequate, therefore, there is a significant need for promising therapeutics that could benefit this patient population."

"The preclinical data presented at AACR on CR011, which combines the specificity of a fully-human monoclonal antibody to target a specific protein located on certain cancer cells and the power of a potent cytotoxic agent, suggests that this therapeutic kills melanoma cells and is able to induce a cure in xenografts models," stated William F. Hahne, M.D., Vice President of Clinical Development. "We look forward to fully exploring the safety and anti-tumor activity of CR011 as a potential treatment for patients with metastatic melanoma. This clinical program is scheduled to begin in the first half of 2006."

About CR011

CR011 is an antibody-drug conjugate (ADC) that utilizes technology licensed from Seattle Genetics to attach potent cell-killing payloads to a fully-human monoclonal antibody being developed by CuraGen that was generated by Abgenix's Xenomouse® technology.

CR011 is designed to be stable in the bloodstream. It targets and binds to GPNMB that is located on the surface of cancer cells. After the ADC binds to the protein and is transported into the cell, the drug payload is released from the fully-human monoclonal antibody once it is activated inside the cancer cell.

Preclinical studies conducted with this potential therapeutic demonstrate that CR011 produces strong, reproducible and durable effects against cancer in animal models of melanoma.

About Melanoma

Melanoma is a very serious form of skin cancer that accounts for the majority of skin-cancer related deaths each year. The number of people diagnosed with melanoma worldwide is rapidly increasing with more than 53,000 new cases diagnosed annually in the U.S. While the chance of developing melanoma increases with age, it remains one of the most common cancers in young adults.

This type of cancer begins in specific cells in the skin and can metastasize, or spread, throughout the body to many organ systems. No significant advances in the treatment of metastatic melanoma have occurred over the past 30 years. Patients with stage 4 metastatic melanoma have a median survival of 6 - 9 months.

New therapy for Advanced Melanoma

Wed, 06 Apr 2005 18:56:38 PST

( from http://www.rxpgnews.com ) Melanoma is a particularly deadly form of skin cancer very resistant to treatment. Researchers at H. Lee Moffitt Cancer Center & Research Institute and the University of South Florida are testing a promising new therapy that prompts the immune system to aid in the fight against melanoma tumors.

"This is a milestone clinical trial because it is the first time that electroporation is being used to deliver plasmid DNA in a gene therapy study in humans," said Richard Heller, PhD, USF professor of medical microbiology and immunology who helped develop the technology used in the study.

Electroporation is a technique in which a hand-held device applied to the skin delivers pulses of electricity to open up pores in the tumor cell membrane. This opening allows a small therapeutic molecule -- in this case a molecule known as a DNA plasmid that contains the gene for Interleukin-12 -- to slip inside the melanoma tumor before the membrane reseals.

"Melanoma does not respond well to standard chemotherapy," said Adil Daud, MD, assistant professor of oncology in the Cutaneous Oncology Program at Moffitt. "Gene therapy gives us the flexibility to introduce a huge variety of potential targets for treatment, but its major limitation has been getting the gene into the cancer. If electroporation can deliver the gene to these tumors reliably and without serious side effects, melanoma and other cancers would be open to many new treatment possibilities."

Six years of laboratory studies by Dr. Heller and his colleagues preceded the initial human trial begun earlier this year at Moffitt. The collaboration of USF and Moffitt in this trial is a good example of translational research -- moving the new application of a gene transfer technology from an animal model to the patient. Dr. Heller's team worked extensively with Dr. Daud to adapt the electroporation technique used on mice to humans.

The researchers injected the DNA plasmid, which encodes a gene that stimulates the immune system, directly into the tumor site in mice. Then, they applied electroporation to the site to help the plasmid move into the tumor cells. The tumor cells used the plasmid's genetic instructions to make proteins. These proteins signaled the immune system to recognize the melanoma tumors as abnormal and attack.

Eighty percent of the mice were cured with this therapy -- their tumors disappeared and the treated animals remained disease free for the full length of the study (100 days), Dr. Heller said.

Furthermore, he said, even when melanoma cells were reinjected into the cured mice the tumors were rejected. This indicates the immune system formed a memory response that recognized the melanoma cells as foreign and prevented tumor regrowth.

"We were very encouraged by the results of the preclinical studies." Dr. Heller said. "We're hoping this translates into a beneficial treatment for patients."

Inhibiting Mutant v599EB-Raf protein could Prevent the Spread of Melanoma

Wed, 23 Mar 2005 19:35:38 PST

( from http://www.rxpgnews.com ) Researchers at Penn State College of Medicine have identified the mechanism by which the most mutated gene in melanoma, called v599EB-Raf, aids melanoma tumor development demonstrating its importance as a therapeutic target.

"Our studies suggest that using therapies to target and inhibit the function of mutant v599EB-Raf protein could prevent the spread of melanoma and halt tumor growth for those melanomas containing the B-Raf mutation," said Gavin P. Robertson, Ph.D., assistant professor of pharmacology, pathology, and dermatology, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center. "With cases of melanoma increasing at about 4 percent per year and no effective treatments available for advanced-stage disease, it's imperative that we continue to look for important proteins that could be targeted therapeutically. Studies like this one that identify how inhibiting important melanoma regulating proteins reduce melanoma development will lead to a better understanding of the disease, and thus, the development of more effective long-term treatment options for patients."

The job of normal non-mutated B-Raf is to relay signals from the cell membrane, which is the boundary of the cell receiving the signals, to the nucleus, which contains genetic material and controls many of the cell's activities. B-Raf is one member of the chain that relays signals playing an important role in cell signaling. The protein is usually only active when needed to relay signals.

In contrast, mutant B-Raf is active all the time, which disrupts the chain's normal function. Previous studies have shown B-Raf is the most mutated gene in melanomas, present in about 60 percent of human melanomas, but the role mutant B-Raf plays in causing melanoma tumors remained unknown.

Robertson used human melanoma cells, applying siRNA, small interfering ribonucleic acids, or BAY 43-9006, a general Raf inhibitor, to show that lowering mutant B-Raf protein reduced melanoma development.

"Reducing B-Raf activity in melanoma cells before tumors had formed significantly decreased the growth potential of the melanoma cells and, in effect, prevented tumor development," Robertson said. "In contrast, reducing B-Raf activity in existing tumors in a mouse model did not shrink the tumors but did prevent them from getting bigger. These discoveries are important for the treatment of metastatic melanoma since therapeutically inhibiting mutant B-Raf could prevent growth of existing tumors and more importantly prevent development of metastatic tumors at secondary sites."

The study shows that in existing melanoma tumors, inhibiting V599EB-Raf activity reduced vascular development, which is essential for tumor growth. Without vascular support the tumors remained the same size. This process occurs by reducing the secretion of VEGF, a factor downstream of B-Raf promoting vascular development, from melanoma cells.

"Because the tumors remained the same size, siRNA or BAY 43-9006 would have to be paired with another therapeutic agent to cause the tumors to shrink or disappear," Robertson said.

Of the major types of skin cancer, melanoma is the most metastatic and lethal form. It is currently the seventh most common cancer in the U.S., with about 52,000 cases diagnosed annually. Furthermore, it is the cancer with the second fastest growth rate. In 2004, an American's lifetime risk of developing melanoma was one in 63 and at the current rate of increase will be one in 50 by 2010. As a direct result of a lack of effective therapeutics, the 2005 prognosis for patients in the metastatic stages of the disease remains very poor with average survival ranging from six to 10 months.

Clinical Trials Tests CpG7909 and Melan-A Combination Melanoma Cancer Vaccines

Fri, 18 Mar 2005 16:37:38 PST

( from http://www.rxpgnews.com ) Results from the first Phase 1 clinical trial of a vaccine composed of a synthetic bacterial sequence, CpG7909 (ProMune TM , Coley Pharmaceuticals), and a melanoma antigen, Melan-A, indicate that this vaccine combination is not only safe but also can improve and bolster immune responses to tumors.

Lead authors and members of the Cancer Vaccine Collaborative, Drs. Daniel E. Speiser and Pedro Romero and their team from the Lausanne Branch of the Ludwig Institute for Cancer Research at the Lausanne University Hospital, Lausanne, Switzerland, reported their promising findings in The Journal of Clinical Investigation. In the clinical trial, the eight melanoma patients who each received four monthly injections of the vaccination all exhibited a strong antigen-specific T-cell response, with a rapid increase in the frequency of Melan-A specific T cells.

These T-cell clones recognize and kill melanoma cells in an antigen-specific manner. It was observed that the majority of T-cell responses developed rapidly with T-cell frequencies peaking seven to ten days after vaccination. Future studies will explore if increased doses of CpG7909 and/or peptides can further enhance the observed T-cell activation.