Advanced Melanoma Tumors Eradicated In Mouse Model

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Cancers arise in the body all the time. Most are nipped in the bud by the immune response, not least by its T cells, which detect telltale molecular markers - or antigens - on cancer cells and destroy them before they grow into tumors. Cancer cells, for their part, evolve constantly to evade such assassination. Those that succeed become full-blown malignancies. Yet, given the right sort of help, the immune system can destroy even these entrenched tumors.

In the Journal of Experimental Medicine, researchers led by Jedd Wolchok, MD, PhD, of the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York describe one way in which that might be achieved. The paper relates how the cancer drug cyclophosphamide (CTX) and OX86 - an antibody that activates a molecule named OX40 on T cells - were combined with a cutting-edge therapy known as adoptive T cell transfer to eradicate advanced melanoma tumors in mice.

Wolchok and his colleagues had previously shown that CTX and OX86 treatment caused the regression of such tumors. Now they wanted to see if adding T cell transfer to the mix would further improve outcomes. T cell transfer is an investigative immunotherapy in which T cells that target tumors are isolated from patients, manipulated, expanded and then transfused back into those patients.

A variety of T cells are of relevance to this approach. One is the CD8

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Trial Of Genetically Engineered Immune System To Fight Melanoma

Main Category: Melanoma / Skin Cancer
Also Included In: Genetics;  Immune System / Vaccines
Article Date: 04 Oct 2012 - 0:00 PDT



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'ACT TIL' Approach Studied For The Treatment Of Metastatic Melanoma

Main Category: Melanoma / Skin Cancer
Also Included In: Immune System / Vaccines;  Clinical Trials / Drug Trials
Article Date: 20 Oct 2012 - 0:00 PDT



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Combining BRAF Inhibitor And Immunotherapy Increases Antitumor Activity In Metastatic Melanoma

BRAF Inhibitor Zelboraf Boosts Effectiveness of Immunotherapy in Mouse Model

Combining the recently approved BRAF inhibitor, Zelboraf with an engineered T cell immunotherapy to treat metastatic melanoma significantly increased tumor responses and survival in an animal model, researchers at UCLA's Jonsson Comprehensive Cancer Center have shown.

The animals in the study that received the combination therapy had better tumor responses and lived more than twice as long as those getting the BRAF inhibitor or immunotherapy alone. The findings provide strong support for testing the combination therapy in human clinical trials, which Jonsson Cancer Center researchers hope to launch within two years.

About 50 percent of patients with metastatic melanoma, or 4,000 people a year, have the BRAF mutation and can be treated with Zelboraf. More than 50 percent of those respond well to the drug, but the responses usually last only a few months. With immunotherapy, fewer patients respond, but the responses are more durable.

By pairing the combination therapy in a one-two punch, researchers hope to maintain the high response rates associated with Zelboraf and combine them with the longer disease-free progression times seen with immunotherapy, said study first author Dr. Richard Koya, a Jonsson Cancer Center scientist and an assistant professor of surgical oncology.

"The idea was to target two different aspects of anti-cancer biology, hitting the tumor cells themselves with the BRAF inhibitor and adding in T cells educated to induce a specific anti-tumor immune response," Koya said. "The results we saw in this study were very promising."

The findings of the two-year study appear Aug. 15, 2012 in the peer-reviewed journal Cancer Research.

The researchers also found that the BRAF inhibitor helped boost the power of the immunotherapy, creating a greater combination effect, said study senior author Dr. Antoni Ribas, a Jonsson Cancer Center scientist and a professor of hematology/oncology.

"We found that both treatments were more effective when administered together, and we were surprised to see that a drug that should only be targeting the BRAF-mutant cancer cells was also having a beneficial effect on the T cells," Ribas said.

In the immunotherapy technique, called adoptive T cell transfer or ACT, lymphocytes are genetically engineered to express a receptor that recognizes melanoma cells, creating an army of immune cells that attack the cancer. The lymphocytes are modified genetically to become specific to the melanoma cells and are injected into the body.

The study was done using a model based on unique cell lines developed at UCLA. Previously, no implantable BRAF mutation-driven melanoma model able to grow progressively in a mouse with a fully competent immune system was available.

It is vital to develop new drugs to treat metastatic melanoma as few options are available for patients. Zelboraf works well, but most patients eventually relapse.

"This is a patient population that we are not able to cure," Koya said. "With what we have now we are just prolonging their lives. We need to have more options, and we hope this combination therapy proves to be an effective alternative."

About 70,000 new cases of melanoma are diagnosed each year in the United States. Of those, 8,000 people will die of the disease.

"In conclusion, combined therapy with the BRAF-specific inhibitor Zelboraf and T cell receptor engineered adoptive cell transfer resulted in superior anti-tumor effects," the study states. "Although the absolute number of T cells infiltrating the tumor was not increased by Zelboraf, the combination increased the functionality of antigen-specific T lymphocytes. Therefore, our studies support the clinical testing of combinations of BRAF targeted therapy and immunotherapy for patients with advanced melanoma."

The study was funded by the National Cancer Institute at the National Institutes of Health (P50 CA086306 and P01 CA 132681), Seaver Institute, Louise Belley and Richard Schnarr Fund, Wesley Coyle Memorial Fund, Garcia-Corsini Family Fund, Fred L. Hartley Family Foundation, Ruby Family Foundation, Jonsson Cancer Center Foundation, Caltech-UCLA Joint Center for Translational Medicine, UCLA Tumor Biology Program, U.S. Department of Health and Human Services, Ruth L. Kirschstein Institutional National Research Service Award, Eugene V. Cota-Robles Fellowship and National Science Foundation Competitive Edge Fellowship.

View drug information on Zelboraf.

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Resistance In Melanoma Patients Delayed By Combination Of Targeted Treatment Drugs

Combined treatment with two drugs targeting different points in the same growth-factor pathway delayed the development of treatment resistance in patients with BRAF-positive metastatic malignant melanoma. The results of a phase I/II study of treatment with the kinase inhibitors dabrafenib and trametinib were published in the New England Journal of Medicine and released online to coincide with a presentation at the European Society for Medical Oncology meeting in Vienna.

"We investigated this combination because of research we and others have conducted into the molecular underpinnings of resistance to BRAF inhibitor therapy," says Keith Flaherty, MD, of the Massachustts General Hospital (MGH) Cancer Center, lead author of the NEJM report and principal investigator of the study. "We found that adding the MEK inhibitor trametinib to BRAF inhibitor dabrafenib clearly delays the emergence of resistance. In fact, the combination was at least twice as effective as BRAF inhibition alone."

In around half of patients with metastatic melanoma, tumor growth is driven by mutations that keep the BRAF protein - part of the MAPK cell growth pathway - constantly activated. In recent years, drugs that inhibit BRAF activity have rapidly halted and reversed tumor growth in about 90 percent of treated patients, but most patients' response is temporary, with tumor growth resuming in six or seven months. Investigations into how this resistance emerges have suggested that the MAPK pathway gets turned back on through activation of MEK, another protein further down the pathway. Based on promising results of animal studies, the current investigation was designed to test whether inhibiting both the BRAF and MEK proteins could delay treatment resistance.

Sponsored by GlaxoSmithKline, the study by researchers at 14 sites in the U.S. and Australia tested two of the company's drugs - BRAF inhibitor dabrafenib and MEK inhibitor trametinib, both oral medications currently being evaluated by the FDA as single-agent therapeutics - in adult patients with BRAF-expressing malignant melanoma. Phase I testing confirmed that there were no drug-to-drug interactions between the two agents and evaluated the safety of different dose combinations. In the open-label phase II portion of the study, 162 patients were randomized into three groups that received different dose combinations: two daily 150 mg doses of dabrafenib plus one 2 mg trametinib dose, the same dabrafenib dose with a 1 mg dose of trametinib, or treatment with dabrafenib alone. Participants receiving dabrafenib alone were able to cross over to the full-dose combination treatment if their cancer resumed progression.

Treatment with both combination regimens led to a significant delay - about four months longer than with dabrafenib alone - in the emergence of resistance. After one year of treatment, 41 percent of those receiving full-dose combination treatment had no progression of their cancer, compared with only 9 percent of those receiving one drug. The occurrence of side effects such as skin rash and the development of squamous cell carcinoma, a less malignant skin cancer, was similar to that typically seen when only one of the two drugs is used, and some side effects were less frequent with the combination therapy.

Noting that the tested combination, now being tested in a larger Phase III study, delayed but did not prevent resistance in most participants, Flaherty says, "We need to continue focusing on resistance mechnisms occuring with this combination approach so we can better understand how to treat patients once resistance emerges or to develop other combination regimens to further prevent relapse. We also need to see if this approach could serve as an effective adjuvant therapy used following surgery to prevent recurrence. That might have the biggest impact on patients." Flaherty is an associate professor of Medicine at Harvard Medical School.

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Zebrafish Provide Insight Into Melanoma

Main Category: Melanoma / Skin Cancer
Also Included In: Cancer / Oncology;  Genetics
Article Date: 19 Jun 2012 - 4:00 PDT



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Dabrafenib Shows Promise For Melanoma Patients

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Main Category: Melanoma / Skin Cancer
Also Included In: Cancer / Oncology
Article Date: 25 Jun 2012 - 11:00 PDT



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Transplant, Lymphoma Patients At Greater Risk Of Melanoma

Main Category: Melanoma / Skin Cancer
Also Included In: Transplants / Organ Donations;  Lymphoma / Leukemia / Myeloma
Article Date: 06 Oct 2012 - 0:00 PDT



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New Research Takes Us Another Step Towards Understanding And Treating Melanoma

These proteins are required for melanocyte stem cell self-maintenance and, as such, correct pigmentation throughout the mice's life span. Without these two proteins, the mice's fur turns white. Their research is published in the review Cell Report and paves the way for serious possibilities in terms of stopping the formation of melanomas, tumours that originate from melanocyte cells.

Melanocytes are cells in the organism used for skin, fur and hair pigment. This pigmentation function provides protection from the sun and lends organisms their colour. Malfunctions in these cells may lead to skin cancer known as melanoma. Melanomas are highly aggressive cancers that become very difficult to treat as they develop and metastases occur.

A few years ago, researchers discovered that, in humans, the B-Raf gene (coding gene for protein of the same name) is mutated in more than 50% of melanoma. Spectacular progress has been made in recent years in the treatment of this cancer, thanks to the development of pharmacological inhibitors that target an enzyme: the B-Raf kinase. However, despite this treatment, cancer returns in several patients, indicating that not all cancerous cells have been eliminated. This led researchers to believe that B-Raf is not the only element driving the cancer process.

In this new research, scientists have tried to understand how melanocytes function normally, to then understand their specific role in cancer. To this end B-Raf protein expression, then, in turn, C-Raf protein expression, were removed from mice with black fur (ideal to clearly see any changes in pigmentation).

No changes in pigmentation were observed for mice that only had their B-Raf or C-Raf expression removed by researchers from the line of cells producing melanocytes. Mice that had both coding genes for B-Raf and C-Raf removed simultaneously had a normal colour at birth. However, they progressively lost their pigmentation as they grew. They turned grey from black, before becoming increasingly white.

For Alain Eychène, the research team leader, "these observations represent a fault in melanocyte renewal. Since the colour black is present at birth, the pigment cells clearly exist. However, the progressive whitening of the fur, once B-Raf and C-Raf have been removed from the cell line, proves that both these proteins are required for melanocyte renewal".

As is the case for all cells, melanocytes originate from stem cells; the latter are responsible for renewal during moulting. This research shows that it is specifically this population of stem cells alone that disappears progressively in mutant mice. For Alain Eychène, "This is the first in vivo demonstration of the role of RAF proteins in the self-renewal of stem cells".

The fact that B-Raf and C-Raf are both involved in controlling and renewing pigment stem cells represents another step towards understanding and treating melanoma. By blocking these proteins (using inhibitors) in patients undergoing treatment, it is possible that in time researchers will succeed in eliminating all cancerous stem cells, i.e. the likely cause behind cases of cancer reoccurrence.

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How Melanoma Cells Circumvent The Immune System

Melanoma is so dangerous because it tends to metastasize early on. New treatment approaches utilize, among other things, the ability of the immune defense to search out and destroy malignant cells. Yet this strategy is often only temporarily effective. A research team under the direction of Bonn University has discovered why this is the case: In the inflammatory reaction caused by the treatment, the tumor cells temporarily alter their external characteristics and thus become invisible to defense cells. This knowledge forms an important foundation for the improvement of combination therapies. The results have been published online in the renowned journal Nature.

In Germany, approximately 15,000 people develop melanoma annually and approximately 2,000 people die from it every year. Malignant melanoma is the most frequently fatal skin diseases. The particular malignancy is based on the fact that small tumors can spread via the lymphatic vessels and the bloodstream. For many years, the working group under Prof. Dr. Thomas Tüting, Director of the Laboratory for Experimental Dermatology at the Bonn University Hospital, has investigated the effect of a targeted immune therapy with tumor-specific defense cells.

Tumor cells behave like a wolf in sheep's clothing

In trials on mice who congenitally develop melanoma, the researchers were able to destroy advanced tumors using so-called cytotoxic T-cells. "But they recover after some time - just as they do in patients in the hospital," explain Dr. Jennifer Landsberg and Dr. Judith Kohlmeyer, lead authors of the study. This form of therapy triggers inflammation. Now the researchers have discovered that the melanoma cells change their external characteristics precisely via this accompanying inflammatory reaction. "They behave like wolves in sheep's clothing and thus evade detection and destruction by defense cells," says Marcel Renn, also a lead author of the study.

The immune system can fight tumors - but it can also protect them

On the search for the underlying mechanisms, the researchers pointed histological investigations of tumors in the right direction: Therapy-resistant melanomas demonstrated a significantly stronger inflammatory reaction with many scavenger cells of the immune system, the so-called macrophages. A messenger primarily released from these immune cells - the tumor necrosis factor-alpha - was able to bring about the change in character of the melanoma cells directly in the Petri dish in the laboratory. Cells treated in this way were subsequently hardly detected by the defense cells. "The immune system is like a double-edged sword," explains Prof. Tüting. "It can fight the tumor - but it can also protect it." Such changes in the tumor tissue are probably of great importance for the formation of resistance to therapy. "According to more recent discoveries, treatment with inhibitors which prevent signal transmission in tumor cells is also affected by this," remarks Prof. Tüting.

Melanoma cells lose their typical characteristics

Molecular genetic investigations revealed that melanoma cells from therapy-resistant tumors had lost the characteristics typical for pigment cells. Instead, they demonstrated traits of connective tissue cells. "It is possible that melanoma cells undergo this change in character so easily because they originate from the embryonic development of cells in the neural crest which can also form connective tissue and nerve cells," says Prof. Dr. Michael Hölzel, co-author from the Institute for Clinical Pharmacology and Clinical Chemistry at the Bonn University Hospital.

Results can also be transferred to humans

Findings initially gained from laboratory mice were also able to be reproduced by the team of researchers with human melanoma cells and various associated defense cells in the Petri dish. The melanoma cells likewise reacted to the messenger tumor necrosis factor-alpha with a loss of pigment cell characteristics and could then no longer be detected by pigment-cell-specific defense cells. "Detection by other defense cells which can search out specific genetic changes in the melanoma cells was not affected by this, however," stresses Prof. Dr. Thomas Wölfel, director of a working group involved in the study at the Medical Clinic III of the Mainz University Hospital.

Important findings for new treatment strategies

As soon as the tumor necrosis factor alpha no longer had an effect on the human and mouse melanoma cells, however, the cells regained their pigment-cell characteristics. Then they were also able to be detected and fought against by all immune defense cells once more. All of these findings yield important information for new treatment strategies. Thus in the future, defense cells against antigens of various categories and specificity should be used and at the same time, the inflammation utilized by the tumor cells should be therapeutically inhibited. "Our experimental model system will help us to develop optimally effective combination therapies as rapidly as possible," says Prof. Tüting. "However, it will still take several years until the clinical application of strategies of this type."

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Measures Needed To Curb Alarming Increase In Malignant Melanoma On The West Coast Of Sweden

Malignant melanoma is as much as 35% more common among people who live in Gothenburg and the region's coastal municipalities than those who live inland. Researchers at Sahlgrenska Academy, University of Gothenburg, Sweden, have found that the number of malignant melanoma cases in the Vastra Gotaland region has quadrupled since 1970.

Malignant melanoma has become increasingly common in the Western world over the past few decades. One of the biggest factors has been excessive and unprotected sunbathing despite widespread awareness of the health risks.

Melanoma takes a long time, sometimes several decades, to develop. For that reason, sunbathing habits from many years ago still affect a person's risk level.

According to a new study by researchers at Sahlgrenska Academy, University of Gothenburg, the number of melanoma cases in the Västra Götaland region has quadrupled among men and tripled among women since 1970.

"This represents a relative increase of more than 3% per year," says Magdalena Claeson, a researcher at Sahlgrenska Academy who participated in the study. "The increase in the region was considerably above average for the entire country."

The study found that 35% more men and 25% more women developed malignant melanoma in Gothenburg than in the inland municipalities. Fifteen per cent more women developed the disease in the coastal municipalities than inland.

One explanation is that inhabitants of Gothenburg and the coastal municipalities are exposed to the sun for more hours a day. A 2007 study conducted by the Swedish National Board of Health and Welfare found that inhabitants of Gothenburg and the coastal municipalities tend to take longer summer holidays in sunny countries and spend more time outdoors when abroad. Meanwhile, they are more likely to work indoors when they are in Sweden.

"The latest research suggests that melanoma is caused by this type of intermittent exposure to the sun," Magdalena Claeson says. "In other words, people get sunburned during their summer holiday and spend a lot of time indoors for the rest of the year."

The results have convinced the researchers that more preventive resources should be appropriated for the Västra Götaland region, particularly Gothenburg and the coastal municipalities.

"Among the measures likely to prove effective are educational initiatives among schoolchildren and sun protection information for people who travel abroad," Claeson says.

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Skin Cancer: Potential New Treatment Target Identified For Melanoma

New research from Western University, Canada, has identified a potential new target for the treatment of melanoma, the deadliest of all skin cancers. Silvia Penuela and Dale Laird discovered a new channel-forming protein called Pannexin (Panx1) that is expressed in normal levels on the surface of healthy skin cells. But they found, in melanoma, Panx1 is over-produced to a pathological level. The researchers also discovered that if you reduce it or knock it down, the cell becomes more normal. The research is published in the August 17th issue of the Journal of Biological Chemistry.

Malignant melanoma only accounts for four per cent of all skin cancers and yet, it's responsible for 79% of skin cancer-related deaths. The World Health Organization says there are 200-thousand cases of melanoma diagnosed each year and 65 thousand melanoma-related deaths (2000 statistics).

"We think this over-production of Panx1, enables the melanoma to become very aggressive. The cells have these extra Panx1 channels and they can leave the primary tumor and invade other tissues," explains Laird, a Professor in the Department of Anatomy and Cell Biology, and Canada Research Chair in Gap Junctions and Disease. "And when you find a protein that is highly up-regulated in a disease cell such as a melanoma, the question becomes, is there therapeutic value in targeting a drug to that protein to reduce its production or block its function. Would that be an effective treatment?"

"We now want to correlate our discovery to patient samples using the human melanoma bank through our collaboration with Dr. Muriel Brackstone and other clinicians at the London Health Sciences Centre, to see if this is a cancer marker," says Penuela, a Postdoctoral Fellow working in the Laird lab. "So if a melanoma lesion has a lot of this protein, it might be a tool for prognosis, in saying this is more advanced, or going to be highly metastatic. And because it's on the skin, it would be more accessible for treatment." Penuela suggests potential treatment might be in the form of a topical medication to use on melanoma lesions.

The scientists also worked with David Litchfield and John Lewis and their teams at Schulich Medicine & Dentistry and the London Regional Cancer Program on this research. It was funded through the Canadian Institutes of Health Research. The Laird laboratory recently received a $200,000 Innovation Grant from the Canadian Cancer Society Research Institute to further its studies on Panx1.

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Studying How Elesclomol Works Reveals New Molecular Target For Melanoma Treatment

A laboratory study led by UNC medical oncologist Stergios Moschos, MD, demonstrates how a new targeted drug, Elesclomol, blocks oxidative phosphorylation, which appears to play essential role in melanoma that has not been well-understood. Elesclomol (Synta Pharmaceuticals, Lexington, MA) was previously shown to have clinical benefit only in patients with normal serum lactate dehydrogenase (LDH), a laboratory test routinely used to assess activity of disease.

For more than 60 years, scientists have known that cancer cells undergo glycolysis, or metabolize glucose, at a much higher rate than normal cells. The observation, called the Warburg effect, demonstrated that the normal energy producing processes in the cell are disrupted in cancer cells, preventing them from using metabolic pathways in the cell's mitochondria (often called the cell's "power plants").

Recently, however, increasing evidence suggests that, in addition to glycolysis, other metabolic pathways may also play a role in cancer, with important therapeutic implications. A promising strategy for targeting cancer cells, while sparing normal cells, is to target these altered metabolic processes with drug therapies. Elesclomol has been shown to trigger cell death in metastatic melanoma cells, primarily by suppressing oxidative phosphorylation - the process that cells use to transform nutrients into energy.

Moschos and his team demonstrated in the lab that metastatic melanoma cells exhibit a higher rate of glycolysis compared to their normal counterpart cells, termed melanocytes, which would be expected due to the Warburg effect.

"But we also found, surprisingly, that these cells have higher rates of oxidative phosphorylation - they are producing energy through more than one pathway, which explains a lot about how the drug works," says Dr. Moschos.

He notes that this drug has an interesting history. In a 600-patient phase III clinical trial conducted almost 4 years ago, Elesclomol had clinical benefit in the subgroup of patients with normal serum LDH. However, the FDA discontinued the trial, because the Elesclomol in combination with another chemotherapeutic drug may have negative effects in patients with high serum LDH, which is associated with poorer patient outcomes in metastatic melanoma. At the time, very little was known about Elesclomol's mechanism of action - blocking oxidative phosphorylation.

"Our inability to show how Elesclomol worked through measurement of biomarkers was the major driver to conduct this laboratory study," said Moschos, whose team took the clinical trial results back to the lab to try to figure out why the drug worked.

"Our results suggest that targeting oxidative phosphorylation in melanoma is a promising strategy for early metastatic disease, before melanoma cells switch their primary metabolic source to glycolysis, as Otto Warburg showed 60 years ago" said Dr. Moschos.

"Second, we were able to demonstrate a mechanism of resistance to Elesclomol, where long-term exposure to the drug leads to the selection of melanoma cells with high levels of glycolysis. This suggests that a two-pronged strategy aimed at blocking both metabolic pathways may be called for."

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Unique Adverse Events With Newly Approved Drug Reviewed By Melanoma Expert

An internationally recognized melanoma researcher at Moffitt Cancer Center and colleagues at the University of Kiel in Germany, including Axel Hauschild, M.D., and Katharina C. Kahler, M.D., have published an article in the Journal of Clinical Oncology that describes immune-related adverse events for patients receiving either tremelimumab or ipilimumab.

Both drugs are anti-CTLA-antibodies with similar mechanisms of action but manufactured by different companies. Ipilimumab is an immunoglobulin G1 with a plasma half-life of 12 to 14 days. Tremelimumab is an immunoglobulin G2 with a plasma half-life of 22 days. Both have been extensively tested in metastatic melanoma, and ipilimumab was approved in 2011 by the U.S. Food and Drug Administration for treating metastatic melanoma and other cancers.

"During treatment with ipilimumab and tremelimumab, a unique set of adverse events may occur called 'immune-related adverse events,' or irAEs," said study lead author Jeffrey S. Weber, M.D., Ph.D., director of Moffitt's Donald A. Adam Comprehensive Melanoma Research Center of Excellence. "These irAEs may include colitis, hepatitis, pancreatitis, lymphadenopathy, neuropathies and nephritis."

According to Weber, appropriate management of these side effects requires the cooperation of a multidisciplinary physician-led team that includes nurse practitioners and infusion nurses. He recommends that specialists, including gastroenterologists, endocrinologists, hepatologists, dermatologists and surgeons, receive education on managing these symptoms. Early recognition of irAEs and initiation of treatment are crucial, the researchers said.

In their review of studies on the drugs' adverse effects, the researchers also found that irAEs correlated with treatment response in some studies. The reduction in tumor burden came in four patterns after week 12 of treatment.

"Anti-CTLA-4 antibodies have shown patterns of anti-tumor response that are different from responses to conventional chemotherapy," explained Weber. "Because responses can occur slowly or be mixed, 12 weeks has been the time to first evaluation with ipilimumab."

Weber and his colleagues also reviewed the new set of response criteria that have been created - immune related response criteria, or irRC - to evaluate disease progression and benefit with immune checkpoint inhibitors such as ipilimumab. The irRC criteria have been compared with modified World Health Organization criteria in studies of patients receiving ipilimumab and can provide valuable information to oncologists as to when to stop or continue treatment with ipilimumab.

"In this study, we provide a detailed description of irAEs and recommendations for practicing oncologists who are managing them along with the unusual kinetics of response associated with ipilimumab therapy," Weber said.

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Human Melanoma Stem Cells Identified

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Cancer stem cells are defined by three abilities: differentiation, self-renewal and their ability to seed a tumor. These stem cells resist chemotherapy and many researchers posit their role in relapse. A University of Colorado Cancer Center study recently published in the journal Stem Cells

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Researchers Find Cause Of Chemotherapy Resistance In Melanoma

Researchers with UC Irvine's Chao Family Comprehensive Cancer Center have identified a major reason why melanoma is largely resistant to chemotherapy.

UCI dermatologist Dr. Anand Ganesan and colleagues found a genetic pathway in melanoma cells that inhibits the cellular mechanism for detecting DNA damage wrought by chemotherapy, thereby building up tolerance to cancer-killing drugs.

Targeting this pathway, comprising the genes RhoJ and Pak1, heralds a new approach to treating the deadly skin cancer, which claims nearly 10,000 U.S. lives each year. Study results appear online in Cancer Research, a journal of the American Association for Cancer Research.

"If we can find a way to turn off the pathway responsible for this resistance, melanoma tumors would suddenly become sensitive to therapies we've been using for the last 20 years," said Ganesan, assistant professor of dermatology and biological chemistry at UCI.

In pursuit of a cause for the chemo tolerance, he and his colleagues performed a genome-wide scan for genes controlling drug resistance in melanoma cells. Their search identified RhoJ, a gene normally involved in blood vessel growth. They saw that in response to drug-induced DNA damage in a melanoma cell, RhoJ activated another gene, Pak1, which initiated a molecular cascade suppressing the cell's ability to sense this damage - and blocking the apoptosis process.

"Normally, such drug-induced DNA damage would result in cell death," Ganesan said. "But this blunting of DNA damage response allows melanoma cells to mutate and proliferate. Being capable of rapid adaptation and change is a hallmark feature of this challenging form of cancer and makes it very difficult to treat."

On the heels of this discovery, he and colleagues have begun exploring methods to inhibit the genes responsible for this DNA damage tolerance. What they come up with could one day supplement chemotherapy treatments for melanoma, Ganesan added.

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Researcher Discovers Homing Device That Attracts Melanoma To The Brain

The process of metastasis, by which cancer cells travel from a tumor site and proliferate at other sites in the body, is a serious threat to cancer patients. According to the National Cancer Institute, most recurrences of cancer are metastases rather than "new" cancers.

Virtually all types of cancer can spread to other parts of the body, including the brain. Once metastatic melanoma cells are entrenched in the brain, patients typically have only a few months to live.

Now Prof. Isaac Witz and his team at Tel Aviv University's Department of Cell Research and Immunology are delving deeper into what attracts metastatic melanoma cells to the brain, and how they survive and prosper in this environment. Their experiments have discovered that melanoma cells produce receptors for two chemokines - a family of small proteins secreted by cells - present in the brain tissue. These receptors may act as a homing device, drawing the cancerous cells to the brain.

"These interactions between the chemokines in the brain and the melanoma cell receptors could be potential targets for new therapies," Prof. Witz says. "With medications that suppress these molecules, you could hope to interfere with this specific migration." Published in the International Journal of Cancer, this research is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

A dangerous attraction

Although metastasis is a well-understood process, researchers are still trying to uncover the underlying mechanisms of why cancer cells begin to migrate in the first place. It is also crucial to understand what allows them to sustain themselves, divide, and propagate once they have arrived at their new location.

To better understand metastacized melanoma cells in the brain, the researchers cultured brain tissue in the lab, then analyzed all of the materials that were expressed by the cells. They identified certain chemokine receptors in brain-metastasizing melanoma cells and corresponding chemokines in the brain tissue which could ultimately be responsible for the cancer cells' being "attracted" to the brain. If a certain chemokine is released from the brain, and the melanoma cells have the appropriate receptors, a chemical attraction will take place where the melanoma cells would be drawn to wherever the chemokine is.

Duplicating nature

The researchers have also developed a method to compare metastatic and non-metastatic cells with identical genetic backgrounds. Though they are derived from the same cancer, some of these cells become metastatic, while others do not. "This is a good way for us to concentrate on the genes that are specific to metastatic cells. Because we have these two types of cellular variants, where only one goes to the brain and metastasizes, it's an important tool" for future research, explains Prof. Witz.

The researchers have found that mice that are inoculated with non-metastatic cells do end up with melanoma cells in the brain, but they are dormant and do not generate overt metastasis. The key is to discover why these originally identical cells differ - why the non-metastatic cells don't develop in the same way.

Understanding the process will help scientists to "duplicate what nature does, and prevent these cells from becoming metastatic," says Prof. Witz. "If there already is metastasis, it is too late - so what we want to do is to prevent development by understanding the mechanism that keeps the non-metastatic cells dormant."

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Drug Trials Seek Combinations Effective For Melanoma

Promising new data from trials aimed at delaying resistance to BRAF inhibitors

Promising new data on drug combinations to treat metastatic melanoma were presented at the ESMO 2012 Congress of the European Society for Medical Oncology in Vienna.

The phase I and II trials focus on combining drugs to slow the development of resistance to drugs that inhibit BRAF, a gene that is mutated in about half of melanomas. Earlier trials with drugs that target BRAF generated excitement for their ability to quickly shrink melanoma tumors in suitable patients. But for many patients the benefits proved short-lived, as the cancer cells develop resistance to the drugs.

"These studies exemplify an important landmark of some tumors, which has emerged from recent laboratory research: the presence of specific mutations, such as the BRAF mutation in metastatic melanoma which exposes an Achilles' heel--MEK in this case," said Prof Yossef Yarden from the Weizmann Institute of Science, Israel. "In-depth understanding of cancers and their mutations is expected to reveal more of these deadly weaknesses in cancer, which we can exploit using new drugs and drug combinations."

Phase II of the BRAF inhibitor dabrafenib alone vs combination with MEK1/2 inhibitor trametinib

Dr Georgina Long from Westmead Hospital and the Melanoma Institute Australia and colleagues report that combining the new drugs dabrafenib and trametinib provided a clinically meaningful improvement in progression-free survival, response rate and duration of response in 162 patients with melanoma that had BRAF V600 mutations.

Patients in the study received either dabrafenib 150mg twice daily; twice-daily dabrafenib plus once-daily 1mg trametinib; or twice daily dabrafenib plus once-daily 2mg trametinib. The combination prolonged progresion free survival over single-drug therapy from 5.8 months to 9.4 months, which represents a 60% improvement. Among patients who received both drugs at the higher dose, 41% had not progressed 12 months after treatment began, compared to 9% in the monotherapy arm of the study.

"The combination therapy of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib prolongs the progression-free survival in patients with V600 BRAF mutation-positive metastatic melanoma compared with dabrafenic monotherapy," Dr Long said. "Importantly, the combination also decreases the rate of the cutaneous toxicities compared with dabrafenib monotherapy, particularly the oncogenic cutaneous toxicity of squamous cell carcinoma."

Phase IB study of vemurafenib in combination with the MEK inhibitor, GDC-0973

A Phase I study in 44 patients shows that the combination of the MEK inhibitor GDC-0973 and vemurafenib can be delivered safely, Dr Rene Gonzalez of the University of Colorado Cancer Center, Denver, and colleagues report.

"BRAF inhibition has resulted in high response rates and improved survival in patients with BRAF mutated melanoma," Dr Gonzalez said. "One of several mechanisms of resistance has been reactivation of the MAPK pathway. Preclinical models show that combined inhibition of BRAF and MEK can delay the acqusition of resistance compared to BRAF inhibitor monotherapy. Inhibition of the pathway downstream from BRAF with the MEK inhibitor GDC-0973 could theoretically overcome or delay this resistance mechanism and improve outcomes."

The study was not designed to evalate efficacy. "While early data in a small number of patients did show tumor reduction, it would be premature to comment on efficacy based on these preliminary results and further research is warranted," Dr Gonzalez said.

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Celgene's Abraxane meets main goal in melanoma trial

Celgene Corp said on Tuesday that in a late-stage clinical trial, patients with metastatic melanoma who took its drug Abraxane lived for a longer period without getting worse than those who received the chemotherapy dacarbazine.

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