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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Photosensitizing Antihypertensive Drugs May Increase Risk Of Lip Cancer

Long-term use of commonly used blood pressure medications that increase sensitivity to sunlight is associated with an increased risk of lip cancer in non-Hispanic whites, according to a Kaiser Permanente study that appears in the current online issue of Archives of Internal Medicine.

Funded by the National Cancer Institute, the study found that photosensitizing antihypertensive drugs such as nifedipine and hydrochlorothiazide were associated with cancer of the epithelial cells known as squamous cells - which are the main part of the outermost layer of the lips and skin.

Researchers compared 712 patients in Northern California with lip cancer to 22,904 people in a control group and found that the risk of squamous cell lip cancer was higher for those with long-term use of photosensitizing blood pressure medications.

"Lip cancer remains rare and an increased risk of developing it is generally outweighed by the benefits of these blood pressure drugs and other photosensitizing medications," said Gary Friedman, MD, an emeritus researcher at the Kaiser Permanente Northern California Division of Research and lead author of the study. "Physicians prescribing photosensitizing drugs should ascertain whether patients are at high risk of lip cancer by virtue of fair skin and long-term sun exposure and discuss lip protection with them. Although not yet confirmed by clinical trials, likely preventive measures are simple: a hat with sufficiently wide brim to shade the lips and lip sunscreens."

The risk of lip cancer appeared to increase with increasing duration of use of these drugs and was not explained by a history of cigarette smoking, also a known risk factor for lip cancer, according to investigators.

Photosensitizing drugs are believed to absorb energy from ultraviolet and/or visible light, causing the release of electrons. This leads to generation of reactive oxygen intermediates and free radicals which damage DNA and other components of skin and lip cells and produce an inflammatory response, Friedman said.

Researchers ascertained prescriptions dispensed and cancer occurrence from August 1994 to February 2008. They identified 712 patients with lip cancer and 22,904 controls in the susceptible group of non-Hispanic whites. Researchers determined their use at least two years before diagnosis or control index date of the commonly prescribed diuretics, HCTZ and HCTZ combined with triamterene (HCTZ/TR), the angiotensin-converting enzyme inhibitor lisinopril, the calcium channel blocker nifedipine, and the beta adrenergic blocker atenolol, the only non-photosensitizer studied. Non- photosensitizing atenolol, when used alone, was not associated with increased risk. Findings for lisinopril were not as clear-cut as those for HCTZ, HCTZ/TR and nifedipine.

Researchers analyzed use of each drug both exclusively and regardless of use of others and focused on duration of use. The analysis controlled for smoking.

Researchers were not able to include basal cell and squamous cell cancers of the skin in this study because these diagnoses have not been recorded in their cancer registry. Also, researchers were not able to adjust for sun exposure, the most important lip cancer risk factor, along with relative lack of pigmentation of the lips. Risk of developing melanoma was not associated with these drugs. This form of skin cancer has been more strongly associated with intermittent sun exposures, especially those producing sunburn, than with chronic sun exposure, so timing of use of photosensitizing drugs could be an important consideration, explain the researchers.

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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 .

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Gene Therapy Drugs Topically Delivered Via Commercial Moisturizers For Skin Disease Treatment

"Getting under your skin" takes on a brave new meaning thanks to Northwestern University research that could transform gene regulation.

A team led by a physician-scientist and a chemist - from the fields of dermatology and nanotechnology - is the first to demonstrate the use of commercial moisturizers to deliver gene regulation technology that has great potential for life-saving therapies for skin cancers.

The topical delivery of gene regulation technology to cells deep in the skin is extremely difficult because of the formidable defenses skin provides for the body. The Northwestern approach takes advantage of drugs consisting of novel spherical arrangements of nucleic acids. These structures, each about 1,000 times smaller than the diameter of a human hair, have the unique ability to recruit and bind to natural proteins that allow them to traverse the skin and enter cells.

Applied directly to the skin, the drug penetrates all of the skin's layers and can selectively target disease-causing genes while sparing normal genes. Once in cells, the drug simply flips the switch of the troublesome genes to "off."

A detailed study of a method that could dramatically redefine the field of gene regulation will be published online during the week of July 2 by the Proceedings of the National Academy of Sciences (PNAS).

Early targets of the novel treatment are melanoma and squamous cell carcinoma (two of the most common types of skin cancer), the common inflammatory skin disorder psoriasis, diabetic wound healing and a rare genetic skin disorder that has no effective treatment (epidermolytic ichthyosis). Other targets could even include wrinkles that come with aging skin.

"The technology developed by my collaborator Chad Mirkin and his lab is incredibly exciting because it can break through the skin barrier," said co-senior author Amy S. Paller, M.D., the Walter J. Hamlin Professor, chair of dermatology and professor of pediatrics at Northwestern University Feinberg School of Medicine. She also is director of Northwestern's Skin Disease Research Center.

"This allows us to treat a skin problem precisely where it is manifesting - on the skin," she said. "We can target our therapy to the drivers of disease, at a level so minute that it can distinguish mutant genes from normal genes. Risks are minimized, and side effects have not been seen to date in our human skin and mouse models."

A co-senior author of the paper, Mirkin is the George B. Rathmann Professor of Chemistry in the Weinberg College of Arts and Sciences and professor of medicine, chemical and biological engineering, biomedical engineering and materials science and engineering. He also is the director of Northwestern's International Institute for Nanotechnology.

Mirkin first developed the nanostructure platform used in this study in 1996 at Northwestern, and the FDA-cleared technology now is the basis of powerful commercialized medical diagnostic tools. This, however, is the first realization that the nanostructures naturally enter skin and that they can deliver a large payload of therapeutics.

"The field of medicine needs new constructs and strategies for treating disease," Mirkin said. "Many of the ways we treat disease are based on old methods and materials. Nanotechnology offers the ability to very rapidly create new structures with properties that are very different from conventional forms of matter. This collaborative study is a case in point."

The key is the nanostructure's spherical shape and nucleic acid density. Normal (linear) nucleic acids cannot get into cells, but these spherical nucleic acids can. Small interfering RNA (siRNA) surrounds a gold nanoparticle like a shell; the nucleic acids are highly oriented, densely packed and form a tiny sphere. The RNA's sequence is programmed to target the disease-causing gene.

"We now can go after a whole new set of diseases," Mirkin said. "Thanks to the Human Genome Project and all of the genomics research over the last two decades, we have an enormous number of known targets. And we can use the same tool for each, the spherical nucleic acid. We simply change the sequence to match the target gene. That's the power of gene regulation technology."

The nanostructures were developed in Mirkin's lab on the Evanston campus and then combined with a commercial moisturizer. Next, down in Paller's Chicago lab, the researchers applied the therapeutic ointment to the skin of mice and to human epidermis. The nanostructures were designed to target epidermal growth factor receptor (EGFR), a biomarker associated with a number of cancers.

In both cases, the drug broke through the epidermal layer and penetrated the skin very deeply, with cells taking up 100 percent of the nanostructures. They selectively knocked down the EGFR gene, decreasing the production of the problem proteins.

After a month of continued application of the ointment, there was no evidence of side effects, inappropriate triggering of the immune system or accumulation of the particles in organs. The treatment is skin specific and doesn't interfere with other cells.

Interdisciplinary research is a hallmark of Northwestern. Paller and Mirkin said their work highlights the power of physician-scientists and scientists and engineers from other fields coming together to address a difficult medical problem.

"This all happened because of our world-class presence in both cancer nanotechnology and skin disease research," Paller said. "In putting together the Skin Disease Research Center proposal, I reached out to Chad to see if his nanostructures might be applied to skin disease. We initially worked together through a pilot project of the center, and now the rest is history."

Northwestern has one of nine Centers of Cancer Nanotechnology Excellence funded by the National Cancer Institute and one of six Skin Disease Research Centers funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

"This study is a landmark achievement in the area of gene regulation - I believe our work has a chance to positively and irreversibly change the field," Mirkin said. "The skin is a very tough barrier to go through, which is why this effective gene knockdown has not been accomplished before. The power and elegance of this system are in its simplicity."

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Who is at Risk For Skin Cancer and How Do You Get Skin Cancer?

Unfortunately the exact cause of skin cancer is not known at this time, but it is known that the number of reported cases of the disease has been steadily increasing since the 1980's. As with many diseases, there are many risk factors that are shown to be associated with Skin Cancer, such as exposure to UVB, UVA or to the sun, or exposure to different compounds and chemicals can trigger it.

Heredity also plays a part in your risk of getting this disease.For a while now, scientist have been trying to figure out the real reasons that people with Celtic Heritage are more at risk of developing skin cancer from the sun. Really, though, the sun can damage any skin type, and all skin types are susceptible to getting cancer. If you are of Celtic heritage (England, Scotland, Wales and Ireland) then you should be double careful in the sun.

Of course, you can't do much about genetic diseases or your genes, but you can take obvious steps so that you will not catch skin cancer.

The number one preventiive measure for Skin Cancer? Stay out of the sun. If you have heard it once, you have heard it a thousand times, "cover up" but did you that exposure to the sun is the biggest risk factor for you for developing skin cancer? And with minor precautions, most people will avoid getting skin cancer?

You must make a conscious effort to limit the amount of radiation to which your skin will be exposed to. Your number one priority is th reduce the amount of UV rays that hit your body. and limit all you can the amount of unprotected radiation your skin absorbs
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Of course, you can stay out in the sun if you are protected, A good way to get protection is to Cover up, protect your eyes with good sunglasses, put the highest SPF you can find aon all exposed parts of your skin, and ask your doctor or pharmacist about any drugs you are taking tha could change your resistance to the UV rays.