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Cancer, Dermatology, Research, Science

Common skin cancer evades treatment via specific mutations

Common skin cancer evades treatment via specific mutations

Anthony OroBasal cell carcinoma is the most common type of skin cancer. It is also one of the most treatable. But people with advanced cases of the disease often experience only a temporary response to the drug vismodegib, and their tumors recur within a few months as the cancer becomes resistant to the drug.

Now dermatologists Anthony Oro, MD, PhD; Jean Tang, MD, PhD; and Anne Chang, MD, have identified the specific mutations involved in the development of vismodegib resistance, and identified another treatment that may be successful even on vismodegib resistant tumors. They’ve recently published their findings in Cancer Cell (with an accompanying companion paper and commentary).

From our release:

Approximately 2 million new cases of basal cell carcinoma are diagnosed each year in the United States, making it the most common cancer in the country. About half of patients with advanced basal cell carcinomas will respond to vismodegib, which belongs to a class of drug compounds called Smoothened inhibitors. About 20 percent of these responders will go on to quickly develop resistance to the drug.

Basal cell carcinomas are uniquely dependent on the inappropriate activation of a cellular signaling cascade called the Hedgehog pathway. Blocking signaling along this pathway will stop the growth and spread of the cancer cells. The Hedgehog pathway plays a critical role in normal development. It’s also been found to be abnormally active in many other cancers, including pancreatic, colon, lung and breast cancers, as well as in a type of brain cancer called medulloblastoma.

The researchers found two classes of mutations in the Smoothened gene that inhibit vismodegib’s effectiveness by keeping the Smoothened protein active. Treating the cells with inhibitors that target a portion of the pathway downstream of Smoothened blocked the activation of the pathway even in cells with the mutations. These inhibitors, called Gli antagonists, could be an effective way to treat vismodegib-resistant tumors, the researchers said.

As Oro told me, “This research sheds new light on mechanisms of how tumors evolve to develop drug resistance, and has already helped us with personalized cancer genetics and therapy for our patients. It is now possible for us to identify those people who may benefit from a combination therapy even before they begin treatment.”

Previously: Studies show new drug may treat and prevent basal cell carcinoma, New skin cancer target identified by Stanford researchers and Another blow to the Hedgehog pathway? New hope for patients with drug-resistant cancers
Photo of Anthony Oro by Steve Fisch

Aging, Chronic Disease, Dermatology, Stanford News

Patching up diabetic ulcers

Patching up diabetic ulcers

Like the more than 29 million people in the U.S, my mother has diabetes. Her eldest sister and my maternal grandmother both died of complications of the disease, and her one surviving sister is coping with complications that will probably claim her life in a few years. I’ve got gestational diabetes (a temporary version of the disease that occurs during pregnancy), and due to that and my family history I’m likely to develop type-2 diabetes down the line, also. So I’m always very interested in hearing about research advances related to the disease.

One such advance: As reported today in the the Proceedings of the National Academy of Sciences, Stanford researchers have developed a new skin patch that delivers a drug to aid the healing of diabetic ulcers. Diabetic ulcers (or open wounds) are one of the most common complications of the disease, with an estimated 15 percent of diabetics developing them. They often occur on the feet and are the leading cause of diabetes-related amputations. The high level of blood sugar in diabetics’ blood impairs the body’s ability to grow new blood vessels, which slows down healing of the ulcers.

Deferoxamine, or DFO, is an FDA-approved drug that can help correct this problem, but it would be toxic if taken for as long as diabetics need it to heal their ulcers. So Stanford researchers developed a local application via a skin patch. In a press release, study authors Dominik Duscher, MD, a plastic and reconstructive surgery postdoctoral fellow, and surgeon Geoffrey Gurtner, MD, talked about the findings of their work in animal models:

Not only did the wounds in the mice heal more quickly, Duscher said, but the quality of the new skin was even better than the original. The researchers also used the DFO matrix on a mouse with diabetes to see if it would prevent ulcer formation — and it did. “We were very excited by the results,” Duscher said, “and we hope to start clinical trials soon to test this in humans.”

“This same technology is also effective in preventing pressure ulcers, which are a major source of morbidity and mortality in patients with neurologic injury or the elderly,” said Gurtner, who is also the Johnson & Johnson Distinguished Professor in Surgery II. “The actor Christopher Reeve actually died from a pressure ulcer and not his spinal cord injury, which really emphasizes the extremely limited therapeutic options for these patients.”

Luckily my mother hasn’t had to deal with diabetic ulcers, though when she gets small cuts or chaps on her skin, they do take forever to heal, so she’s super-vigilant about avoiding them. The possibility of preventing more serious ulcers with this patch is a development I’ll be following closely.

Previously: A primer on preventing or delaying type 2 diabetes and New medicine? A look at advances in wound healing

Aging, Dermatology, Public Health, Videos

Don’t skip the sunscreen in wintertime

Don’t skip the sunscreen in wintertime

When you’re spending time outdoors during the wintertime, it’s easy to justify skipping the sunscreen when the sun isn’t beating down on you mercilessly and you’re bundled up instead of sporting a swimsuit. But UV rays from the sun can penetrate clouds and snow can reflect sun onto your face, hands and any other exposed skin. So it’s important to remember to take sun safety precautions even on cold or overcast days, too.

This  Stanford Health Care video featuring dermatologist Justin Ko, MD, MBA, includes important tips for preventing skin cancer year-round. As I, like many others, prepare for a family trip to Tahoe to take advantage of the recent snow, Ko’s reminder about sun safety habits during the winter comes at a good time. For example, I suspect I’ve been skimping on sunscreen: Ko says you need a shot glass-full to completely cover your body. If you’re using a spray-on sunscreen, you need to spray for a full 60 seconds.

Watch the video to learn more information about how to identify possible cancerous moles and preventing high-risk exposures, like tanning beds.

Previously: Skin cancer linked to UV-caused mutation in new oncogene, say Stanford researchers, Humble anti-fungal pill appears to have a noble side-effect: treating skin cancer, Skin cancer images help people check skin more often and effectively, and The importance of sunscreen in preventing skin cancer

Biomed Bites, Cancer, Dermatology, Genetics, Research, Videos

Spotting broken DNA – in the DNA fix-it shop

Spotting broken DNA - in the DNA fix-it shop

It’s Thursday. And here’s this week’s Biomed Bites, a weekly feature that highlights some of Stanford’s most innovative research and introduces Scope readers to innovators in a variety of disciplines.

Neon green streaks across the screen. The phrases “End mismatched ligation” and “Repair of DNA double-strand breaks” flash at me. Did I stumble across an online, genetic fix-it shop? Sort of –  in that Stanford biochemist Gilbert Chu, MD, PhD, studies broken DNA and has a website to match.

Chu describes his research in the video above: “We started out in the lab trying to understand and recognize DNA that’s been damaged by ultraviolet radiation, which causes skin cancer. This led to the discovery of a protein that turned out to be missing in patients with a very rare disease called xeroderma pigmentosum.”

XP afflicts about 1 in 1,000,000 people in the United States. Without the protein Chu mentioned, mutations and damage accumulates in sufferers DNA, causes cancers and extreme sensitivity to the sun.

Chu’s team has also developed methods that allow other researchers to examine the expression of genes across an entire genome and to determine which cancer patients might be harmed by treatment with ionizing radiation.

“The reason I got interested in this research is that as a member of the Department of Medicine, I am an oncologist and I’m very interested in trying to help cancer patients,” Chu said.

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving forward biomedical innovation here.

Previously: Skin cancer linked to UV-caused mutation in new oncogene, say Stanford researchers, Radiation therapy may attact circulating cancer cells, according to new Stanford study and How ultraviolet radiation changes the protective functions of human skin

Dermatology, Research, Science, Stanford News, Stem Cells

The politics of destruction: Short-lived RNA helps stem cells turn on a dime

The politics of destruction: Short-lived RNA helps stem cells turn on a dime

Many stem cells live a life of monotony, biding their time until they’re needed to repair tissue damage or propel the growth of a developing embryo. But when the time is right, they must spring into action without hesitation. Like Clark Kent in a phone booth, they fling aside their former identity to become the needed skin, muscle, bone or other cell types.

Now researchers at Stanford, Harvard and the University of California-Los Angeles have learned that embryonic stem cells in mice and humans chemically tag RNA messages encoding key stem-cell genes. The tags tell the cell not to let the messages linger, but to degrade them quickly. Getting rid of those messages allows the cells to respond more nimbly to their new marching orders. As dermatology professor Howard Chang, MD, PhD, explained to me in an email:

Until now, we’ve not fully understood how RNA messages within the cell dissipate. In many cases, it was thought to be somewhat random. This research shows that embryonic stem cells actively tag RNA messages that they may later need to forget. In the absence of this mechanism, the stem cells are never able to forget they are stem cells. They are stuck and cannot become brain, heart or gut, for example.

Chang, who is a Howard Hughes Medical Institute investigator and a member of the Stanford Cancer Institute, is a co-senior author of a paper describing the research, which was published today in Cell Stem Cell. He shares senior authorship with Yi Xing, PhD, an associate professor of microbiology, immunology and molecular genetics at UCLA, and Cosmas Giallourakis, MD, an assistant professor of medicine at Harvard. Lead authorship is shared by postdoctoral scholars Pedro Batista, PhD, of Stanford, and Jinkai Wang, PhD, of UCLA; and by senior research fellow Benoit Molinie, PhD, of Harvard.

Messenger RNAs are used to convey information from the genes in a cell’s nucleus to protein-making factories in the cytoplasm. They carry the instructions necessary to assemble the hundreds of thousands of individual proteins that do the work of the cell. When, where and how long each protein is made is a carefully orchestrated process that controls the fate of the cell. For example, embryonic stem cells, which can become any cell in the body, maintain their “stemness” through the ongoing production of proteins known to confer pluripotency, a term used to describe how these cells can become any cell in the body.

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Dermatology, Stanford News

From the newsstands to exam rooms: My chat with Stanford dermatologist Laurel Geraghty

From the newsstands to exam rooms: My chat with Stanford dermatologist Laurel Geraghty

Laurel G

First thing to know about Laurel Geraghty, MD: She can geek out with the best of them. Don’t be fooled by her fashionable clothes or her graceful manner: Geraghty can riff on mole types and describe the symptoms of psoriasis with passion. Geraghty had to suppress her science savvy as an editor at Glamour magazine, although there were plenty of other perks – including weekend jaunts to Las Vegas or the Caribbean and “working” celebrity-packed Manhattan fashion shows.

Now, she’s a second-year dermatology resident at Stanford, married and the mother of a 3-year-old and a 5-year-old. In a recent interview, I chatted with Geraghty about her career change, future plans, skin cancer, acne, and even tattoos. About the latter, she told me:

Tattoos can be safe if done by a reputable professional using new and sterilized equipment. There is a risk of transmitting communicable diseases, including hepatitis, if needles are re-used or are not sterilized. There are a variety of different itchy, red, skin reactions that people can get from tattoo ink, especially red ink, which contains mercury sulfide, and that can be hard to deal with when it happens.

But tattoos don’t have to be forever. Skin lasers can break down tattoo ink within the skin, though the treatments can be painful and expensive. Some say the laser removal is more painful than getting the tattoo. Red tattoo ink is by far the most difficult color to remove and has the highest risk of causing a skin reaction, so avoiding red may be a good choice

And for Geraghty herself? No tattoos. “When I went away to college, my mother told me she would not pay my tuition if I ever came home with a tattoo. So I never did.”

Previously: Skin cancer linked to UV-caused mutation in new oncogene, say Stanford researchers, Ask Stanford Med: A focus on on scleroderma, New study: Genes may affect skin youthfulness
Photo by Norbert von der Groeben

Cancer, Dermatology, Research, Science, Stanford News

Skin cancer linked to UV-caused mutation in new oncogene, say Stanford researchers

Skin cancer linked to UV-caused mutation in new oncogene, say Stanford researchers

sunbathingA link between the UV rays in sunshine and the development of skin cancer is nothing new. We’ve all (hopefully) known about the damage sun exposure can wreak on the DNA of unprotected cells. But it’s not been known exactly how it causes cancers like squamous cell carcinoma or melanoma. Now, Stanford dermatologists Paul Khavari, MD, PhD and Carolyn Lee, MD, PhD have identified a UV-induced mutation in a protein active during cell division as the likely driver in tens of thousands of cases of skin cancer. Although the protein hasn’t been previously associated with cancer, the work of Khavari and Lee suggests it may actually be the most-commonly mutated oncogene in humans.

Their work was published yesterday in Nature Genetics. As we describe in our release:

Lee and Khavari made the discovery while investigating the genetic causes of cutaneous squamous cell carcinoma. They compared the DNA sequences of genes from the tumor cells with those of normal skin and looked for mutations that occurred only in the tumors. They found 336 candidate genes for further study, including some familiar culprits. The top two most commonly mutated genes were CDKN2A and TP53, which were already known to be associated with squamous cell carcinoma.

The third most commonly mutated gene, KNSTRN, was a surprise. It encodes a protein that helps to form the kinetochore — a structure that serves as a kind of handle used to pull pairs of newly replicated chromosomes to either end of the cell during cell division. Sequestering the DNA at either end of the cell allows the cell to split along the middle to form two daughter cells, each with the proper complement of chromosomes.

If the chromosomes don’t separate correctly, the daughter cells will have abnormal amounts of DNA. These cells with extra or missing chromosomes are known as aneuploid, and they are often severely dysfunctional. They tend to misread cellular cues and to behave erratically. Aneuploidy is a critical early step toward the development of many types of cancer.

The mutation in KNSTRN is a type known to be specifically associated with exposure to UV light. Khavari and Lee found the mutation in pre-cancerous skin samples from patients, but not in any samples of normal skin. This suggests the mutation occurs early, and may be the driving force, in the development of skin cancers. As Khavari, chair of the Department of Dermatology and dermatology service chief at the Veterans Affairs Palo Alto Health Care System, explained in the release:

Mutations at this UV hotspot are not found in any of the other cancers we investigated. They occur only in skin cancers… Essentially, one ultraviolet-mediated mutation in this region promotes aneuploidy and subsequent tumorigenesis. It is critical to protect the skin from the sun.

Previously: Master regulator for skin development identified by Stanford researchers and My pet tumor – Stanford researchers grow 3D tumor in lab from normal cells
Photo by Michael Coghlin

Cancer, Dermatology, In the News, Public Safety, Research, Stanford News

A closer look at new research showing disproportionate rates of melanoma in Marin County

Last week, Cancer Prevention Institute of California/Stanford Cancer Institute researcher Christine Clarke, PhD, shared results of a new report (.pdf) showing that a county in California has higher numbers of melanoma skin cancer than the rest of the state. On this morning’s Forum Clarke joined two other guests, including Stanford dermatologist Susan Swetter, MD, director of the Pigmented Lesion and Melanoma Program at the Stanford Cancer Institute, to discuss the research and to offer skin safety and screening tips for the summer.

It’s worth a listen – especially if you live in the county just north of San Francisco.

Previously: Melanoma rates exceed rates of lung cancer in some areasWorking to protect athletes from sun dangers, As summer heats up take steps to protect your skin, Stanford study: Young men more likely to succumb to melanoma, New research shows aspirin may cut melanoma risk and Working to prevent melanoma

Cancer, Dermatology, Public Health, Research, Stanford News

Melanoma rates exceed rates of lung cancer in some areas

Melanoma rates exceed rates of lung cancer in some areas


Californians, step away from the beach and grab a hat and sunscreen. Our team of researchers from the Cancer Prevention Institute of California/Stanford Cancer Institute released a new report (.pdf) this week documenting the rapidly growing burden of melanoma in Marin County, California. This small, homogenous (and wealthy) county just over the Golden Gate Bridge from San Francisco has been the focus of cancer studies before, as high rates of breast cancer were first reported there in the late 1990’s (rates declined there as in the rest of the country in 2003 when women stopped taking hormone therapy).

Our most recent cancer registry data show that rates of malignant melanomas in Marin County are 43 percent higher than the rest of the San Francisco Bay Area and 60 percent higher than other parts of California among non-Hispanic whites, who because of their fairer skin tones are diagnosed with melanoma at 20-30 times the rate of other ethnic groups. Also of concern is that the death rate due to melanoma is 18 percent higher in Marin whites than whites in other regions, a significant difference not seen before. Most of the elevated rates are limited to persons over age 65, especially men.

The Bay Area news media reported our findings as front-page news. Most coverage centered on the question of why the rates are so much higher in Marin County. Our best guess is that the higher average socioeconomic status of its residents corresponds to a higher proportion of people with the known risk factors for melanoma: fair complexion (pale skin, blonde or red hair, blue or green eyes) and a history of “intense intermittent” sun exposure over their lifetimes (exposure in big doses like you might get on a beach vacation in the winter).

However, it is also likely that better access to health care and skin screening has resulted in earlier diagnosis, a notion confirmed by the higher proportion of melanomas in Marin County caught when thin and more curable. Local dermatologists reacted to the statistics with some surprise, but didn’t change their standing advice regarding skin cancer prevention: talk to your doctor about skin screening and stay sun safe by wearing hats, long-sleeves and broad-spectrum sunscreen during outdoor activities.

One statistic mostly overlooked by the media was our finding that melanoma is now the second most common cancer diagnosed in men living in Marin County, as rates have surpassed those for lung cancer. This pattern is very different than that observed for whites in the US and world, for whom prostate or lung are first, and melanoma is ranked much lower. With one of the most successful public tobacco control efforts in the world, most populations in California have seen rapid declines in the incidence of smoking-related cancers of the lung and respiratory system.

Unfortunately, it seems for older white persons in Marin County (as well as parts of Utah and Hawaii, where smoking rates have also declined), melanoma and skin cancers represent a major—and relentlessly growing—cancer threat. Perhaps putting down the cigarettes was accompanied by more time at the pool or beach without adequate sun protection. Although California was the first state to ban tanning bed use by minors, we should look to Australia and other countries also battling rising skin cancer rates for innovative new policies and strategies for encouraging safe sun exposure in our at-risk communities.

Christina A. Clarke, PhD, is a Research Scientist and Scientific Communications Advisor for the Cancer Prevention Institute of California, and a member of the Stanford Cancer Institute.

Previously: Beat the heat – and protect your skin from the sun, Working to protect athletes from sun dangers, As summer heats up take steps to protect your skin, Stanford study: Young men more likely to succumb to melanoma and How ultraviolet radiation changes the protective functions of human skin
Photo by stefan klocek

Dermatology, In the News, Public Health

Don't feed the bedbugs: Tips for travelers

hotel bedHere’s something to think about before heading out for a summer weekend adventure: bedbugs. They still exist. And a new article from Wired offers a few practical tips to spot and avoid bringing home unwelcome guests.

From the piece (weigh the pros and cons of viewing “itch-inducing photos” before clicking the link below):

Tools you will need: A flashlight, or the flashlight feature of your phone. Use your phone to take photos of anything suspicious.

What you are looking for: Bedbugs hang out near their food source–you. After feeding, bed bugs poop, creating tell-tale brown stains of your clotted blood. You typically won’t see bugs — they are fairly tiny and can scurry quickly — but you will see these stains. You can find many itch-inducing photos here to help you know what to look for.

Author Gwen Pearson reminds readers that luggage is a popular mode of transportation for bedbugs, so stow your bags in the hotel room bathtub until the coast is clear. Check everything in sight. Sleep tight! And if you’ve made it through the night, check your sheets in the morning.

Previously: A (mostly bleak) bedbug updateWhy we worry about bedbugs and Image of the week: Bedbug
Photo by Simon Davison

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