skin cancer Archives - Sanford Burnham Prebys

Tag: skin cancer

Institute News

Perkins Fellow Trains Immune System Against Melanoma

AuthorGreg Calhoun
Date

May 15, 2024

Sreeja Roy, PhD, headshot in the lab

Sanford Burnham Prebys scientist works on new methods to boost the body’s natural defenses against melanoma and other cancers

When she was growing up in India, Sreeja Roy, PhD, looked up to her father as he applied his scientific knowledge to care for the patients in his medical practice.

“He was my inspiration,” says Roy. “I found that I was particularly good at biology, and I liked learning about the mechanisms of how things work. Along the way, I realized I didn’t want to be a medical doctor and began focusing on biomedical research—and I fell in love with it.”

After earning her undergraduate degree in biotechnology from The Australian National University in Canberra, Roy obtained a master’s degree in infection biology from the Universität zu Lübeck in Germany. She returned to The Australian National University for her doctoral degree in immunology with an emphasis on viral vector-based vaccine immunology. After completing graduate school, Roy worked as a postdoctoral researcher at Albany Medical Center in New York before joining Sanford Burnham Prebys in September 2021 as a postdoctoral associate in the Immunity and Pathogenesis Program.

“I had been working on basic science in Albany,” notes Roy. “I really wanted to do translational research so I could work on things that would benefit people much sooner. That is why I chose to move to Sanford Burnham Prebys and focus on cancer immunotherapy.”

Roy’s background in immunology prepared her to enter the emerging field of cancer immunotherapy. This discipline involves developing treatments that enhance the human body’s innate immune response to better locate and dispose of cancer cells. She learned about an opportunity to support her interest in translational immunotherapy through the Jean Perkins Foundation Fellowship.

Roy received one of two prestigious fellowships designed to support postdoctoral researchers in the lab of Carl Ware, PhD, director of the Infectious and Inflammatory Diseases Center and professor in the Immunity and Pathogenesis Program.

“The Jean Perkins Foundation Fellowship has been fantastic,” says Roy. “I can work without the pressure of writing an academic grant, which allows me to focus on the science and be more productive.”

Roy’s project at the Ware lab involves making immunotherapies more effective in treating melanoma, the deadliest form of skin cancer.

“Unfortunately, some tumors never respond to immunotherapy treatments,” explains Roy. “Also, tumors can initially begin to shrink before becoming resistant to a treatment.”

Under Ware’s direction, Roy is testing ways to enhance existing immunotherapies through the lymphotoxin-β receptor, which is found on some types of immune cells.

“When the immune system encounters a foreign substance that may cause an infection, a sample of the invader can be shuttled to the lymph nodes as a way of learning about the threat and generating a better immune response,” explains Roy. “Depending on which tissues are being infected, the lymph nodes cannot always be involved, so an active lymphotoxin-β receptor is able to approximate their effect by organizing immune cells in something akin to training centers so that a better attack can be launched.”

Roy and the Ware lab are developing ways to take advantage of the lymphotoxin-β receptor’s ability to recruit and train immune cells as an approach to making immunotherapies more effective.

“If I can target the lymphotoxin-β receptor signaling against tumors, does that enhance the anti-tumor immunity?” asks Roy. “Do the tumors become more responsive to the treatments now? That is what we’re trying to find out.”

With the help of the Jean Perkins Foundation Fellowship, Roy is determined to continue developing her translational science expertise and find ways to improve the effectiveness of immunotherapies for melanoma and other cancers.

“We’ve made quite a bit of progress,” says Roy. “I look forward to sharing our results and seeing how this project advances from the bench to the bedside.”

Institute News

Solar power gone awry

AuthorZe’ev Ronai, PhD
Date

July 29, 2019

towel on beach - sun exposure - melenoma

Are you enjoying the summer? Out grilling, swimming and hiking? Beware: those sunny days may come with a cost. 

When the sun’s rays touch your skin, they don’t stop there. Ultraviolet (UV) light enters your cells, and photons—tiny particles of light—landing on the proteins and DNA in your cells. With just the right amount of activation energy, proteins change their shape and function, and your DNA becomes damaged, or as we say—mutated. Under normal circumstances, cells use special proteins to repair mutated DNA, but when the repair proteins are damaged, DNA mutations become permanent.

Certain DNA segments called genes are more vulnerable to mutations than others. The BRAF gene, which normally makes a protein that controls cell growth, is mutated in more than 50% of melanomas—the most dangerous type of skin cancer. Melanoma appears when BRAF mutations crop up with other mutations in the same skin cell. For patients with these tumors, drugs that target BRAF and related proteins are often successful at slowing or stopping melanoma growth—but only for a while.

Unfortunately, patients who initially respond to such targeted therapy often relapse. Some patients relapse because their tumors generate a new mutation, making it resistant to the drug.  Overall, it may be only a small fraction of cells within the original tumor that develop resistance. So although 99.5% of the cancer cells in a tumor may have a mutated BRAF gene, the other 0.5% can harbor different mutations that either evolved during therapy or were present in the first place, but didn’t drive the initial tumor. For these patients, the bulk of BRAF mutant cancer cells are killed with targeted therapy, but another melanoma can evolve from the remaining 0.5%. This is why combination therapy, where drugs aim for multiple targets, are important.

But targeting every single mutation in a tumor may not be feasible. There will always be a fraction of cells with a different mutation that evolves, making patients vulnerable to a relapse. This is where attacking the tumor from another angle comes into play.  

Checkpoint immunotherapies—which have revolutionized the treatment of melanoma—attack tumors independent of their mutational makeup. They work by loosening the brakes of the immune system—brakes that normally prevent immune cells from attacking our own self. Tumors are very good at hiding from the immune system, but with the brakes released, tumors become exposed and are successfully attacked by the immune system, irrespective of their mutational makeup. 

But not everyone responds to immunotherapy—and we don’t yet know why. Is it the tumor? Is it the patient’s immune system? There is even evidence that the gut microbiome plays a role. Once we understand why some patients respond and or stop responding to immunotherapy, we can improve selection of patients for therapy, the effectiveness of these treatments and the possible combinations that work best. 

So where is skin cancer therapy headed? A combination of checkpoint immunotherapy with targeted therapies, as well as some new tricks we are learning, such as coaching tumor cells to be better recognized by the immune system, are moving the needle.

In my lab at Sanford Burnham Prebys we are dissecting the cell signals that drive cancer. Our studies are guided by data derived from patients’ tumors, coupled with advanced bioinformatics. We seek to understand how physiological processes are modified as cancer develops and how they can be exploited for cancer therapy. For example, we recently demonstrated a connection between the composition of the gut microbiome and the response to immunotherapy, establishing new paradigms, but raising important new questions. Can we better predict who will respond to immunotherapy? Can we enhance the response to immunotherapy by manipulating the gut microbiome? Can we make tumors that don’t initially respond start responding to immunotherapy? The bar is always raised, as one discovery opens so many new avenues to explore and advance our understanding, aspects that members of my lab are working hard on to answer.  

Yes—we are making progress. But preventing the initial sun exposure by using protective gear and sunscreens is needed now as much as ever.

Ze’ev Ronai, PhD, professor in Sanford Burnham Prebys’ Tumor Initiation and Maintenance Program, is a world-renowned cancer research expert and recipient of the Lifetime Achievement Award from the Society of Melanoma Research. The award recognizes his major and impactful contributions to melanoma research over the course of his career.

Institute News

Skincare safety in the sunshine state

AuthorDeborah Robison
Date

June 14, 2017

happy retired senior couple sitting on the beach holding hands and enjoying summer vacations

Current melanoma incidence in older white men (65 and older) is about five times that of the general population.

Before age 50, the incidence of melanoma in women is higher than men but by age 65, melanoma incidence rates are twice as high in men. By ages 80 and older, the rate is three times higher in men than women of the same age.

Why are older men highly susceptible to melanoma? Over a lifetime, men spend more time outdoors accumulating ultraviolet exposure and are less diligent about wearing sun protection. They may also be less likely to perform skin self-exams and have physician check-ups. Also, research shows that melanoma may advance differently in men than women and that men’s tumors may grow more rapidly.

Prevention through early detection of melanoma is especially important in reducing mortality in high-risk groups – older men being the largest high-risk group of all. Part of the reason for the high mortality rate is the difficulty in distinguishing benign skin moles from malignant melanomas.

Ranjan Perera, PhD, associate professor at Sanford Burnham Prebys Medical Discovery Institute at Lake Nona pinpoints the problem:  “Current tests are inconclusive at least 15 percent of the time, requiring repeated biopsies.” His lab is researching new biomarkers that could provide clinicians with earlier and more reliable diagnostics for melanoma. His approach focuses on micro-RNAs (non-protein coding genetic material) that may contribute to the formation and progression of melanoma.  

Research suggests that the majority of melanomas – nearly 90 percent – are considered to be preventable, so following guidelines to limit exposure to damaging UV (ultraviolet) sunlight is the first line of defense.  Severe sunburns, especially during childhood, increase your risk of developing melanoma and other skin cancer. Just one blistering sunburn can double your chances of developing melanoma later in life.

Perera and collaborator Michael Steppie, MD, assistant professor of dermatology at Florida State University, are investigating various skin disorders. Dr. Steppie, a noted Florida dermatologist, offers these sun safety suggestions for people who live in warm weather regions.  

Follow these tips to reduce your risk of developing melanoma.

  • Remember that all skin types can develop skin cancer including people who tan easily or have naturally dark skin.
  • Generously apply sunscreen to all exposed skin — even on cloudy days — year-round.
  • Use a sunscreen that provides broad spectrum protection from both UVA and UVB rays and has a sun protection factor (SPF) of at least 30 SPF.
  • Apply approximately one ounce of sunscreen (a shot-glassful) 15 minutes before sun exposure.
  • Reapply sunscreen every two hours and after swimming or sweating.
  • Keep newborns out of the sun. Sunscreens should be used on babies over the age of six months.
  • Wear a long-sleeved shirt, pants, a wide-brimmed hat (preferably sun-protective clothing, accessories and swimwear carrying a UPF 50+ label) and UV-Blocking sunglasses.
  • Seek shade when possible. The sun’s rays are the strongest between 10 a.m. and 4 p.m.
  • Water, snow and sand reflect and magnify the damaging rays of the sun, increasing your chance of sunburn. Especially during peak hours while at the beach, stay in the shade from an umbrella carrying a UPF 50+.
  • Avoid tanning beds – there is no way to get a tan through UV exposure without increasing the risk for skin cancer. Using a tanning bed before age 35 increases your risk for melanoma by 75 percent.
  • Be aware that certain prescription medications and over-the-counter drugs can increase your skin’s sensitivity to sunlight
  • Sun-proof your car windows with UVA-filtering window glass or film.

Source: Melanoma Research Foundation, American Academy of Dermatology

Institute News

What SBP Scientists are Researching to Battle Skin Cancer

AuthorHelen I. Hwang
Date

May 16, 2017

Nevus sample from Peter D. Adams' lab

Skin cancer is one of the most common of all cancers, and melanoma accounts for about 1 percent of skin cancers. However, melanoma causes a large majority of deaths from that particular type of cancer. Alarmingly, rates of skin cancer have been on the rise in the last 30 years. Here in Southern California, our everlasting summer comes with a price. Exposure to sun increases our risk to melanoma.

Melanoma occurs when the pigment-producing cells that give color to the skin become cancerous. Symptoms might include a new, unusual growth or a change in an existing mole. Melanomas can occur anywhere on the body.

At Sanford Burnham Prebys Medical Discovery Institute (SBP), we have several researchers working on the causes of melanoma and discovering new ways to treat this deadly disease.

Here is a roundup of SBP’s latest research:

Key findings show how melanoma develops in order to identify potential therapeutic targets

Ze’ev Ronai, PhD
Professor and SBP Chief Scientific Advisor

Ronai’s laboratory has been studying how rewired signaling networks can underlie melanoma development, including resistance to therapy and metastatic propensity. One player in that rewiring is a protein called ATF-2, which can switch from its usual tumor-preventive function to become a tumor promoter when combined with a mutation in the human gene called BRAF.

Ronai’s work on a protein, ubiquitin ligases, led to the identification of RNF125 as an important regulator of melanoma resistance to a common chemotherapy drug. RNF125 impacts melanoma resistance by its regulation of JAK2, an important protein kinase which could play an important role in melanoma resistance to therapy.

Work on the ubiquitin ligase Siah2 identified its important role in melanoma growth and metastasis, and its contribution to melanomagenesis. Melanoma is believed to be a multi-step process (melanomagenesis) of genetic mutations that increase cell proliferation, differentiation, and death.

Work in the lab also concern novel metabolic pathways that are exploited by melanoma for their survival, with the goal of identifying combination drug therapies to combat the spread of melanoma. Earlier work on the enzyme PDK1 showed how it can be a potential therapeutic target for melanoma treatment.

Immunotherapy discovery has led to partnership with Eli Lilly

Linda Bradley, PhD
Professor, Immunity and Pathogenesis Program, Infectious and Inflammatory Diseases Center

Bradley’s group is focused on understanding how anti-tumor T cells can be optimized to kill melanoma tumors. They discovered an important molecule (PSGL-1) that puts the “break” on killer T cells, allowing melanoma tumors to survive and grow. Using animal models, they removed this “break” and T cells were able to destroy melanoma tumors. They have extended their studies and found that in melanoma tumors from patients, T cells also have this PSGL-1 “break”. Bradley’s lab has partnered with Eli Lilly to discover drugs that can modulate PSGL-1 activity in human disease that may offer new therapies for patients.

Knocking out a specific protein can slow melanoma growth 

William Stallcup, PhD
Professor, Tumor Microenvironment and Cancer Immunology Program

The danger of melanomas is their metastasis to organs, such as the brain, in which surgical removal is not effective. By injecting melanoma cells into the brains of mice, we have shown that the NG2 protein found in host tissues makes the brain a much “friendlier” environment for melanoma growth.

Specifically, NG2 is found on blood vessel cells called pericytes and on immune cells called macrophages. The presence of NG2 on both cell types improves the formation of blood vessels in brain melanomas, contributing to delivery of nutrients and thus to accelerated tumor growth. Genetically knocking out NG2 in either pericytes or macrophages greatly impairs blood vessel development and slows melanoma growth.

Mysterious molecule’s function in skin cancer identified

Ranjan Perera, PhD
Associate Professor, Integrative Metabolism Program

Ranjan’s research uncovered the workings of a mysterious molecule called SPRIGHTLY that has been previously implicated in colorectal cancer, breast cancer and melanoma. These findings bolster the case for exploring SPRIGHTLY as a potential therapeutic target or a biological marker that identifies cancer or predicts disease prognosis.

 Drug discovery to help babies has led to a clinical trial at a children’s hospital

Peter D. Adams, PhD
Professor, Tumor Initiation and Maintenance Program

Approximately 1 in 4 cases of melanoma begins with a mole, or nevus. Genetic mutations can cause cells to grow uncontrollably. By investigating how this occurs, we can understand why melanoma develops from some moles, but not others.

Babies born with a giant nevus that covers a large part of the body have especially high risk of melanoma, and the nevus cells can spread into their spine and brain. Adams’ research identified a drug that deters the cells from growing. The drug identified will be used in a clinical trial at Great Ormond Street Children’s Hospital in London, England that may help babies with this debilitating disease.

Discovery of a receptor mutation correlates with longer patient survival

Elena Pasquale, PhD
Professor, Tumor Initiation and Maintenance Program

Pasquale’s work has included whether mutations in the Eph receptor, tyrosine kinases, play a role in melanoma malignancy. Eph receptor mutations occur in approximately half of metastatic melanomas. We found that some melanoma mutations can drastically affect the signaling ability of Eph receptors, but could not detect any obvious effects of the mutations on melanoma cell malignancy.

Bioinformatic analysis of metastatic melanoma samples showed that Eph receptor mutations correlate with longer overall patient survival. In contrast, high expression of some Eph receptors correlates with decreased overall patient survival, suggesting that Eph receptor signaling can promote malignancy.

Institute News

Super-oncogenic protein that promotes development of melanoma

AuthorJessica Moore
Date

May 19, 2016

Header image

An international collaborative study led by scientists at the Sanford Burnham Prebys Medical Discovery Institute (SBP) has identified a malicious form of a protein that drives the formation of melanoma. The findings, published in Cell Reports, reveal unexpected insight into how this lethal skin cancer develops and progresses, and may help understand and develop novel therapies against these aggressive tumors.

“We found that an inactive version of a protein called activating transcription factor 2 (ATF2) elicits a tumor-promoting effect in a way not seen before,” said Ze’ev Ronai, PhD, chief scientific advisor of SBP and professor of its NCI-designated Cancer Center. “We have known for years that the active version of ATF2 promotes melanoma, but this result was a surprise because we thought ATF2 transcriptional activity was essential to activate cancer-related genes.”

Ronai’s team has been studying ATF2’s role in melanoma for two decades. Their past work led to the view that it’s dangerous when it’s in the nucleus because it controls cancer-enabling genes, but benign when it’s not.

In the current study, researchers looked at the oncogenic potential of a ‘dead’ form of ATF2 in mice with mutations in BRAF, a kinase that transmits signals promoting cell division and is often mutated in pigmented skin cells. The same mutation is found in about half of all human melanomas.

“Inactive ATF2, in mice with mutant BRAF, resulted in the formation of pigmented lesions and later, melanoma tumors,” said Ronai, senior author of the study.

“What makes this discovery relevant to human melanoma is that we identified a structurally similar form of inactive ATF2 in human melanoma samples that has the same effects on cancer cells,” added Ronai. “Inactive ATF2 could be an indicator of tumor aggressiveness in patients with BRAF mutations, and maybe other types of cancer as well.”

“Unlike models with more complex genetic changes, like the inactivation of PTEN and p16 combined with BRAF mutations that result in rapid tumorigenesis (within a few weeks), the inactive ATF2 caused BRAF mutant mice to develop melanoma much slower, more similar to the timescale seen in patients,” commented Ronai. “This improves our ability to monitor the development of melanoma and efficacy of possible interventions.”

“We’re now investigating why inactive ATF2 so potently promotes BRAF-mutant melanoma, and looking for other types of cancer where it acts the same way,” Ronai said. “Our findings may guide precision therapies for tumors with mutant ATF2.”

The paper is available online here.

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A sugar found in seaweed may help treat skin cancer

Authorsgammon
Date

December 8, 2015

Header image

New research from scientists at Sanford Burnham Prebys Medical Discovery Institute (SBP) suggests that a rare sugar found in seaweed, mushrooms, seeds and other foods may be able to help treat skin cancer. The sugar, called L-fucose, has previously been linked to a number of pathological conditions including inflammation and certain cancers. The current study, published in Science Signaling, is the first to associate L-fucose with melanoma, the most dangerous form of skin cancer.

“Our findings offer new, unprecedented detail into the sugar’s role in cancer,” said Ze’ev Ronai, PhD, senior author and scientific director of SBP’s La Jolla campus. “We found that by tampering with L-fucose metabolism, we could inhibit melanoma tumor metastasis. Not only were the tumors affected but also their microenvironment—the cells surrounding the tumor that play a critical role in sustaining the cancer—making the discovery even more impactful.”

Sugars, such as glucose and sucrose, come from many different sources and are used by the body in unique ways. Some sugars, including L-fucose, provide crucial tags on cell-surface proteins that signal inflammation and help direct cell migration. Previous research has shown that changes in the amount of L-fucose on cells are associated with breast and stomach cancers.

The study started with a broader investigation of activating transcription factor 2 (ATF2), a protein that controls the expression of many other proteins and that has been implicated in the development of melanoma and other cancers. Ronai’s group has been studying ATF2 for more than 20 years.

“To our surprise, one of the genes found to be regulated by ATF2 was fucokinase (FUK), which controls the ability of cells to process the dietary sugar, L-fucose, into a form that is useable for the modification (fucosylation) of proteins, many of which are on the cell surface, said Ronai.”

“In human samples, we found reduced fucosylation in metastatic melanomas and a better prognosis for primary melanomas with increased fucosylation. We suspect that the absence of L-fucose on melanoma cells makes them less sticky and more mobile in the body, making them more likely to metastasize,” Ronai explained.

Importantly, in mice with melanoma, the researchers were able to increase fucosylation either by adding the sugar to their drinking water or by genetic manipulation. Both methods inhibited the growth and metastasis of the tumors.

“Many patients develop resistance to current melanoma drugs. If we can add something like L-fucose to enhance these therapies, that’s very exciting, and it’s something we’re actively looking into,” said lead author Eric Lau, PhD, who is extending studies on the role of L-fucose in melanoma at the H. Lee Moffitt Cancer Center in Tampa, Florida,

“The dietary result was especially gratifying, because it suggests that modifying fucosylation could be achieved by the simple addition of L-fucose to drinking water.

“Our results further suggest that the addition of dietary sugar may help fight melanoma by boosting numbers of helpful immune cells. We are continuing our exploration of how fucosylation and other sugar coatings affect the immune system and impact cancer,” added Ronai.

To read the paper click here