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Wistar Melanoma Researchers Discuss Risks and Solutions for Melanoma Awareness Month

Written by The Wistar Institute on . Posted in Featured News.

Three of The Wistar Institute’s foremost melanoma researchers: professor Meenhard Herlyn, D.V.M., D.Sc.; associate professor Jessie Villanueva, Ph.D.; and assistant professor Noam Auslander, Ph.D. discussed the progress and potential in melanoma research. Each brings their own distinct expertise to the field of melanoma research with decades of combined experience, and in reflecting on the state of the field, Drs. Herlyn, Villanueva, and Auslander covered both how they came to melanoma research and how they continue to tackle the challenge of this disease every single day at Wistar.

There are a lot of cancers out there. What brought you to melanoma?

Dr. Noam Auslander: As someone who works on the computational side of things, I was attracted to melanoma research mainly because of the quantity of data. In science generally but in computational science in particular, more data is better — because that allows researchers to design high-fidelity models, which, with cancer, can lead to all sorts of benefits, like predictions of who will respond to what therapy, or which genetic patterns are implicated in a cancer.

I can access and analyze melanoma data in large batches simply because there’s a lot of it. Part of that is because it’s a common cancer — which isn’t a good thing — but because it’s both common and a subject of study for more than 40 years, that allows my team and I to improve our models.

Dr. Jessie Villanueva: For me, melanoma research began as pure scientific interest. Melanoma is an aggressive cancer, and when I started as a postdoctoral fellow, there were no approved targeted therapies or immunotherapies; if chemotherapy, radiation, and surgery all failed, there really weren’t other options.

That problem attracted me to the field as a scientist who wants to solve problems, and shortly afterward, the professional interest became a personal one: a childhood friend whom I’d known since kindergarten was diagnosed with melanoma, and not long after that, so was my uncle. Unfortunately, my uncle passed away, but my friend survived, and that combination of loss and hope solidified melanoma as something I wanted to dedicate myself toward working against.

Dr. Meenhard Herlyn: My story is not so inspiring. I was young — so I suppose it was something like a hundred years ago — but my boss told me to help him with a melanoma project, and that was that. But I was very lucky, because that project involved a man named Wallace Clark: a great pathologist of the disease, whose research laid the foundation for much of what we know today about melanoma. Much of his work was characterizing these melanoma cells under a microscope — a necessary first step — and thinking of stories in his mind about how they might behave. Characterizing and theorizing. So as a young scientist, I thought to myself, “we must find a way to fill in these stories with real data.” And I’ve followed that ever since.

There are other skin cancers; melanoma is just a subtype. What makes it so dangerous?

J.V.: Melanoma comes from cells that originally have an innate level of pluripotency (the ability to transform into different cell types); they have remarkable migratory abilities; and they give rise to a diverse array of cell types throughout the body. When those cells become cancerous, they are highly plastic and skilled at adapting to their environment. This plasticity also allows melanoma to evade treatment and become drug-resistant. Drug resistance is a big problem in the field; often when using drugs targeting one pathway, the tumors find an alternative pathway to exploit.

By collectively studying all the inner workings of melanoma — like its genetics (the kind of mutations it collects), epigenetics (how genes are turned on or off), and signaling pathways (controlling processes like cell growth, proliferation, and survival) — we aim to develop strategies that prevent tumors from evading treatment. We’ve made great progress treating melanoma, but tumors still develop strategies to bypass therapies. This ongoing challenge drives our relentless search for innovative and effective solutions, fueled by the hope of achieving cures and improving the lives of melanoma patients.

N.A.: Melanoma is associated with an unusually high inter- and intra-tumor heterogeneity; the mutational profile is exceptionally complex between different melanoma cells and even within melanoma cells. That’s why large-scale data analysis of melanoma with computational models isn’t just important but necessary — patterns that can help us fight this cancer exist, but distinguishing between patterns and noise both within a tumor and between tumors requires the help of advanced computational techniques.

Meenhard has talked about how we need to listen to cells, and that’s how I try to help Meenhard & Jessie’s work: by fine-tuning computer systems to listen for signals amid the chaos in cancer.

M.H.: We also have to remember that the cells that become melanoma are highly mobile by their very nature. As Jessie said, melanocytes have a certain amount of innate plasticity, which contributes to the cancer’s aggression once a melanocyte goes from normal to cancerous.

But that wouldn’t necessarily be as big a problem if it weren’t for these cells’ motility. When you have aggressive cancer cells moving throughout the body, that creates a situation that lends itself to metastasis. A skin cancer that isn’t melanoma doesn’t present as much danger because it’s probably more localized; I’m not saying that’s not serious, but a non-metastatic tumor on the skin is a lot easier to treat — at the simplest level, you just cut it off. With melanoma, once that diagnosis comes, the clock is ticking to stop the cancer before the metastatic impulse gets out of control.

More people are getting melanoma, with U.S. incidence up by more than 50% since 1999. Why do you think that is, and how can people protect themselves?

J.V.: The short answer is that we don’t yet know for sure — there are several ongoing epidemiological studies which we expect will provide clear answers. Lifestyle is a big part of it. Outdoor activity can be healthy; however, being outdoors means more sun & UV exposure. Anecdotally, since the pandemic, we’ve noticed more people spending more time outdoors. And that’s a risk factor.

We’re seeing a sharp increase in melanoma for young people, particularly young women. Cancer tends to be correlated with age — the older we get, the higher the probability of having cancer — but melanoma is the most frequently developed cancer in people in their 20s and 30s.

M.H.: I agree that lifestyle is probably a big factor in the increase in cases. Everything from tanning beds to taking a vacation to lie on the beach is going to give UV rays more opportunity to cause damage that could lead to melanoma. Sunlight feels good to everyone, but unprotected exposure is harmful. People get addicted to damaging UV because our skin secretes endorphins when exposed to UV, and that’s more reason to be cautious.

It’s true that people with less melanin in their skin are more at risk — which is why, for example, more leisure travel from countries in the Global North to equatorial regions that get more sun probably causes more melanoma overall — but everyone has skin, which means anyone can get melanoma. And that’s why awareness of exposure risk is so important.

Learning to Listen to Our Cells: 20 Years of The Society for Melanoma Research with Dr. Meenhard Herlyn

Written by The Wistar Institute on . Posted in Featured News.

Meenhard Herlyn, D.V.M., D.Sc., founded the Society for Melanoma Research 20 years ago at Wistar. The Society’s annual Congress just celebrated its 20th anniversary and presented Dr. Herlyn with the Founders Award, an honor commemorating his work in creating an organization that has been integral to the advancement of melanoma research.

We were told that, before you received the Founders Award, it was supposed to be a surprise. Did they succeed in surprising you?

Oh, they absolutely succeeded. I had not been expecting anything at all. I am not really a surprise person, but I was quite moved by this gesture. Everyone got up — it was a real honor. I felt so energized by the moment that I gave a little spontaneous pep talk.

A pep talk? What did you say?

I spoke about the SMR mission, which is bringing together clinicians and researchers against melanoma. The idea is to bring together the strengths of research and clinical practice — but this can only happen when we are transparent and open. Throughout my career, I’ve found that progress is made by sharing: sharing data, sharing methods, sharing tools — everything! I know that, sometimes, scientists might not show all their data publicly, out of administrative concerns or something — but to me, that is a big no-no, especially in an organization like the SMR. We are proud to be transparent because that is how we move forward.

Do you think that the openness in your field has increased over the years?

Oh, of course; the openness has expanded tremendously, and I’m proud to say that our field stands out for its collaborative approach. We now almost have the opposite problem, where so much data accrue thanks to what we call “omics” technologies (as in, genomics, proteomics, etc.). These datasets require specialized bioinformatics knowledge to interpret because of their complexity and sheer size. My lab has approximately 80 terabytes of data, and I estimate that by this time next year, that quantity will have doubled or even tripled. We have great resources, yes. But we are also searching for needles in haystacks.

Our cells speak to us. They tell us at each and every step how they feel, what they do, and with whom they interact. As researchers, it is our job to listen to what our cells are saying, but that listening is quite difficult. We do our best with modern technology to gather all these signals from RNA, DNA, proteins — and all of this for each cell, tens of thousands of them. It’s like a big crowd, roaring. To listen to the cells, we must sort out the noise from the useful information to see which genes and proteins are talking, telling us what’s wrong.

What inspired you to start the SMR?

20 years ago, we had two communities: we had the researchers, busy in the lab, looking at data; and we had the clinicians, diagnosing and treating patients while relying primarily on clinical experience. At the time, I was working with a very gifted pathologist, Dr. Wallace Clark, and we were investigating melanoma, a field where there was very little progress being made; the treatments worked maybe 2% of the time. While working on the project and trying to obtain samples, I realized how big the gap between researchers and practitioners was. The two groups were each cooking their own soup, not talking to each other. So I figured that bridging the gap was essential for making any progress at all, because having the clinic separate from the lab just wasn’t working. That’s where the idea for the SMR came from.

It wasn’t SMR at first, though. We were the Noreen O’Neil Foundation for Melanoma Research. Noreen was a melanoma patient who saw that there was very little melanoma research, and she also recognized that this had to change. She spoke with her clinician, Dr. DuPond Guerry, and we began the work of putting together the organization. Unfortunately, Noreen died of her illness, and so her sister Kate O’Neil took over. With their generosity, we had $50,000 in the bank, which gave us two options. The first was awarding grants, of which we could award two and then the money would be gone. Or, we could use the money to set up a meeting for melanoma researchers and clinicians. So we got to work finding a space, inviting speakers, making sure that the lab perspectives were balanced with the clinical perspectives — and the Congress was born.

The first SMR Congress was an enormous success. We decided to hold it in a new city every year after, to keep it fresh and exciting, but having the 20th anniversary back in Philadelphia where it started was a nice touch.

How far have you come, and how much further do you have to go?

We have many miles to go yet, but I’m proud to look back on the progress we’ve made. Not only scientifically, but also in terms of widening the community. Researchers and clinicians work together against melanoma now, sharing their insights with each other — that shows the power of openness in science. I’m especially proud of the work that my colleague Dr. Jessie Villanueva is doing for Diversity, Equity, and Inclusion in science. Science only works when people come together to solve problems; there can be no room for exclusion or bias because everyone’s insight is needed to advance the field.

On the other hand, we need to keep pushing forward. With the frequency of melanoma cases rising, research is more important than ever; keep in mind that, for all the advances the field has seen, we can still only successfully treat 50% of patients long-term. When every other patient eventually dies of their illness, that tells you just how vital it is to keep up the work. Only by bringing more talent into the fold across disciplines will we be able to sustain progress against this cancer.

Unraveling The Enigmas of Melanoma

Written by The Wistar Institute on . Posted in Featured News.

Meenhard Herlyn, D.V.M., D.Sc., is known internationally as one of the fathers of melanoma research. As the founder of The Wistar Institute Melanoma Research Center, he has led the way with breakthrough discoveries about this mysterious and hard-to-treat cancer. A highlight of his work includes building Wistar’s collection of patient-derived xenografts — a groundbreaking tool that allows tumor cells to be implanted into models for melanoma research.

Now, a new generation of melanoma researchers are building on that foundation. This up-and coming-scientific force includes Chengyu Liang, M.D., Ph.D., a rising star in studying how UV exposure damages cells.

“Dr. Herlyn is a great mentor and a great scientist,” Liang said. “He established the platform, the foundation, that has been indispensable not only for Wistar melanoma research, but for the entire melanoma research field.”

BUILDING A BETTER MODEL

“One of the guiding forces in our research has been to mimic human disease, to figure out what makes cells become cancer, and to use this knowledge for new strategies to develop therapies,” Herlyn said.

One of these strategies involves the use of artificial skin. Lab-grown skin had previously been developed for wound healing. Using this existing technology, Herlyn pioneered its application to melanoma research. Herlyn’s team was the first to use artificial skin to grow and study melanocytes — normal pigment cells — which they have used to understand how cancer cells form and how to make treatment more effective.

“We wanted to really know what tumor cells do, and to understand that, we first need to know what normal cells do and where the tumor cells come from,” he explained.

Herlyn joined Wistar in 1976 and spent the early years of his career focused on developing monoclonal antibody treatments, a breakthrough drug that mimics or enhances the immune system’s natural disease fighting activity to attack cancer cells.

One of Herlyn’s frequent collaborators during this time was his wife, Wistar scientist Dr. Dorothee Herlyn, who is now retired. “She was the immunologist of the family,” he said. Together, they helped develop a number of monoclonal antibody molecules, some of which are still used in cancer therapies today.

Herlyn is also behind Wistar’s patient-derived xenograft program which supports a collection of patient cancer tissues. These samples can be implanted into genetically altered mice to more closely mimic conditions in the human body. It’s a powerful tool scientists can use to conduct cancer experiments and test new treatments under conditions that more closely mimic the disease in humans.

“We now have more than 500 tumors from patients,” Herlyn said. “These come directly from the patient and are implanted without ever being cultured, making them much more like real life tumors.”

THE “SUNSCREEN GENE” AND MELANOMA

Dr. Liang didn’t set out to study melanoma. Originally trained as a medical doctor, she became a research scientist with the mission of improving patient outcomes. Her drive to understand cancer and develop better treatments became more personal after her mother passed away following a two-year battle with cancer.

“When someone you love has cancer, you’re trying to find answers. Why did this person have cancer? Why is this treatment not helping?” she said. “Eventually, that drove me to get my Ph.D. in medical science. I wanted to know more.”

Liang initially focused her research on tumor virology, studying how viruses cause cancer. During her research, she encountered a gene called UVRAG that piqued her interest in melanoma.

Previous work had found that this gene seemed to be involved in protecting skin cells from UV radiation, but the mechanism behind it was unclear. Liang’s team showed how the gene repaired DNA damage from UV radiation, and that disrupting the gene could increase a person’s risk of melanoma and other skin cancers. They nicknamed UVRAG the “sunscreen gene.”

The finding sparked many questions about how UV radiation causes genetic mutations that lead to cancer. “The question we asked is, ‘What makes melanoma melanoma?’” she said.

One thing that sets melanoma apart is its extremely high rate of genetic mutations — much higher than other cancers. “It’s in the skin, which is where the body interconnects with the environment and UV radiation, so in a way, that’s not surprising,” she explained.

Liang’s recent research has focused on identifying signs of DNA-repair deficiency as an early sign of damage that can trigger melanoma-driving mutations. “If we can find genetic signs that can predict this process, we might be able to catch the disease much earlier,” she noted.

CULTURING COLLABORATION

Herlyn not only laid the groundwork for Liang and fellow cancer researchers. He also serves as a leader and mentor who is generous with his knowledge and support, Liang said. “He’s like a big dictionary of melanoma,” she described. “When you have a question, he can always share something instructive.”

This philosophy of collaboration, Herlyn shared, has been a driving force in his work. “One of the major strengths at Wistar has been our flexibility and our ability to look for collaborators,” he pointed out. “My approach has always been to look for the best people I could work with.”

This has included a longtime collaboration with oncologists, pathologists, and other clinical colleagues at the University of Pennsylvania as well as other institutions. “I’ve always believed strongly in a good connection between the laboratory and the clinician,” he said.

Herlyn also helped found the Society for Melanoma Research, the first ever medical conference dedicated to bringing together researchers, clinicians, and patients to share knowledge about melanoma. Liang emphasized that with such a complex and unique disease, it’s critical for scientists to work together to find new diagnostic tools and treatments.

“There’s still a lot of mystery,” she stated. “Despite all the tremendous progress we have made in the melanoma field, I think we are still at the tip of the iceberg.”

Discussing the Mysteries of Melanoma

Written by The Wistar Institute on . Posted in Featured News.

A Q&A with Drs. Chengyu Liang and Meenhard Herlyn on skin cancer research at The Wistar Institute, including a few questions from melanoma survivors.

Melanoma is the most aggressive form of skin cancer. Work at The Wistar Institute’s Melanoma Research Center aims to understand the biology behind the disease to help develop new therapies and improve existing treatments. In this Q&A, we spoke with Dr. Chengyu Liang, a professor in the Molecular & Cellular Oncogenesis Program at Wistar’s Ellen and Ronald Caplan Cancer Center who joined Wistar in 2020 and Dr. Meenhard Herlyn, director of The Wistar Institute Melanoma Research Center and Professor in the Molecular & Cellular Oncogenesis Program. The research they conduct aims to have impacts on melanoma patients and survivors. Thus, this National Melanoma and Skin Cancer Awareness Month, we included questions from melanoma survivors and staunch Wistar supporters Eleanor Armstrong and Pat Dean who organize an annual fundraiser walk for the Institute’s melanoma research program.

Dr. Liang, what attracted you to studying melanoma?

Dr. Chengyu Liang: My passion and curiosity! A few years ago, we identified a so-called “sunscreen” gene that helps cells to repair after they have been damaged by UV rays; and we know that UV-induced DNA damage is a major risk factor for melanoma – the most aggressive type of skin cancer. This inspired us to find out more about how this genetic sunscreen system plays in human beings and what it means to melanocytes (the origin of melanoma) and melanoma when the system is running out of order.

What are you working on now specifically regarding melanoma and what is this work’s potential impact on cancer treatments?

CL: The question that we are always intrigued by is: What makes melanoma melanoma? Compared to most other types of human cancers, one striking feature of melanoma is that its genome is flooded with mutations associated with UV-induced damage. Now, the burning questions are: What drives such genetic change? What are the molecular mechanisms underlying the UV-footprint in melanoma? Understanding these mechanisms not only enable early-risk prediction but also help oncologists and researchers to develop cancer treatments with responses that have long-term durability.

Second, melanoma originates from an easily spread and multipotent cell population, which can help explain the inborn aggressiveness and treatment resistance of the skin cancer. In addition to targeting specific pro-cancer mechanisms to kill cancer cells that are often, if not always, encountered by tumor resistance, is it possible to force cancer cells to resume the process of normal growth control or differentiation? To this end, we are trying to understand the molecular mechanisms that control melanoma differentiation. This work holds promise to identify new vulnerabilities in melanoma that can be targeted to revert the negative effects of mutations and strengthen anti-tumor immune responses to melanoma.

How important is a person’s immune system in preventing skin cancer and is there anything that can be done to strengthen a person’s immune system against melanoma?

CL: It can’t be more important! Our immune system is like the ‘shepherd’; its duty is to keep ‘sheep’ protected. Melanoma is like the ‘wolf’. A powered immune system is an experienced shepherd that could easily and quickly identify and target the wolf in the flock and clear it up. As a matter of fact, what immunotherapy does is release the built-in brake system of our immune system and revive and direct its killing energy to cancer cells.

The immune system is an ecosystem – a complex network of cells, tissues, and organs that orchestrate to maintain homeostasis to protect human bodies against internal and/or external assaults. If a well-balanced immune system is considered healthy to life, a well-balanced life would also be considered beneficial to the immune system. Many tips have been suggested such as healthy diet, exercise, mental and physical support, etc. Notably, fasting and calorie restriction (CR), have been shown experimentally and in clinical trials, to be able to slow and even stop the progression of cancer, kill cancer cells, boost the immune system, and significantly improve the effectiveness of chemotherapy and radiation therapy. With our growing understanding of this sophisticated system, we might be able to come up with more effective strategy to boost it or manipulate it to outsmart cancer.

You’ve previously done research on UV radiation causing mutations that contribute to melanoma. What are some daytime hours that have the highest risk of damaging UV radiation and sun exposure?

CL: This depends. The lighter the skin, the more sensitive to sunburn and/or skin damage by UV rays. Human skin pigmentation is an evolutionary adaptation to UV radiation. Fair skinned people may easily burn within 20 minutes of exposure to direct sunlight, thus wearing a broad-spectrum sunscreen is always encouraged. Certainly, you also want to have a strong genetic sunscreen system as noted before.

What future directions will you take your work?

CL: Our ultimate goal is to make melanoma a curable disease. The current challenge is that we still have more than 50% of melanoma patients who are not responsive to any treatment. We need to solve this puzzle. We also need to figure out what’s the right therapy to be used for the right patient at the right time. Why does therapy work in some patients, but not others? We believe that prevention is the most effective treatment of melanoma. Thus, identifying a new biomarker for early detection is equally important and urgent. All these challenges depend on a deeper understanding of the biology of melanoma as a cancer, and the biology of melanoma interaction with the human body as a system.

Dr. Herlyn, why is building the cancer research talent at Wistar important (eg. Dr. Chengyu Liang joining the Cancer Center)?

Dr. Meenhard Herlyn: Every research field needs a critical mass of researchers, both junior and senior. Any institution needs ‘new blood’, meaning investigators who may have experience, knowledge, and connections in the critical field. Dr. Liang brings important expertise not only to Wistar but the entire larger field here and beyond. Her work on DNA damage and repair fills an important gap for us.

What would you like to see for the future of melanoma research at Wistar?

MH: Melanoma has been a major focus for research at Wistar. We have developed a strong outreach program in which we collaborate not only with our colleagues at Penn but also with numerous national and international research laboratories. Melanoma research at Wistar should remain multi-disciplinary. Our strong biology is the foundation and platform for collaborations that ensure continuing progress. Melanoma investigators should incorporate cutting edge technologies and strategies. We have developed strong ties to our clinical colleagues, and we expect that in the future these ties will strengthen as our research more and more directly benefits patients. Thus, we not only translate research from bedside-to-bench but also from bench-to-bedside.

Why are supporters such as those fundraising and donating to the Institute important?

MH: There are many areas of research that are essential to run a successful program but that cannot be funded through National Institute of Health or industry grants. For example, there are meetings with other scientists to exchange ideas and develop new collaborative strategies, seed funding for new projects that are still in the exploratory phase, collaborations with clinicians for specimens and preparing reagents for diagnostic studies, developing high risk/high gain projects and ideas, and obtaining new research tools. Supporters like our donors and fundraisers are integral to our work at Wistar, without whom we could not have as great an impact as we do.

Wistar and Penn Medicine Awarded $11.7 Million Melanoma Research Grant from the National Cancer Institute

Written by The Wistar Institute on . Posted in Press Releases.

PHILADELPHIA — (Sept. 22, 2021) —The Wistar Institute and Penn Medicine have been awarded a prestigious $11.7 million Specialized Programs of Research Excellence, or SPORE, grant from the National Cancer Institute. The five-year award will fund three new melanoma research projects that translate fundamental laboratory discoveries made at The Wistar Institute and in the Perelman School of Medicine at the University of Pennsylvania into new therapeutics to treat skins cancers.

The grant also includes a career enhancement program focused on training and retaining underrepresented minorities in skin cancer research, and a pilot award program that will expand research into non-melanoma skin cancer.

The SPORE team at Wistar and Penn will carry on a long tradition of developing new treatments for skin cancer with the grant, which follows a $12 million SPORE grant awarded to the institutions in 2014. The new projects will be supported by core research labs, including a tissue specimen core with over 11,000 banked specimens.

Meenhard Herlyn, D.V.M., D.Sc., director of Wistar’s Melanoma Research Center and professor in the Molecular & Cellular Oncogenesis Program in Wistar’s Cancer Center, and Ravi K. Amaravadi, M.D., associate professor of Hematology-Oncology in Penn’s Perelman School of Medicine and the co-leader of the Cancer Therapeutics Program at Penn’s Abramson Cancer Center, and will serve as the co-directors of the SPORE.

“Despite dramatic improvement brought about by immunotherapy, we still have major challenges for the majority of patients and new approaches are urgently needed,” said Herlyn. “Building on major breakthroughs by our team, we are poised to address crucial unanswered questions to improve immunotherapy response and identify new biomarkers to inform patient management and reduce therapy toxicity.”

“Our longstanding team approach to science and new therapies has been recognized by the NCI once again with this new SPORE grant. We can now expand on this collaboration—which has already led to important developments in melanoma,” Amaravadi said. “From new fundamental insights about how skin cancer escapes treatments to new treatment options for patients, these projects—and the people leading them—are at the cutting edge of translational medicine, and are entirely focused on improving the health of our patients.”

Melanoma is the deadliest form of skin cancer and the fifth deadliest form of cancer, overall. According to NCI statistics, more than 100,000 new cases of melanoma will occur in 2021 in the U.S. alone. The incidence of melanoma and other skin cancers, such as Merkel cell carcinoma and squamous cell carcinoma, are rising both nationally and regionally. If caught early, skin cancer is considered treatable; however, when these cancers metastasize, they are especially deadly.

Other Wistar faculty on the team include professor David W. Speicher, Ph.D., associate professor Jessie Villanueva, Ph.D., and assistant professor Andrew Kossenkov, Ph.D., from The Wistar Institute Cancer Center.

Other Penn faculty involved with the project include Wei Guo, PhD, the Class of 1965 Endowed Term Chair in Biology, Xiaowei Xu, MD, PhD, a professor of Pathology and Dermatology, Phyllis Gimotty, PhD, a professor of Biostatistics and Epidemiology, Giorgos Karakousis, MD, an associate professor of Surgery, Gregory Beatty, MD, PhD, an associate professor of Medicine, Tara Mitchell, MD, an associate professor of Medicine, Lynn Schuchter, MD, chief of Hematology-Oncology and director of the Tara Miller Melanoma Center, and E. John Wherry, Chair of the department of Systems Pharmacology and Translational Therapeutics.

The three main SPORE melanoma research projects include:

Project 1: Exosomal PD-L1 in immunotherapy resistance

Co-Project Leaders: Guo, Xu, Mitchell, and Wherry

Currently, there is no approved assay that can help determine which melanoma patients will respond to immunotherapy. This project builds on a fundamental discovery that small segments of cells called exosomes that carry PD-L1 on their surface are floating in the blood of melanoma patients. Exosomal PD-L1 is an immunosuppressive factor, and can be measured in the blood noninvasively with assay developed by Guo and Xu. Working with collaborators at the John Wayne Cancer Institute, MD Anderson Cancer Center and New York University, the team will conduct rigorous clinical utility studies designed to demonstrate this blood-based measurement as a highly sensitive and specific predictive biomarker for response to immunotherapy in melanoma.

Project 2: Targeting autophagy to improve immunotherapy in melanoma

Co-Project Leaders: Amaravadi and Speicher

Currently, there are limited options for patients whose tumors have progressed on immunotherapy in melanoma. Based on extensive preclinical data and a new molecular target in the autophagy pathway, the team has developed a clinical trial of combined immunotherapy and autophagy inhibition. Targeting autophagy during immunotherapy can reprogram cells within the tumor to enhance the efficacy of T cell killing of melanoma cells. This clinical trial will include a novel PET imaging tracer that can track T cells as they enter the tumors in patients. The project also works with several biotech companies developing new autophagy inhibitors for cancer.

Project 3: Neoadjuvant immunotherapy for early-stage melanoma

Co-Project Leaders: Beatty, Karakousis, and Herlyn

Currently, patients with stage III melanoma are treated with immunotherapy after surgical resection. Some stage II melanoma patients have a higher risk of metastasis than stage III patients, but there is no approved therapy to reduce this risk. Based on previous work showing that one cycle of immunotherapy given before surgery can produce major benefits in stage III melanoma patients, the team has launched a clinical trial of neoadjuvant immunotherapy in stage IIB/C melanoma patients. Besides in-depth characterization of the immune response, the project’s preclinical studies, which include several innovative mouse models to study immunotherapy in stage II melanoma, will lead to new strategies for enhancing the immune stimulatory capacity of dendritic cells in the tumor microenvironment.

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The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.

Melanoma, It’s Not All Written in the Genes 

Written by The Wistar Institute on . Posted in Featured News.

It is well established that some cancer risk factors are interconnected to genetics or other unchangeable factors, such as age or gender. We also know that external factors, such as sun exposure, increase one’s risk of developing melanoma. It’s now emerging how important other external aspects – related to our lifestyle – are for melanoma survival and response to therapy.

During the third annual Noreen O’Neill Melanoma Research Symposium at Wistar, speakers discussed inflammation, certain medications, vitamin D levels, obesity, and the bugs that populate our gut as potential modifiers of patients’ survival and outcome from targeted and immune therapies.

The Symposium, made possible through the Noreen O’Neill Melanoma Research Fund and supported by the Melanoma Research Alliance and the Melanoma Research Foundation, attracts a world class line up of speakers and has become a regular appointment for melanoma experts to come together and collectively discuss how melanoma research is advancing.

With its rates on the rise, it was estimated by the American Cancer Society that melanoma will strike 96,480 Americans in 2019. The research community has made giant leaps forward in the past decades with targeted and immune therapies that have brought tangible improvements in survival of patients for whom almost no hope was available before.

Yet, there is still a long way ahead to defeat the disease. And, as it often happens, when major advances hit the clinic, basic researchers are already working behind the scenes finetuning next steps, tackling drawbacks and figuring out the reasons for failure.

Melanoma is a highly-diverse disease. Within the same tumor, multiple cell populations exist that impact tumor growth and sensitivity to therapy differently. To further complicate the picture, melanoma cells change their characteristics over time or in response to therapy.

This complex aspect of the disease was the main theme of the Symposium.

Delving into the Science

Speaker Jean-Christophe Marine, Ph.D., professor and director of the VIB-KU Leuven Leuven Center for Cancer Biology, Belgium, discussed the adaptive ability of melanoma cells as the origin of therapy resistance.

Relapse after therapy is driven by a small number of cells that remain alive upon drug exposure while the bulk of the tumor is killed. This status is known as minimal residual disease. Drug tolerance is acquired by these cells through genetic mutations and, as recently discovered, non-genetic mechanisms that allow them to quickly adapt and survive.

Marine postulated that “single cell approaches” for tracking and isolating single residual cancer cells are the most effective way to tackle melanoma cell diversity. Such approaches allowed his laboratory to hunt for vulnerabilities of these cells that can be exploited to enhance therapy.

Martin McMahon, Ph.D., professor of cancer biology and senior director for preclinical translation at the University of Utah, discussed his most recent findings that explain why certain targeted therapies that were originally predicted to be the holy grail for melanoma failed to deliver clinical benefits.

According to McMahon’s results, one of these drugs called trametinib activates a particular process called autophagy, which allows the cells to recycle their building blocks and sustain survival.

Based on this discovery, a clinical trial is about to begin that combines trametinib with a drug that blocks the autophagy process. The researchers will evaluate if this drug combination can enhance the antitumor effects of trametinib in melanoma patients.

Research presented by Jennifer McQuade, M.D., assistant professor and physician scientist at MD Anderson Cancer Center, focuses on patient factors that contribute to shaping immunity and response to immunotherapy.

She discussed the obesity paradox in melanoma. This is the observation that obesity – well-established as a risk factor for several cancer types – predisposes to melanoma but is associated with better outcomes in response to immune and targeted therapies.

McQuade also spoke about the role of the microbiome (bacteria that populate our gut) in affecting therapy response. As less than 10% of the microbiome composition is determined by the host’s genetic makeup, and diet, environment and medications are major components, the microbiome is an external factor that can be modified with diet.

In fact, studies have shown that melanoma patients whose diet is high in fiber respond better to immunotherapy, while over-the-counter probiotics are associated with lower microbiome diversity.

To establish if diet intervention can influence outcomes in immunotherapy, McQuade’s team at MD Anderson is conducting rigorously controlled clinical trials in which melanoma patients undergoing immunotherapy also receive high-fiber diet.

On a similar theme, Julia Newton-Bishop, Ph.D., professor at the University of Leeds, U.K., reported evidence for a number of host factors and environmental exposures that modify the tumor microenvironment and influence melanoma survival, including systemic inflammation, which might be therapeutically controlled, smoking and vitamin D levels.

Wistar’s Meenhard Herlyn, D.V.M., D.Sc., director of the Melanoma Research Center and professor in the Molecular and Cellular Oncogenesis Program, took the audience on a historical journey through the different stages and accomplishments of melanoma research, from the era of monoclonal antibodies, believed to be “magic bullets” that would cure cancer, through the discovery of the genetic basis of melanoma and the causative effect of gene mutations, to immunology studies.

Despite those accomplishments, by the early 2000s, Herlyn said, it seemed like nothing worked. Then, the modern era of melanoma research began with the discovery of targeted therapies and, since then, giant leaps have been made.

A pioneer and witness to how the field has expanded, Herlyn has made important contributions to all those stages. He showed an overview of the many experimental models his laboratory has developed over the years, starting with melanoma cell lines, through 3-D skin reconstructs, to latest efforts in the creation of a patient-derived xenograft collection for preclinical drug testing, and “humanized mice”, in which the human immune system is rebuilt in a mouse. These powerful models have allowed the Herlyn lab and many other laboratories around the world to make important discoveries, and continue to be unique tools to advance melanoma research.

Closing the Symposium, Wistar’s Jessie Villanueva, Ph.D., associate professor in the Molecular and Cellular Oncogenesis Program, invited everyone back to Wistar in 2020 with their next breakthroughs in melanoma research.