Identifying Melanoma as a Single Cell

A recent study published in the journal Science could provide important clues for melanoma diagnosis.  Led by Leonard Zon, M.D., of Boston Children’s Hospital, the study looked at cancer in zebrafish from the very beginning – when it starts as just a single cell.

Funded in part by MRA, the study is the first to see melanoma – or any other cancer – begin this early. The researchers found that the cancer developed from an interesting process: the cells reprogrammed back to an embryonic state.

“The process was surprising to us,” noted Dr. Zon. “The melanoma essentially reprogrammed melanocytes to a stem cell, similar to an embryo’s neural crest.”

While the study looked at melanoma in zebrafish, Dr. Zon said human melanomas work similarly. Moles contain melanocytes, the pigment-producing cells. Most moles have a common genetic alteration in a gene called BRAF, but very few moles turn deadly. Understanding the early process of how and why cancers develop could help target treatments, or perhaps reveal prevention strategies.

Dr. Zon’s team used fish that had the BRAF mutation. They created a way to make the fish cells light up in bright green if the embryonic gene called crestin was turned on. The fish that lit up with the bright green signal were the same fish that developed melanomas.

“There are important implications of this work for cancer diagnosis with a newly found tumor, and potential opportunities to stop cancer before it ever begins,” explained Dr. Zon.

The new published research builds off of earlier work by Memorial Sloan Kettering Cancer Center’s Richard White, MD, PhD, recipient of the Maria and Bill Bell – MRA Young Investigator Award, who observed that the melanomas in zebrafish were derived from crestin-expressing cells. Dr. White is a co-author in this new paper.

Dr. Zon told the Harvard Gazette that these findings could not only lead to genetic tests for suspicious moles to see if the embryonic cells have been activated, but also help researchers develop treatments that could prevent a mole from becoming cancerous.

You can read more about Dr. Zon’s research in the New York Times.

A Father Turns His Grief into Fundraising

Ross King lost his daughter, Jackie, to melanoma when she was just 22 years old. Since then, Ross has become a passionate supporter of melanoma research to help fulfill a promise he made to Jackie. Ross talked with us about his experience and what motivates him to take up the cause.

Tell us a bit about when you first learned of Jackie’s diagnosis.

Jackie and Ross

Jackie had a mole on her back that was causing her pain because it was rubbing against her bra strap. When it started bleeding, she went to the dermatologist. The biopsy revealed that she had Stage 2 melanoma.

What were you thinking when you first learned about Jackie’s melanoma diagnosis?

Initially, I was not able to comprehend the severity of Jackie’s diagnosis because I did not know the four stage cancer rating system.  The doctor told us that her records and initial biopsy were being immediately transferred to Emory University’s Winship Cancer Institute.  I immediately knew the severity of her diagnosis at that moment.

Can you share with us a little bit about what the next few months after Jackie’s diagnosis were like?

Jackie had her initial surgery to clean the margins on her back where the mole was located on her 19th birthday – March 26, 2011.  They also removed four lymph nodes from her neck.  We were told one week later that one of the lymph nodes proved that the melanoma had spread to other locations in her body. After her recovery, she started to go back to her normal activities and began to embark on her adult life.

Then Jackie’s condition worsened. Can you tell us what that was like?

Jackie was having pain in her abdomen – which she attributed to working out too hard – but we soon learned that the melanoma had spread to her abdomen. Around this time, I became acquainted with the team at the Melanoma Research Alliance, who put me in touch with some doctors who were helping to develop new drugs, such as vemurafenib, to treat melanoma. Jackie was having a tough bout with radiation, which left her bedridden and unable to eat on her own. After consulting with these doctors, we decided to try a new drug for Jackie. Within three days of starting the new therapy, Jackie was moving around and able to walk up and down stairs.

What do you remember from Jackie’s last months?

Unfortunately Jackie’s cancer progressed, with her melanoma migrating to Stage 4. It became clear that we needed to move Jackie into a new medical care environment. We were introduced to doctors at Brigham and Women’s Hospital, and decided to transfer her care there.

One day, I received a call from her mom telling me Jackie had taken a turn for the worse. I flew up immediately to be with her. Within 24 hours of arriving, the care team was talking about taking her to a hospice facility.

There were so many emotions during her two and a half weeks in hospice. It was painful, peaceful, and calming.

How are you honoring Jackie’s legacy?

After she was diagnosed, Jackie did a lot of advocacy work to bring awareness and attention to melanoma. She told me that she didn’t want her memory to be forgotten. So I made a promise to her to keep her legacy alive, and we’re doing that by fundraising for an MRA Young Investigator Award. I’m proud to say that we hit our fundraising goal just before the one-year anniversary of Jackie’s passing. We now officially have a Jackie King-MRA Young Investigator Award, but we’re not done. I want to keep raising funds for this important cause.

What’s your hope for the field of melanoma research?

I want to see a much more aggressive approach to drug approval, specifically in the area of melanoma. In five years, my resolute hope is that we’d be in a place where we could have a quicker process for getting therapies to the marketplace to benefit patients.

 

To make a donation in memory of Jackie King, please visit Ross King’s fundraising page.

Understanding Immunotherapy Part 1: What is Immunotherapy?

By Amrita Bhatt, MRA Intern

If you follow science, you have probably heard about immunotherapy. In just the last year or two, immunotherapy has burst into the mainstream media, with coverage from the New York Times to Time Magazine bringing this emerging field to light beyond the scientific community. More recently, President Jimmy Carter helped put a face on immunotherapy when he announced its use in treating his metastatic melanoma.

While there is a broader understanding of immunotherapy now than there was a few years ago, there is a lot to discuss on this complex topic. We’ll be starting a blog series to help readers understand immunotherapy – and how it is being used to treat melanoma and other cancers.

Let’s start with a little background. Just 10 years ago, there were hardly any treatments available for patients diagnosed with melanoma, and a diagnosis of metastatic melanoma was an almost certain death sentence. Since MRA’s founding, the FDA has approved 11 therapies for melanoma. These have included targeted and immunotherapies – and combinations of the two. With nearly $68 million in funding to date, MRA continues to play an integral role in making revolutionary changes available for patients.

So, what is immunotherapy?

It’s a method of treatment that involves engaging the patient’s own immune system to fight cancerous cells. Four of the eleven FDA approved therapies since 2011 have been checkpoint therapies, including one combination therapy, and MRA’s funding has been vital to keeping the momentum going.

How does immunotherapy work?

Our immune system protects us by warding off foreign invaders such as bacteria and viruses. The immune system can also sometimes recognize cancer cells. However, since cancer cells arise from our normal cells, sometimes the cancer just isn’t different enough for the immune system to attack it.

In some cases, even when recognized as foreign, cancers use other strategies to evade the immune response. Immunotherapy works to boost your body’s immune response in order to attack cancer cells and prevent them from evading our defenses.

This video provides a visual explanation for how immunotherapy works.

Figuring out how to engage the immune system to fight cancer has been a goal for many years. MRA has funded a great deal of research in this area, including research on two proteins that allow cancer cells to escape attack from the immune system – PD-1 and CTLA-4.

In this continuing blog series, we’ll explain what these proteins are and how MRA funded researchers are strengthening our understanding of their role in cancer progression and treatment. Immunotherapy is broadening the scope of patient therapies and we must continue to fund vital research that keeps the momentum going.

Cancer’s Week in the Spotlight

Cancer has been in the news a lot this week. We learned that two pop-culture artists – David Bowie and Alan Rickman – lost their battles with cancer. It’s a stark contrast to the news we heard last month about President Jimmy Carter, who has had a positive treatment response to his melanoma, according to news reports.

As MRA’s founder, Debra Black, and President and CEO-Elect, Robin Davisson, penned in USA Today recently, the number of new treatments available for patients like Mr. Carter has grown rapidly in the last few years. And therapies that have been pioneered in melanoma are showing benefit for many other types of cancer. But there is no time for complacency.

While we don’t know details about the cancers that took the lives of Bowie and Rickman, their deaths underscore the breadth and devastation of this disease. They also highlight the need to focus our resources and collective efforts to address cancer.

But even factoring in optimistic expectations, experts agree that we are nowhere near curing or conquering this disease for all patients. The ongoing need for research is still extremely compelling. – Debra Black and Robin Davisson, in USA Today

On Tuesday, in the State of the Union address, President Obama announced a new initiative to coordinate national efforts to fight cancer. Vice President Biden, who lost his son to cancer last year, will spearhead the effort, Moonshot Initiative to Cure Cancer, which he explains on Medium.

While the goals are lofty and there won’t be one cure-all for cancer, many organizations have come out in support of this effort, including the National Comprehensive Cancer Network. As President Obama said in his State of the Union Speech: “For the loved ones we’ve all lost, for the family we can still save, let’s make America the country that cures cancer once and for all.”

 

Researcher Q&A: Dr. John D’Orazio

In the latest blog post, we chatted with the University of Kentucky’s John D’Orazio, M.D., Ph.D., a pediatric hematologist oncologist, and a 2015 MRA grant awardee. Read on to learn what he has to say about melanoma research and prevention efforts.

How did you get interested in melanoma and your field of research?

I am a physician scientist who combines a clinical career in pediatric oncology with basic research aimed at understanding the molecular mechanisms of melanoma development. Kids don’t usually get melanoma, thankfully. But prevention is such an important part of combating this disease – particularly during childhood since pediatric UV exposure plays such an important causative role for melanoma later in life. My overarching interest, related to pediatric oncology, is understanding cancer predispositions.

Tell me about your research.

During my fellowship, I paired up with Dr. David Fisher, who is one of top melanoma biologists in the world and who happened to also be my ward attending on the pediatric oncology service at Boston Children’s Hospital. David approached me with a research project relating to understanding why fair-skinned people get melanoma so much more than dark-skinned individuals. We knew it wasn’t just about melanin since albinos – people with normal numbers of melanocytes but who don’t make melanin at all because of inherited defects in melanin synthetic enzymes – almost never get melanoma.

In the Fisher lab, I focused on the contribution of the melanocortin 1 receptor (MC1R) in pigmentation and melanocyte UV sensitivity. We chose to study MC1R since loss-of-function MC1R polymorphisms are very common among fair-skinned people and raise lifetime melanoma risk by about four-fold. Using a unique mouse model that I developed, David and I discovered that MC1R controlled whether a mouse’s skin would express dark or light melanin.

We found that pharmacologic replacement of MC1R signaling function, through the topical application of cAMP-promoting drugs to the mice, was enough to turn the skin from a blonde UV-sensitive and cancer-prone complexion to a heavily melanized UV- and cancer-resistant phenotype instead. We had demonstrated sunless tanning by pharmacologic manipulation of the MC1R signaling axis, suggesting that skin could be shielded from UV damage by melanin stimulation.

Since establishing my own lab, we’ve focused on other ways in which MC1R signaling enables melanocytes to resist UV damage and carcinogenesis. We’ve been studying how cAMP signaling increases the efficiency by which melanocytes recover and repair UV DNA damage.

How has MRA funding helped your work?

MRA funding absolutely lets us open up a new avenue of research that wouldn’t have otherwise been possible. We’re still focused on MC1R signaling but are now funded to study the natural hormonal regulation of this pathway in the skin. The MRA grant allows us to study how the pathway impacts melanoma risk on multiple fronts.

What do you hope to see more of in the future of melanoma research?

Melanoma incidence just keeps getting higher. Whatever is underlying it, we have to do something about it. Almost 2% of the population is going to be affected by melanoma in their lifetime. It’s a big problem, and although exciting advances are being made in the field of anti-melanoma therapeutics (especially targeted therapy and immunotherapy), it is still far better to avoid the disease in the first place. I would like to see more focus put into active melanoma prevention, not only through policy and indoor tanning regulation, sun protection, and public health aspects, but by using a science-based approach to enhance the skin’s ability to resist UV-mediated carcinogenesis.

What do you do when you’re not seeing patients or conducting research?

I’m a family guy. I have one daughter, a wife who is in science, and a dog. I love to cook, enjoy nature photography and have gotten pretty good at pickleball.

 

Learn more about MRA’s Research.

 

Fast and Furious: Melanoma Research in 2015

By Louise Perkins, Ph.D.

Chief Science Officer

The world of melanoma has changed dramatically in a way one might not have envisioned in 2011. How can you tell?  From the stories of patients and their caregivers. A common story can go like this: Just diagnosed with Stage 4 melanoma. Need to select the best treatment approach sooner than later. Many options to choose from. What questions should they ask the doctor?

In 2008, when MRA’s first grants were made, no one would have imagined we’d be talking about how to choose among so many treatments for patients. The pace of change has been fast and furious since 2008, and it’s picked up steam in 2014 and 2015.

In less than 5 months, there have been 5 new treatment approaches approved by the FDA. Think about that for a minute! This pace of treatment change is beyond unprecedented and includes a number of “firsts.”  What were these changes and what does it mean for patients?

“Firsts” for Melanoma in 2015:

  • The first combination immunotherapy – ipilimumab and nivolumab – approved
  • Nivolumab is approved as a first line of treatment, marking the first anti-PD-1 immunotherapy drug for previously untreated BRAF wild-type melanoma
  • T-VEC, an oncolytic viral therapy that’s directly injected into a tumor, is the first of its kind treatment to be approved
  • Vemurafenib and cobimetinib is approved by the FDA, the first melanoma combination approval that includes a never-before-approved drug
  • Ipilimumab is approved for adjuvant treatment, the first checkpoint inhibitor drug approved in the adjuvant setting
  • Pembrolizumab is approved as a first line of treatment for metastatic melanoma regardless of a patient’s BRAF status – the first anti-PD-1 therapy to receive such designation

All of these ‘firsts’ should give you a sense of the true innovation in new treatment approvals that melanoma is spearheading with the help and support of patients, doctors, companies, and the FDA. These offer good options for patients as they pick their Plan A.

So, patients should always be thinking about Plan B in discussion with their doctors. Why? Because cancer is tricky, and it sometimes roars back just when it seems like it’s been beaten. In addition to that, not all patients respond to immunotherapy or targeted therapy. Others simply can’t tolerate the treatments and have to be taken off for their own safety.  This means we still need different options to battle this awful disease.

What’s Needed for Melanoma Research?

New studies are underway that address two main needs:

  1. How to use the drugs we have now in better ways, either alone or in combination
  2. Defining the biology of difficult-to-treat disease and figuring how that knowledge can be used to find new targets and treatments

Fine-tuning the drugs we have

Finding the optimal order by which to give treatments (e.g. Drug A then Drug B or Drug B then Drug A or Drug A and B at the same time) remains key if we are going to maximize the utility of these existing miraculous treatments. The field needs to think broadly about cause and effect of using various drugs, their impact on cancer cells, the immune system and the body as a whole especially as it relates to having drugs work in otherwise resistant melanomas.

Tackling difficult-to-treat melanoma

It is becoming increasingly clear that altered signals inside the cell that flow through a node called ERK are important in the vast majority of melanomas. The presence in half of melanomas of BRAF mutations that ultimately activate ERK provided the first clue that this was important. Further studies are showing that a panoply of alterations turn ERK signaling on even in the absence of activated BRAF. This highlights the need to more effectively target ERK signaling and resistance to such inhibition.  And new ways to stimulate the immune system would be a plus, too. All of this is the sort of research that MRA has supported and continues to as much as possible.

Making a long story short, there is an overriding need for continued innovation. Too many patients are not benefiting from these new therapies, and we have to ensure that new targeted and immunotherapy approaches are invented and tried – based on sound science.  What are the next new immune therapies? New signaling inhibitors?  Is there a critical mass of info that can form the basis of the next leap in progress?  This is where we need to push.

11Therapies Approved

Daughter Celebrates Her Mom’s Health This Holiday Season

By Hilary Rogers

In this guest post, Hilary Rogers, a member of the Leveraged Finance Fights Melanoma Steering Committee, shares her perspective on her mom’s battle with melanoma.

In the winter of 2012, my family and I found out that our mother’s stage 3 melanoma diagnosis had progressed to her lungs. Even though this was not that long ago, the treatments available at the time only promised to delay the inevitable by a few years at most. On the tails of a wonderful

Rogers family

Author Hilary Rogers, left, and her family.

Thanksgiving and Christmas, it was heartbreaking to imagine it being one of the last holiday seasons that my mother, father, brother, sister and I would all spend together as a family. While I am sure that our parents shared the same fears that my siblings and I did, they were determined to not let melanoma interrupt our family’s future holidays together. They remained positive and researched various clinical trials, and we were thrilled when our mother was admitted into a trial for the new and promising immunotherapy drug, nivolumab.

After only a few months of receiving the treatment, the tumors on our mother’s lungs began to shrink. We were ecstatic when her doctor reported that the tumors were no longer there in the fall of 2014. It has been over a year since we received the incredible news, and we are happy to report that our mom is as healthy as ever.

Through good times and bad over the last three years, our mom continues to be the first one up on Christmas morning as she always has been. Rather than eclipse our family holidays, her fight has brought our family and friends even closer together.

When the FDA approved several of the immunotherapy drugs last year, my family and I were thrilled for the thousands of melanoma patients whose lives were about to potentially change by having access to these groundbreaking drugs.  My family and I are extremely grateful for the work and dedication that go into the research, funding and development of these innovative drugs that have changed the medical landscape, and most importantly, the lives of those affected by melanoma.

What we’ve gone through has brought new awareness to my family and everyone we know. I can’t get into my brother’s car without seeing his SPF 70 sunscreen handy in the center console. My sister and I go to the dermatologist regularly for skin checks. This year we’re even taking a family trip for New Year’s to foggy London rather than some warm beach as we have done in the past.

Most importantly, we as a family understand the risks of this disease, but also the hope that lies in today’s new treatments. It has been our goal and pleasure to spread this awareness to people and families going through what we went through so that their holidays may continue to be happy too.

We would like to thank MRA as well as the researchers, doctors and –above all else – the patients who have enrolled in these groundbreaking trials. Your hard work, dedication and bravery have made it possible for our family as well as countless others to look forward to enjoying many more joyful holidays together in the years to come. For that, we are eternally grateful.