Sun, Skin, and Science

There was a lot to be excited about in the field of cancer care when F. Stephen Hodi began his fellowship in medical oncology at Dana-Farber Cancer Institute in the mid 1990s. But for patients with metastatic melanoma—cancers that begin in melanin-producing skin cells then spread to other parts of the body—he could offer little help.

Although new chemotherapy drugs and genetic insights were making inroads against many cancers, treatments for metastatic melanoma worked in only about 15 percent of patients. The median survival was 11 months.

Seeing two to four new patients each week with the disease, Hodi would ask himself, “Why are you doing this?”

Yet even while asking the question, he knew why: He, along with some other oncologists, suspected that this deadly disease might be vanquished by training the immune system to attack tumor cells.

“Trying to find that Achilles’ heel posed a big challenge,” Hodi recalls, “but it made it that much more interesting to get up in the morning and go to work.”

Twenty-five years later, immune and targeted therapies, developed and tested by researchers including Hodi and others in the HMS community, have changed melanoma’s narrative. Half of patients with metastatic disease now survive for at least five years.

Hodi, an HMS professor of medicine, the Sharon Crowley Martin Chair in Melanoma, and director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber, says, “We still have a ways to go, but now patients have a fighting chance.”

David Fisher, the HMS Edward Wigglesworth Professor of Dermatology and head of the Department of Dermatology at Massachusetts General Hospital, has similarly been thrilled to see—and to help—metastatic melanoma transform from “one of the worst diseases to treat” to “one of the more predictably responsive diseases” in little more than a decade.

The trajectory of the change, he says, has “really been wild.”

The new treatments wouldn’t have been possible without fundamental discoveries in immunology, genetics, skin cell biology, and cell signaling. HMS has long been a beating heart for these basic and clinical advances, and its scientists and physicians continue to push forward on multiple fronts, recognizing that melanoma’s story has not yet reached a fully satisfying conclusion.

“With the advent of highly efficacious treatments, there’s a tendency to celebrate the fifty percent who are cured, and we should, but it’s time to buckle down and think about the fifty percent who don’t make it.”

HMS clinicians and researchers are working to improve diagnosis and catch more melanomas early, when they’re still self-contained and highly treatable. They seek to prevent or delay relapse, predict which melanomas will turn deadly and which will respond to immunotherapy, and reduce the side effects and costs of treatment. They also are pushing to devise treatments for patients with advanced melanoma who haven’t benefited from the new therapies.

“With the advent of highly efficacious treatments, there’s a tendency to celebrate the fifty percent who are cured, and we should, but it’s time to buckle down and think about the fifty percent who don’t make it,” says Hensin Tsao, an HMS professor of dermatology and director of the Melanoma and Pigmented Lesion Center and the Melanoma Genetics Program at Mass General. “The sort of forgotten population.”

Successes in the lab and the clinic, however, remain vulnerable. Clinicians, researchers, and public health leaders struggle to convince people to change behaviors that increase risk, while keeping a wary eye on a rising incidence of melanoma, prepare for the increased risks that ozone depletion and climate change have begun to unleash, and rally to confront the racial disparities that persist in survival rates.

“Science has melanoma on the run,” says Tsao. “But it hasn’t eradicated the disease in any way.”

Rising sun

Skin cancers are far and away the most common cancers in the United States. Basal and squamous cell carcinomas make up the vast majority, with somewhere between 1 million and 5.4 million new instances diagnosed each year. However, because these two malignancies don’t have to be reported to cancer registries, precise numbers aren’t known: The cancer officially ranked as the most common in this country is breast cancer, with 270,000 new cases each year. Melanoma is ranked fifth, with about 100,000 new diagnoses expected in 2020, reports the American Cancer Society (ACS).

Melanoma may account for a small percentage of skin cancers, yet it causes an estimated 75 to 80 percent of skin cancer deaths. Caught early, it has a 99 percent five-year survival rate, but if it slips patients’ and clinicians’ notice, digs deeper into the skin and spreads beyond the lymph nodes, that rate can drop to 25 percent, according to the National Cancer Institute. The ACS predicts there will be 6,850 deaths in the United States from melanoma this year.

Although improved therapies for metastatic melanoma have helped tamp down death rates, incidence in this country has risen by about 4 percent per year since the 1970s, reports the World Health Organization. There are several theories as to why: Tissue that some doctors would consider precancerous, others are removing and reporting as melanoma abnormalities; most melanomas occur in older adults, and the U.S. population is aging; and more people may be baring unprotected skin to natural and artificial sunlight.

Light weight

The sun gives life, yet its light is not benign. Exposure to ultraviolet radiation remains the most significant environmental cause of melanoma—and the most preventable. A good deal of work by HMS researchers is helping to reveal exactly how sunlight leads to melanoma through genetic mutations and other changes in unprotected skin and through suppression of the immune system.

Melanoma is more than twenty times more likely to arise in white than in Black people, the ACS reports. Although more skin pigment provides more protection, melanin itself has a sun protection factor, or SPF, of less than 5, says Fisher, suggesting that it functions physiologically as more than mere sunblock. He and others have clarified how different types of melanin raise or lower melanoma risk, and they’ve shown that any minimal benefit provided by tanning, such as the production of vitamin D, doesn’t outweigh the DNA damage caused by UV exposure. These findings have inspired Fisher and colleagues to seek UV-free ways to stimulate the tanning pathway while also preventing melanoma.

Research by Fisher and others indicates why some people pursue risky behaviors even after they’ve had melanoma: UV exposure is addictive, activating reward centers in the brain in the same way opiates do. Fisher theorizes that the pleasure of soaking up the sun evolved to help ensure that the body synthesizes enough vitamin D.

“We’re fighting an evolutionary drive,” he says.

In addition to individual risky behavior, humanity is collectively compounding its melanoma risk. Depletion of the ozone layer, which absorbs high-wavelength, or UVC, rays and captures most medium-wavelength, or UVB, rays, has allowed more cancer-spawning radiation to reach Earth’s surface. Ozone damage has slowed since international reductions in ozone-eroding chemicals went into effect in the 1980s, but experts say it will be decades before our planetary sunscreen is restored. The WHO estimates that because of ozone thinning, U.S. populations of European descent will see a 10 percent increase in skin cancer by 2050.

Melanoma incidence may rise further as the planet warms. A 2002 study in mice conducted by researchers in the Netherlands found that UV light becomes 5 percent more carcinogenic for each 1 degree Celsius rise in environmental temperature. This could disproportionately harm people whose access to shelter is limited as well as those who may spend more time outdoors as winters and the climate at higher elevations turn milder.

Close the gap

UV light isn’t at the root of all melanomas. Some occur on non-sun-exposed or hairless skin, particularly the palms and soles and under the nails. These acral melanomas are most common in people with darker skin. Since health care providers aren’t always trained to look for cancers in these areas, and since melanomas there may look different from images traditionally featured in textbooks, acral melanomas tend to be caught later, when they’re harder to treat, says Tsao. The result has been a schism in outcomes.

Fifty-two percent of Black patients and 26 percent of Hispanic patients receive their melanoma diagnosis after the cancer has progressed to a late stage, compared to 16 percent of white patients, reports the Skin Cancer Foundation, an international organization based in New York City. So while Black people are overall less likely to develop melanoma, those who do are more likely to die from it. The five-year survival rate, which runs as high as 94 percent among white people, languishes at only 70 percent among Black people, according to the foundation.

Then there are the rare, noncutaneous melanomas, which occur in mucous membranes or the eye. These also occur more often in non-white populations. Beyond being linked to a few inherited genetic mutations, the causes of these noncutaneous melanomas remain obscure, and the cancers themselves don’t respond well to current therapies.

Mutations galore

As the Human Genome Project neared completion at the turn of the millennium, researchers leapt to understand which inherited, or germline, mutations raise the risk for melanoma and which acquired, or somatic, mutations in the tumor itself promote growth and metastasis and define therapeutic response. Geneticists, including Tsao and others at HMS and the Broad Institute of MIT and Harvard, have identified numerous germline and somatic mutations that help illuminate the genetic causes of this skin cancer.

Melanomas turn out to be packed with more mutations than any other cancer, and these mutations provide a wealth of targets that drug developers can aim for. Although most of the genes have not panned out as targetable therapeutics, a few have led to breakthrough treatments.

The poster child is BRAF. About half of melanomas contain mutations in this gene, a link in a major signaling chain that regulates cell proliferation, differentiation, movement, and self-destruction. Most have the specific mutation V600E.

Researchers were able to identify a drug that could lock onto and disable B-Raf proteins containing the V600E mutation. In contrast to classic chemotherapy drugs, targeted therapies act on abnormal proteins found only in the tumor or its immediate vicinity. Chemotherapeutics attack any cell—friend and foe—that divides quickly.

The first B-Raf inhibitor for melanoma, vemurafenib, entered human trials, where clinicians led by Keith Flaherty, an HMS professor of medicine and director of the Henri and Belinda Termeer Center for Targeted Therapy at Mass General, demonstrated that it indeed improved survival for participants with late-stage disease. In 2011, it received FDA approval.

“It was pretty extraordinary,” recalls Tsao, who as a cancer geneticist was delighted to see anti-B-Raf therapies make a dent in the disease. “In less than a decade, they went from identifying the first mutation in BRAF to a B-Raf(V600E)-specific drug. The era of molecular therapies came into being.”

Researchers developed other inhibitors for B-Raf as well as for a related protein, MEK. Again, Flaherty took a leading role in demonstrating their effectiveness—and showing that in combination, B-Raf and MEK inhibitors are even more powerful and produce fewer side effects. One of the drugs developed for melanoma has also worked for non-small cell lung cancer.

“It’s humbling how little we understand about the immune system.”

Research continues in an effort to solve challenges associated with B-Raf inhibitors and other targeted therapies. First, their effects wear off over time, with about half of patients developing resistance after six months. Solutions to this problem may soon come as Flaherty and others have uncovered reasons why some melanomas become resistant.

In addition, B-Raf inhibitors sometimes stimulate growth of other skin cancers and precancers even as they attack melanoma, requiring a supplemental treatment. In 2019, Michael Eck illuminated the problem. Eck, a professor of biological chemistry and molecular pharmacology at HMS and professor of cancer biology at Dana-Farber, used cryo-electron microscopy to capture the first high-resolution images of B-Raf bound to MEK and another key protein in active and inactive states. His work suggests ways to prevent this collateral damage.

Self-defense

Certain types of immune cells attack anything they perceive as harmful. For these cells each mutation, each unfamiliar protein in a tumor, provides, Fisher says, a “wonderful opportunity for the immune system to say, Oh, what is this terrible thing? Destroy.”

Cases of immune system attacks on cancer have been recorded for more than a century, including spontaneous remission of melanomas and other skin abnormalities. Martin Mihm Jr., an HMS professor of dermatology, part-time, and director of the melanoma program and the Mihm Cutaneous Pathology Consultative Service at Brigham and Women’s Hospital, helped demonstrate that the presence of white blood cells in melanomas, called tumor-infiltrating lymphocytes, signals better outcomes from the disease. He continues to study tumor-infiltrating lymphocytes to improve prognostic accuracy, and others are investigating them as a melanoma treatment option.

Despite the clues that immune cells could be powerful anticancer allies, it was clear that they didn’t always, or even often, win the battle. Until recently, attempts to bolster immune responses met with mixed success. Finally, in the early 1990s, researchers discovered a crucial reason why: Cancer cells don camouflage.

“The tumor appears to push back with a signal that says, Hold on. I’m part of you,” says Fisher.

Biologists over the next 20 years identified the molecular camouflage and devised ways to strip it off. They found that many of the body’s healthy cells have surface proteins that bind to other proteins on T cells and send a “do not attack” signal. They further discovered that tumor cells can sprout proteins that trick these so-called immune checkpoints, sending false signals for the T cells to stand down.

Using those insights, researchers showed that blocking one of the key proteins—whether on the T cells, such as CTLA-4 or PD-1, or on the tumor cells, such as PD-L1—exposes the tumors as dangerous and releases the brakes on the immune system. Arlene Sharpe, MD ’82 PhD ’81, the George Fabyan Professor of Comparative Pathology and chair of the Department of Immunology at HMS, and Gordon Freeman, PhD ’79, a professor of medicine at HMS and Dana-Farber, made pivotal contributions to the understanding of immune checkpoints and their inhibition.

Finally, immune checkpoint inhibitors dangled within reach like ripe fruit, and melanoma researchers lifted their hands. Hodi, who meets regularly with Sharpe and whose office is a few doors down from Freeman’s, ran the first Phase III trial of a CTLA-4 inhibitor. Although many participants still died from metastatic melanomas during the trial, a significant number responded to the treatment. Immune cells at long last reached their potential for treating cancer.

“We saw clumps of white cells and dead melanoma cells in previously intractable lymph node and brain metastases,” says Hodi of tissue samples from participants early in the trial, “so we knew there was something potentially powerful happening. We couldn’t give up on that.”

That something powerful led to the drug ipilimumab, which received FDA approval in 2011 for late-stage melanoma. It was the first immune checkpoint inhibitor for any cancer. Inhibitors of PD-1 and PD-L1 followed. The first two of those, approved for late-stage melanoma in 2014, now treat more than a dozen other cancers, including kidney, colorectal, and endometrial cancers. Researchers have gone on to develop four more FDA-approved checkpoint inhibitors that tackle a variety of cancers.

Immune checkpoint therapies can provide longer disease control for melanoma patients than other therapies, but they are expensive. Reducing their cost will be necessary to ensure equal access and spare health care budgets. Another shortcoming: some patients develop immune overactivity and need additional treatments or to stop immunotherapy treatment. About half of patients do not receive a long-term benefit.

“It’s humbling how little we understand about the immune system,” says Hodi.

No dearth of ideas

In less than two decades, melanoma has risen from failing student to head of the class.

“Melanoma led the way as a proof of principle that you can use immunotherapy as a general rather than as a disease-specific treatment modality,” says Hodi.

“I do think melanoma has had a disproportionate influence,” says Fisher, who is also director of the Cutaneous Biology Research Center at Mass General and the Melanoma Program at the Mass General Cancer Center, “particularly in the immunotherapy space. It jump-started the most important chapter in recent memory. Hopefully that progress will continue.”

But melanoma researchers at HMS are not resting on any laurels. Investigation continues in an effort to improve all stages of the patient experience, from prevention to cure.

Mihm laid foundations in the 1960s and ’70s for early detection and classification of melanoma into subtypes. Tsao recently published a paper detailing a range of melanoma presentations to help clinicians catch these malignancies earlier, improve consistency, and reduce disparities. Fisher hopes to see noninvasive diagnostic methods in the near future. Such tools could reduce unnecessary biopsies. Today, for each person who receives a melanoma diagnosis, there are an estimated twenty-five people whose biopsies do not reveal melanoma.

To improve prognosis, Tsao hopes genetics will help researchers predict more than just the risk of cancer. His next goal is to identify inherited changes that can predict the risk of developing a lethal cancer. For instance, Tsao and Ivana Kim, an HMS associate professor of ophthalmology at Massachusetts Eye and Ear, showed that germline mutations in the gene BAP1 may increase the risk that a melanoma in a specific layer of the eye, the uvea, will metastasize.

To halt earlier-stage melanoma in its tracks, researchers are exploring the use of immune checkpoint blockades and targeted therapy to prevent the return or spread of cancer. So far, B-Raf and PD-1 inhibitors appear to cut relapse rates in half for patients with stage 3 melanoma, where disease has crept into the lymph nodes. Although it’s too early to tell, Fisher and others hope that those cases represent not just a delay in relapse but permanent eradication.

In cases where melanoma does advance, HMS researchers are teaming up to improve current treatments and identify new ones.

“Melanoma led the way as a proof of principle that you can use immunotherapy as a general rather than as a disease-specific treatment modality.”

They’re testing checkpoint inhibitors in combination with each other and with targeted therapies. They’re working to evolve the immunotherapies themselves to help more patients and reduce adverse events. A major short-term goal is to predict who will respond to checkpoint therapy so those who won’t can seek alternative treatments and be spared the side effects.

They’re building better vaccination treatments, including adding antigens to tumors that flag melanoma cells for immune attack. They’re engineering therapeutic viruses to prefer cancer cells, both killing the cells directly and drawing the immune system in afterward. And they’re investigating not only the best combinations but also the best order in which to deliver treatments.

The path for developing entirely new therapies is not yet clear, says Hodi, who is himself exploring the possibilities of manipulating tumor blood supply and modeling the three-dimensional tumor microenvironment in collaboration with neighbors at the Wyss Institute for Biologically Inspired Engineering.

“To get past that fifty-percent bar, we have to take a step backward and return to basic investigation, basic principles, basic questions,” he adds.

Conversations continue among clinicians and scientists across specialties, sparking new ideas for how to raise survival rates until the day arrives when we can look back in disbelief that metastatic melanoma was once a death sentence.

Stephanie Dutchen is a science writer in the HMS Office of Communications and External Relations.

Images: Dung Hoang (top); John Soares (Fisher and Tsao)