AT THE FOREFRONT OF CLINICAL CHALLENGES:
Tackling Melanoma Brain Metastases
Not many people can pinpoint the exact moment their lives changed forever, but for Dr. Inna Smalley, Assistant Member at Moffitt Cancer Center, that moment came after a health scare when she was young. “I had a growing tumor that affected me,” she says. “It was a lymphatic malformation. I went from resection and relapse for years without anyone knowing what to do, what it was, or how to treat it.”
But hope finally came. “One day I met a clinician who said, ‘I know what this is, and I know of a clinical trial.”
The clinical trial was a success in more ways than one. Smalley responded well to treatment — and she got her first glimpse into medical research. “I thought, ‘Wow! There are people doing research and it affects how things are managed clinically,” says Smalley. “That’s when I knew I was interested in this work.”
Today, Smalley’s research — supported in part by an MRA Young Investigator Award co-funded by the Tara Miller Melanoma Foundation — is focused on one of the biggest challenges facing patients with melanoma today: treating those who have brain metastases. This is an urgent area of unmet patient need, because despite dramatic advancements in melanoma research overall, the understanding and treatment of brain metastases has lagged behind.
“I want to do something that makes a difference for patients that don’t have a lot of options right now. We wanted to take on a challenge that could alter the course of disease for these patients.”
Dr. Inna Smalley
Not many people can pinpoint the exact moment their lives changed forever, but for Dr. Inna Smalley, Assistant Member at Moffitt Cancer Center, that moment came after a health scare when she was young. “I had a growing tumor that affected me,” she says. “It was a lymphatic malformation. I went from resection and relapse for years without anyone knowing what to do, what it was, or how to treat it.”
But hope finally came. “One day I met a clinician who said, ‘I know what this is, and I know of a clinical trial.”
The clinical trial was a success in more ways than one. Smalley responded well to treatment — and she got her first glimpse into medical research. “I thought, ‘Wow! There are people doing research and it affects how things are managed clinically,” says Smalley. “That’s when I knew I was interested in this work.”
Today, Smalley’s research — supported in part by an MRA Young Investigator Award co-funded by the Tara Miller Melanoma Foundation — is focused on one of the biggest challenges facing patients with melanoma today: treating those who have brain metastases. This is an urgent area of unmet patient need, because despite dramatic advancements in melanoma research overall, the understanding and treatment of brain metastases has lagged behind.
“I want to do something that makes a difference for patients that don’t have a lot of options right now. We wanted to take on a challenge that could alter the course of disease for these patients.”
Dr. Inna Smalley
Above: Rendering of astrocyte. Right: The late Tara Miller
Brain metastases represent one of the most difficult-to-treat complications of melanoma and are a significant cause of patient morbidity and mortality.
• Today, nearly 40% of patients with metastatic melanoma have brain metastases at diagnosis. This figure increases to 75% of patients at autopsy.
• While currently approved therapies do work in the brain in some patients, they are far less effective at treating tumors there than in other parts of the body.
• Among solid tumors, rates of brain metastases are higher in melanoma patients than many other cancers.
“Historically the brain has been an area that’s difficult to study,” says Smalley. “We haven’t had a lot of access to brain metastatic tumors to even figure out what’s going on. We really don’t know why cells respond differently to therapy in the brain than they do at other sites.”
What Smalley’s research hopes to do is better understand how melanoma metabolism in the brain affects the pro-tumor, immune-suppressive functions of cells called astrocytes. Astrocytes play an incredibly important role of protecting brain tissue, supporting homeostasis of the central nervous system, and helping repair damage.
In many ways, astrocytes are like our body’s police, emergency medical technicians (EMTs), and traffic safety unit all in one: They help keep orderly function, support healthy blood flow, and can protect and repair. However, when tumors spread to the brain, they adapt to their new environment by changing their metabolism which can affect the function of normal cells surrounding them such as astrocytes. As a result, astrocytes don’t just ignore tumor cells, they treat them like never-healing wounds, ultimately promoting tumor survival in an otherwise harsh environment. Smalley is studying the metabolic programs in melanoma cells that have infiltrated the brain to identify vulnerabilities within the tumor-astrocyte interaction. Doing so could lead to the identification of new drugs that can increase the effectiveness of existing treatments, and ultimately weaken the tumor’s hold on the brain.
Smalley’s award is co-funded by the Tara Miller Melanoma Foundation, which was founded by Tara Miller in 2014 following her diagnosis with melanoma. While Tara tragically passed away later that year at just 29 years old, her legacy continues. Over the last decade, the Tara Miller Melanoma Foundation has raised over $7.5 million to support melanoma research at both University of Pennsylvania and in partnership with MRA.
“I’m truly honored to have received the award from MRA and the Tara Miller Melanoma Foundation,” says Smalley. “Tara’s faith in research and vision of rendering cancer powerless by advancing science resonates with me.”
Smalley says grant awards like the one she received are both humbling and incredibly impactful. “The funding environment can be brutal, especially for young investigators because we don’t yet have a history of successful funding. These grants are like a bridge to begin our research and secure future funding. They allow us to take risks with good ideas, build up evidence, encourage more people to study it, and make an impact clinically.”
Smalley says that the intent of her research is to be very translational. To do this, she tries to be as tuned into what’s happening clinically as possible, so she regularly participates in tumor boards and discussions with clinicians. When possible, she even shadows clinicians to better understand patient perspectives and what is important to them. “I want to address questions that are directly relevant to patient care in the clinic,” says Smalley.
And she is. Although it’s still early in the research project, preliminary data suggests that Smalley’s hypothesis may be right: Tumor cells affect astrocyte function; and astrocytes may be improving tumor cells’ ability to grow and survive in the brain microenvironment.
“This work is possible because of advocacy and patient involvement. Without having access to tissues to study and samples to study, we wouldn’t be able to do any of this. I want to tell patients and their families how valuable their contribution has been to our research in the field,” says Smalley. “I want them to know that their willingness to participate makes a huge difference in advancing scientific knowledge and we are very grateful.” 