Spotlight on James Alvarez

On the Hunt for Deadly Dormant Breast Cancer

James Alvarez, Cell Biologist

It’s not just about the science for Dr. James Alvarez, a cancer cell biologist with Fred Hutchinson Cancer Center’s translational research program. It’s also personal.

Alvarez investigates metastatic recurrence in breast cancer, also known as stage 4 or MBC, which happens when cancer cells spread from their original site to other organs of the body such as the brain, bones, liver and lungs. Metastatic breast cancer is often treatable but is not yet curable.

Alvarez wants to change that.

“My mother-in-law was diagnosed with triple-negative breast cancer when my wife was in college,” he said. “Usually with triple-negative disease, if there’s no recurrence after five years, you’re good. But she developed a metastatic recurrence at six years and died a couple of years later.”

Metastatic recurrence is not uncommon. Around 20% of early-stage breast cancer patients will develop metastasis within 20 years, although “mets,” as it’s known, can happen five, 10, 20, even 30 years after initial treatment (and some women are diagnosed with stage 4 from the start). Hutch scientists believe later recurrences are driven by disseminated tumor cells that travel from the original cancer site and lie undetected, inactive and protected within the body’s bone marrow, until these dormant cells somehow awaken and start to create new tumors.

Once disease has become metastatic, it’s harder to treat. The cancer develops resistance to drugs and therapies — sometimes after years, sometimes mere weeks.

It’s this resistance that Alvarez hopes to overcome.

“It’s clear in breast cancer and in cancer in general,” he said. “Coming up with a molecularly targeted therapy against an oncogene [cancer-driving gene] is only the beginning. You also have to think about, from the outset, how tumors might develop resistance to that drug and eventually recur.”

In other words, you need to go on the offensive. On the hunt, even.

“That really was my scientific impetus for exploring this area of research,” he said. “The central goal of my lab is to identify cellular and molecular pathways that govern the survival and eventual recurrence of residual dormant tumor cells.”
Dr. James Alvarez biking
Cancer biologist, Dr. James Alvarez riding his bike. Photo courtesy of James Alvarez

Exploring new pathways

In his last position at Duke University School of Medicine, Alvarez used mouse models to better understand the mechanism of recurrence and resistance in a subtype of breast cancer known as HER2-positive. HER2+ cancers have an excess of a growth-promoting protein, HER2.

Now he wants to see if that work will translate to cancer patients.

Alvarez will be working with patient specimens so will know “from the very beginning that the pathways we’re identifying are relevant to recurrence in patients,” he said.

And he’s homing in on the metabolic pathway and a master regulator protein – Nrf2 – which he said is “really important for cancers to recur after a treatment with a HER2+ targeted therapy.”
“We think that if we can figure out a way to target it, we could prevent the emergence of recurrence,” he said. “In mouse models, we showed that’s true.”

The big question, he said, is how do you target it? If it was an enzyme, you could develop a drug to block its catalytic activity. If there were telltale proteins on the surface, you could use an antibody to home in on them.

“But it’s none of those things,” he said. “It’s a transcription factor; it just turns genes on and off. These are historically difficult to drug — they’re undruggable. So how do you target it? We have a couple of ideas.”

Alvarez plans to pursue these ideas in his new lab at the Hutch. And to continue to explore Nrf2’s role in metastasis, especially since his previous research showed high levels of Nrf2 in recurrent breast cancer tumors, whether they appear in the bone or the brain or the liver and whether the subtype of breast cancer is HER2+ or ER+ [estrogen receptor positive].

”We only had a small sample size but said it was really encouraging and good evidence that Nrf2 is really activated in a wide range of metastatic recurrences in patients,” he said.

So how would he go about targeting it? Isn’t it supposed to be undruggable?

“If you can’t target the protein yourself, you can target the pathway,” he said.

‘Part of the push on recurrence’

While research is Alvarez’s primary focus, he also hopes to find a few opportunities to teach and mentor, as well.

“I’m really interested in DEI [diversity, equity and inclusion] issues and training the next generation of scientists from underrepresented backgrounds,” he said. “At Duke, I taught a lot. I’m passionate about teaching. It challenges me in a good way, keeps me from getting too comfortable. The students are always asking questions I don’t know the answer to. They’re raising interesting perspectives.”

He's also looking forward to learning from his MBC research role models and new translational research colleagues, Drs. Kevin Cheung and Cyrus Ghajar.

“One of the big reasons I came here is the nucleus around Cyrus and Kevin,” he said. “I’m very excited to be part of the push toward working on metastatic recurrence. My mother-in-law knew there was the possibility of recurrence; it was always looming over her. Every breast cancer patient feels that way. It creates a lot of distress for patients with breast cancer. It’s important to work on this.”

On the trail

When not hunting down cures, Alvarez said he’s been busy exploring the parks of the Pacific Northwest with his wife, their three kids and their hound dog, Maple, a rescue they brought with them from North Carolina.

“I’m probably not ambitious enough to climb Mt. Rainier, but I do bike and would love to get involved in Obliteride [the annual Fred Hutch community fundraiser],” he said.

He’s also looking forward to meeting and working with researchers throughout the Hutch and connecting with local advocates.

“At Duke, I was connected to the patient community and I’m definitely looking forward to meeting the advocate community in Seattle,” he said. “It’s so important. I definitely want to set up new relationships and continue working with patient advocates.”

Most of all, though, this dedicated researcher keeps his eye on his prey.

“How are these tumor cells persisting in the patient’s body for five, six, even 20 years?” he asked. “It’s an important question and it has very important implications for patients. I also think it’s fascinating, scientifically.”

— By Diane Mapes, Oct. 22, 2021


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