Why do cancer patients die?
For those with solid tumors, it’s usually because their cancer has metastasized. It’s spread beyond the spot where it first cropped up — the breast, colon, lung, pancreas, ovary, prostate, testicle or other tissue — and continued to grow and to colonize distant sites around the body.
Metastatic cancer is deadly, although many stage 4 patients are able to prolong their lives with treatments. Metastatic cancer is also one of, if not the most, challenging areas of cancer biology, which is why there hasn’t been a ton of focused, funded metastatic research and few actual cures.
Fred Hutchinson Cancer Center hopes to change that with the launch of the Center for Metastasis Research Excellence, or MET-X, a focused research program aiming to crack one of the toughest biological challenges in medicine.
Led by translational researcher Cyrus Ghajar, PhD, MET-X will be an interdisciplinary and collaborative program focused solely on solid tumor metastasis: its detection and prevention, but also treatments and ultimately, cures for this advanced stage of cancer.
“The establishment of MET-X is an exciting step on our path toward building world-class solid tumor research that spans basic, translational and clinical research,” said Dr. Thomas J. Lynch Jr., Fred Hutch president and director and holder of the Raisbeck Endowed Chair. “This new program will bring researchers with common interests together to tackle the toughest challenge in cancer and will become part of the lens through which Fred Hutch will recruit new talent.”
Not just preventing, but curing ‘mets’
Ghajar said MET-X is not just about trying to prevent early-stage cancers from progressing to metastatic disease. He believes that, with the right amount of research, it’s possible to both prevent and cure metastasis (also referred to as advanced, secondary or stage 4 cancer).
“A big part of my research program in breast cancer has been targeting the seeds of metastasis before they can sprout — preventing it that way,” said Ghajar, who along with Fred Hutch’s Christopher Li, MD, PhD, and Stanley Riddell, MD, recently received $25 million in funding from the U.S. Department of Defense to do just that.
“But even if we were entirely successful, many patients present with de novo metastatic disease — they’re stage 4 from day one,” he said. “We have to be able to do something for them. We have to be able to target and treat mets far more effectively than we’re doing now.”
Riddell holds the Burke O’Reilly Family Endowed Chair in Immunotherapy and Li the Helen G. Edson Endowed Chair for Breast Cancer Research.
MET-X will take a non-incremental approach to dealing with treatment resistance, according to Ghajar. Instead of profiling the patient’s tumors over and over, looking for new mutations or pathways to target after the cancer develops resistance, they want to look at the commonalities by which metastasis takes hold — and thrives — in various organs of the body.
“We need a transformative approach to metastasis,” Ghajar said, “We don’t want to confine ourselves to seeking out disease-specific vulnerabilities that a tumor will find its way around in a few months. Our aims will be broader. For instance, studying metastatic sites like the liver and brain to uncover tissue-specific and tumor-agnostic ways that metastases, within these tissues, evade immunosurveillance. Or, figuring out how we can fool tumor cells into thinking that they’re actually part of that organ so that they differentiate into innocuous masses.”
The whole point, Ghajar said, is for MET-X to inspire new ways to think about late-stage disease.
“But we’re not making this about one cancer,” he said. “This is about all solid tumors.”
The metastatic patient’s perspective
J Caldwell, husband of the late Beth Caldwell, said she would have been “ecstatic” to learn about the new initiative.
A Seattle disability rights attorney who was diagnosed with metastatic neuroendocrine cancer of the breast at age 41 and died three-and-a-half years later, she actively lobbied for metastatic research funding on social media and before legislatures and co-founded the activist group MET-UP, organizing “die-ins” to remind people metastatic breast cancer, or MBC, doesn’t come with a happy ending.
“I think Beth would be very encouraged to hear Fred Hutch is going after the fundamentals of metastasis,” J Caldwell said. “Metastatic research has had slow, painful progress because we haven’t had the technology or the understanding or the money. Metastasis isn’t sexy, it’s not revenue-generating so it lacks funding.”
According to the nonprofit Metavivor, only around 2-5% of the funds raised for breast cancer research are spent on studies of metastatic disease. Making mets a focus of research is both smart and in sync with what patients truly want, he said.
“And Cyrus Ghajar has a great track history,” he said. “He sees metastatic cancer from the patient’s point of view. That’s a really good sign.”
Teri Pollastro, an MBC patient and research advocate with the Translational Breast Cancer Research Consortium, TCBRC, has worked with Ghajar on numerous research projects. She’s also already agreed to join MET-X’s internal advisory committee.
“It makes so much sense to me that MET-X will include multiple cancer types,” she said. “As more targeted therapies are created, it’s become less and less about the type of cancer you have and more about the mutations in the tumor. These mutations are shared across cancer types so I think this particular focus will make major strides in cancer. And there couldn’t be a better person running MET-X.”
Lynda Weatherby, a former health care administrator who developed mets after early breast cancer treatment, said she was incredibly hopeful.
“This is different than what’s going on at other institutions,” she said. “This is practice-leading now. I’m excited for it to become practice-changing.”
Weatherby worked with Pollastro, Caldwell and others to launch the annual patient-centered NW MBC Conference and is currently a Fred Hutch patient advocate, a member of the MBC Alliance’s Executive Group and a host on the Our MBC Life podcast.
She and her husband Todd, a Seattle tech executive, are longtime philanthropic supporters of metastatic research and Fred Hutch.
“We are really passionate about hopeful, big solutions for patients, like the MET-X approach,” she said. “The majority of the research going on now seems to be about treatments. But that’s always temporary. Mets patients are always grateful for new therapies that can extend our lives, but we need a solution.”
Weatherby likened current treatment practices to a game of “metastatic whack-a-mole.”
“With metastatic disease now, you’re stable and then you have progression, so they test to find out what’s different. If there’s a mutation that’s actionable and there’s a drug that will target it, you try that next and stay on it until it doesn’t work anymore,” she said. “Then you go back and do the same thing all over again.”
Ghajar’s vision for MET-X is different, she said.
“Cyrus has made it clear he wants to focus on the drivers of metastasis. He wants to figure out how you can arrest it. That just really resonated. He’s going after an answer that’s not whack-a-mole. Once he said that, I was like, ‘I’m in. What do you need?’”
Seeking MET-Xcellent researchers
Ghajar is currently recruiting a “dream team” of researchers from a variety of disciplines to join the MET-X program.
“There are lots of existing resources at the Hutch already — both intellectual and physical,” he said. “We have the Immunotherapy Integrated Research Center, we have people working to understand the tumor microenvironment and the microbiome, and we have a burgeoning developmental oncology program. We have some of the best blood cancer and HIV researchers in the world. We want and need all of these groups to be involved.”
He’s also hoping to attract researchers familiar with spatial profiling, which allows you to image and track gene expression within specific cells and tissues, as well as basic researchers interested in tissue-specific metastasis.
Metastatic cancer clinical trials will also be a signature part of the program, he said.“There is an inextricable element of precision oncology to this,” he said, adding that the new Stuart and Molly Sloan Precision Oncology Institute will be a major partner with MET-X.
The plan, Ghajar said, is to create an environment that will foster the risk-taking necessary for this type of research.
“We need to cultivate an environment where we encourage pursuit of daring questions that could result in transformative and curative therapies,” he said. “And we need to create a clinical trial infrastructure that provides an opportunity to benchmark the products of these studies in the pre-metastatic and metastatic settings.”
“We have to go after every facet,” Ghajar said. “We want to create an environment where people can be more daring — more open and vulnerable — so they can think more cutting edge, beyond the realm of what seems possible.”
Making metastasis ’a true focus of research’
Fred Hutch Lung Cancer SPORE patient advocate Janet Freeman-Daily, a former rocket scientist who has lived with metastatic lung cancer for 12 years, said she’s very encouraged by MET-X.
“I’m always encouraged when I see more people wanting to work on metastatic cancer,” she said. “That’s what actually kills stage 4 patients.”
A member of the external advisory board for the Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium and a national patient research-advocate, Freeman-Daily said the 5-year survival rate for metastatic non-small cell lung cancer was only 5% when she was first diagnosed in 2011. The survival rate is slowly increasing, thanks to newer targeted therapies and immunotherapy, but current data show it’s still only 7%.
“I would love to see more progress in this area,” she said. “But I’m no longer a starry-eyed patient. I know metastasis is a really tough problem.”
Ghajar agrees that cracking metastasis comes with many challenges — including, perhaps, a lack of focus by the research world.
“Metastasis is what kills the majority of patients, but despite that, there are few places that make it a true focus of research,” he said. “Maybe because they assume they’re doomed to failure, so people shy away from it. But we don’t make that assumption. We’re willing to meet this head-on.”
Weatherby feels strongly this is the right time and the right place, as well.
“Mortality is still increasing every year for metastatic breast cancer patients,” she said. “It used to be 40,000 who died every year and now it’s more than 42,000 a year. And the incidence of more aggressive, later-stage breast cancers and de novo MBC is rising fastest in women between the ages of 25 and 39. As cancer patients, we need more. And if we can’t do it here, with the talent at Fred Hutch and the support of this rock star community, where is it going to happen?”
This story was published by Fred Hutch News Service on February 3, 2023. It is republished with permission.