NEW YORK – A new program at the Fred Hutchinson Cancer Center is hoping to shake up precision oncology norms by focusing on research into strategies for preventing tumors from spreading and curing metastatic disease.
Headed by Cyrus Ghajar, a professor of public health at Fred Hutch, the MET-X program will bring together a multidisciplinary team of researchers to generate hypotheses and tackle ambitious new lines of research. "We've made very little progress on metastasis over the course of history," Ghajar said. "For patients with stage IV disease, it's a death sentence, and that hasn't really changed."
About 90 percent of cancer deaths are estimated to be due to metastatic disease. The prevailing paradigm in precision medicine for addressing metastasis is to profile the patient's tumor upon each recurrence and look for new mutations or pathways to shut down and stop cancer cells that have found ways to circumvent the pathways closed off by prior treatments. With the MET-X initiative, Ghajar is embarking on a transformative approach, in which researchers would focus on the sites where cancers have spread to understand tissue-specific mechanisms of metastasis rather than looking only at the oncogenic driver mutations. Ghajar's group will also build a tumor sample bank from metastatic cancer patients and advance new clinical trial protocols to capture endpoints relevant to metastasis.
When cancers metastasize, mutations in the tumor interact with the tumor microenvironment, Ghajar noted. Targeting the mutations with treatment buys the patient time, but the cancers ultimately develop resistance to those treatments and continue to spread. "You go from applying the new drug and getting a few months of non-progression, or maybe even response, to the patient progressing," Ghajar said. "You put the patient in the cycle of drug after drug after drug. They are very grateful for the extra time, but they are putting their bodies through hell."
In order to overcome metastasis and cure patients, Ghajar believes it will be necessary to go beyond targeting individual driver mutations iteratively. The impetus for the MET-X program is drawn from his background studying the tumor microenvironment and tumor dormancy in breast cancer. Ghajar said that when tumor cells from one site proliferate and reach distant organs like the lung, bone marrow, liver, and brain, these organs have the ability to regulate tumor cells and "put them to sleep," so they don't cause metastatic cancer.
Ghajar's group is working to gain a better understanding of the biological processes behind tumor dormancy and leverage that knowledge to either keep tumor cells dormant indefinitely or kill them while they're dormant so they don't have a chance to become active and cause metastases in the future. "We've been able to develop a pretty strong biologic understanding of what might be underpinning dormancy in our models," said Ghajar. "I emphasize in our models because what we don't know is exactly what's going on in humans because the specimens haven't been available."
Ghajar and colleagues recently received a grant from the US Department of Defense that will support the collection of patient specimens in which they can test those theories. But Ghajar has set his sights higher and wants to build something that can help patients with all types of metastatic cancers, especially those who present with de novo stage IV disease. He pitched the idea for a new research center of excellence focused on studying metastasis to the leaders at Fred Hutch Cancer Center with the goal of curing patients, not just prolonging their survival.
Meanwhile, his vision for the MET-X program is to establish a culture where risk-taking is embraced. "We have a really great critical mass of faculty here with expertise across the board who don't necessarily get together and talk about science," said Ghajar.
Fred Hutch faculty with wide-ranging expertise in topics such as minimal residual disease, tumor microbiota, HIV, and circulating tumor cells have already gotten together to generate ideas and give each other feedback in a series of brainstorming sessions. "We have retreats where groups with disparate expertise get together to come up with a novel solution," Ghajar said, describing how researchers present their ideas to the group at these retreats and choose the best idea to fund and fast-track into testing within high-risk pilot studies.
The research infrastructure backbone of MET-X will be a tissue bank drawn from rapid autopsies of patients who have died of stage IV cancer. The autopsies are carried out within four hours of death in order to capture the biology and spatial architecture of both the metastatic sites and surrounding tissues. Several research-oriented cancer centers have invested in building rapid autopsy programs in the hopes of developing better precision oncology strategies, and the MET-X group is in discussions to try to expand a longstanding rapid autopsy program in prostate cancer at Fred Hutch to more cancer types.
While precision therapeutics in cancer are largely only approved for patients with late-stage cancer, Ghajar said that moving them into earlier lines of therapy to prevent metastasis will require clinical trials with robust surrogate endpoints to generate evidence that the drugs are safe and more effective than other available options. Treatments for earlier-stage disease would also require a rationale rooted in disease biology that the drug is able to target disseminated disease.
"You need really strong evidence and an appropriate preclinical model that this drug, whatever it may be targeting, [for example] a PIK3CA or KRAS mutation, is actually efficacious in the setting of minimal residual disease," said Ghajar. "And then, you need to think about what those readouts are going to be in the patient when you apply that drug to say it's going to have long-term efficacy based on a shorter-term surrogate endpoint."
One of the more promising avenues to accomplish that, according to Ghajar, is in the area of cellular immunotherapy. Ghajar's group has been working with Fred Hutch immunologist Stanley Riddell to investigate cellular immunotherapies as a way to directly target dormant tumor cells. "In preclinical models, we have pretty extraordinary results with these cells using model antigens," he said. "That begs the question: What are the antigens that are actually presented on these cells in people?" If he and his colleagues can find those antigens, they believe they can develop specific cellular therapies that only target disseminated tumor cells, which would minimize on-target, but off-tumor effects.
Research within MET-X will span basic, translational, and clinical research. That's going to require innovation in experimental design, Ghajar said, especially clinical trial design. For example, he said "it's almost cliché" to say immunotherapies work poorly in metastatic solid tumors, except melanoma. Cellular immunotherapies also struggle in that setting, but it's important to ask why, Ghajar said. "I don't think we're going to get to that question by only superficially profiling the tumor microenvironment," he added.
To that end, in addition to building its library of specimens, MET-X will be partnering with oncologists to develop new clinical trial protocols and endpoints that can provide the answers needed. "That innovation is going to require people like me who have a Ph.D. talking with people who have an M.D. who are willing to do something a little different in the metastatic setting," said Ghajar.