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Three young international investigators working in metastatic breast cancer research at Fred Hutchinson Cancer Research Center recently received postdoctoral fellowships totaling nearly $500,000.
The researchers, Drs. David (Jinxiang) Dai of China, Arko Dasgupta of India and Laura Pisarsky of France all work in the Laboratory for the Study of Metastatic Microenvironments under translational researcher Dr. Cyrus Ghajar.
Their work there focuses on disseminated tumor cells, or DTCs, which migrate from primary tumors early on in order to take up residence in the microenvironment of organs such as the lungs, liver and bones. There, the cancer cells may remain dormant throughout the course of a patient’s life — even during chemotherapy for early stage disease — or they may “wake up” and begin to create new metastatic tumors, or “mets,” ending the cancer’s remission and eventually, the patient’s life.
“These awards are a testament to how hard all three of these fellows have worked since coming to the Hutch; how much progress they’ve been able to make on their projects and how creatively they’ve approached them,” said Ghajar of the researchers. “It also shows how the field is starting to recognize how important tumor dormancy is. We need new strategies to target metastasis and we’ll do that by developing an understanding about dormant disseminated tumor cells.”
Ghajar said his postdocs will be pursuing work that will shed light on the “conversations” DTCs are having with their microenvironments, or “tissues of residence,” as well as how those conversations change upon therapy.
“I feel comfortable saying we’re going to make substantial progress in the next two to three years and these three individuals will be a big reason why,” he said.
Dr. David Dai, who came to the Hutch after receiving a Ph.D. in cell and developmental biology from the University of Colorado, received a prestigious Breast Cancer Research Program Breakthrough Postdoctoral Fellowship Award from the Department of Defense.
The $300,000 award will fund three years of research into the cellular and molecular mechanisms of disseminated tumor cell dormancy in brain metastasis. Dai will be co-mentored by Fred Hutch molecular biologist and neurosurgeon Dr. Eric Holland.
“We’re trying to discover the mechanism of how disseminated tumor cells interact with the brain’s microenvironment,” Dai said. “We’re trying to see how they survive, how they wake up and once they wake up, how they grow bigger — the cascade of colonization in the brain as a specific, unique environment.”
Thanks to improvements in treatment, metastatic breast cancer patients are living longer, but a longer life also means a higher chance of developing metastasis to the brain. While treatments are often successful at targeting common metastasis sites like the liver, the lungs and the bones, the blood-brain-barrier prevents most therapies from reaching tumor sites in the brain.
“They can cure the other relapsing organs but somehow the brain mets arise and become resistant to these treatments,” Dai said. “It’s a big factor now, more than in years past.”
Dai believes the brain’s microenvironment, and its innate immune system, may hold the key to eventually destroying these tumor cells.
“The brain is considered immune-privileged tissue — it’s believed that T cells and B cells [cells of the immune system] don’t get there — but they actually get there when a tumor cell is there,” Dai said. “We’re looking for disseminated tumor cells that are there. These cells often stop dividing, but a long time later, [they] wake up and start creating tumors. We believe the unique microenvironment in the brain provides a protective niche environment for the DTCs. We’re looking for systems to provoke these innate cells to their supposed function: kill the tumor.”
Dr. Arko Dasgupta came to the Hutch two years ago after receiving his Ph.D. in genetics and biochemistry at Dartmouth College. He is the recipient of a two-year 2018 Terri Brodeur Breast Cancer Foundation grant totaling $100,000.
His research will also focus on the process that renders dormant DTCs resistant to chemotherapy. Previous research has shown that the microenvironment protects dormant prostate cancer cells; preliminary work by Dasgupta suggests that it protects dormant breast cancer cells from chemotherapy, as well.
“It’s like the tumor cell is hijacking the stabilizing aspects of the blood vessels,” he said. “The blood vessel is trying to protect itself from the chemo and the dormant tumor cell hijacks it by being in that area. But if we can target factors generated by the microenvironment and then block them, maybe we can make the dormant cells more sensitive to the chemotherapy. Maybe we can figure out how to destroy them before they wake up. ”
Dasgupta will use mouse models and 3-D model systems to recreate the microenvironment and study how it reacts to chemotherapy. He will also use throughput technologies to find potential targets that result from the dormant cells’ response to the chemotherapy.
“Something in the microenvironment at the distant sites keeps them asleep and keeps them chemo- resistant,” he said. “We’re trying to figure out the cross talk of the microenvironment and the breast cancer DTCs. If we can actually eradicate these cells before they grow out in the patient — we prevent metastatic breast cancer-associated mortality and give these patients peace of mind.”
Dr. Laura Pisarsky, who joined the Hutch in 2016 after receiving a Ph.D. in cell biology from the University of Basel in Switzerland, received her second Postdoc.Mobility fellowship from the Swiss National Science Foundation, allowing her to continue with her research at the Hutch for another 18 months. The award comes with approximately $79,000 (she previously received $90,000).
“Reactivation of disseminated tumor cells directly transforms breast cancer from ‘remission’ into an incurable, metastatic disease,” she said. “Understanding the molecular mechanisms implicated in DTC dormancy and/or reactivation is therefore essential to design therapies able to maintain dormancy and avoid patient relapse.”
To do this, Pisarsky will look at anti-angiogenic therapies, which are drugs designed to stop cancers from growing new blood vessels. She believes these drugs disrupt microvascular homeostasis, or equilibrium, shutting down the tumor-suppressive nature of the tissues surrounding the blood vessels and allowing the dormant cells to start actively multiplying, leading to the development of metastatic tumors.
“My aims are to analyze the response of DTCs to blood vessel disruption following anti-angiogenic therapy, characterize the molecular changes within the perivascular niche that occur upon treatment with these therapies and then design combination therapies that target angiogenesis and dormant tumor cell reactivation,” she said. “A better understanding of this mechanism will help us prevent recurrence.”
Pisarsky will use animal models to validate her findings. Once validated, she will attempt to optimize therapy regimens by combining current anti-angiogenics with new Food and Drug Administration-approved inhibitors.
“Understanding the reason underlying anti-angiogenic therapeutic failure will help us uncover the biology of tumor dormancy and the mechanisms involved in reactivation of DTCs in response to vascular damage,” she said. “It will allow us to design more efficient regimens that will hopefully offer durable remission to breast cancer patients.”
All three postdocs expressed gratitude to mentor Ghajar, referring to him as a “creative thinker” with “bold ideas.”
“Cyrus is a great mentor,” Dai said. “He’s very open to discussing all the possibilities of what’s going on in the science realm. And he’s open to challenging assumptions.”
Ghajar said he was thrilled regarding his postdocs’ success and emphasized the importance of a collaborative approach to science.
“It’s worth emphasizing that each of these fellows has come from outside the U.S. to study here in our country and to ultimately conduct cancer research at the Hutch,” he said. “It’s a testament to cancer being a world problem. We need to expand beyond borders to solve it. And I think it’s great that there are organizations in the U.S. willing to fund the best and the brightest minds.”
— Diane Mapes / Fred Hutch News Service
Fred Hutch file photos
Fred Hutchinson Cancer Research Center has received three grants of $500,000 each from the Cancer Research Endowment (CARE) Fund, a public-private partnership that supports cancer research in Washington. The grants will support the work of three researchers as part of the CARE Fund’s inaugural Distinguished Researchers program.
The Hutch’s three CARE Distinguished Researchers are:
- Dr. Heather Greenlee, an associate member of the Cancer Prevention Program in the Public Health Sciences Division, is a doctor of naturopathic medicine who has a doctorate in epidemiology. As a population scientist, her research focuses primarily on cancer survivorship with an emphasis on the issue of obesity in cancer survivors. Her research portfolio currently includes funded studies examining a dietary intervention among Hispanic women with breast cancer and studying factors associated with cardiovascular outcomes in breast cancer survivors. “Her behavioral intervention research on cancer survivorship in racial and ethnic minority populations was deemed to have high significance and high potential for translation into patient care,” according to a CARE Fund statement.
- Dr. Mark Headley, an affiliate investigator in Immunology in the Clinical Research Division, whose seeks to understand the biology of cancer metastasis to the lung and finding new ways to treat such metastatic cancer. In particular, he is interested in studying interactions between the pulmonary immune environment and cancer spread. “His work has significant translational potential and [is] anticipated to guide a new generation of metastasis-targeted interventions,” according to a CARE Fund news release.
- Dr. Lev Silberstein, an assistant member of the Clinical Research Division, who studies factors that regulate the behavior of normal and malignant stem cells in the bone marrow. According to the CARE Fund, “His research program has translational implications for addressing the important clinical problems posed by bone marrow failure, myelodysplasia, and related syndromes.”
“This is an incredibly talented and diverse group of researchers who will advance cancer research and health outcomes in our state,” said Dr. Frederick Appelbaum, chair of the CARE Fund board and executive vice president and deputy director of Fred Hutch. “We know that cancer research breakthroughs occur through the work of talented and well-resourced scientists, and the CARE Fund is pleased to support the recruitment of these distinguished researchers. With each of them will come additional research dollars, laboratory and other jobs, and the promise of real cancer research progress.”
Other CARE Fund recipient institutions announced Jan. 16 included the Institute for Systems Biology and Washington State University.
The CARE Fund was made possible by $2.5 million in awards of public funds to support cancer research, which will be matched by more than $6 million in private or other non-state resources.
In addition to this first cohort of Distinguished Researchers, the CARE Fund launched its Breakthrough Research Grant Program Fund in January to provide grants of up to $750,000 to support innovative, cross-disciplinary cancer research. A second cohort of Distinguished Researchers will be evaluated and selected this spring.
— Based on a CARE Fund news release
Photo by Scott Streble for Fred Hutch
Dr. Damian Green, a translational researcher at Fred Hutchinson Cancer Research Center, is part of an inaugural class of 33 Next Gen Innovators honored recently by HemOnc Today, a publication for oncology professionals. The award announcement coincided with the American Society of Hematology annual meeting in December.
HemOnc Today editorial board members, along with other leaders in the field, nominated the Next Gen Innovators, “a highly select group of early career hematologists and oncologists who have advanced their field through innovative approaches in the clinical and research settings,” according to the publication.
The publication will tap the Next Gen Innovators in several ways, according to HemOnc Today Editorial Director Mark Leiser. "They will be encouraged to share story ideas or suggest trends we should cover for our print issue or our online platform, Healio.com. They will provide perspectives — brief third-party commentaries — that give them the opportunity to share their reflections on study results published in peer-reviewed literature or presented at scientific meetings, and also offer insights into the potential clinical implications of those results." Next Gen Innovators also can serve as sources for cover stories or feature articles, and they will be welcome to contribute editorials or commentaries on topics related to their clinical or research interests, he said.
“We look forward to working with this unique group of early career hematologists and oncologists to help bring a broader scope and perspective to our readers,” said Joan-Marie Stiglich, chief content officer of SLACK Inc., the publisher of HemOnc Today.
“It is an honor to be selected as a Next Gen Innovator,” Green said. “I met with fellow awardees at the American Society of Hematology last month and was able to make new connections that have promise for future collaboration.”
Green, an associate member of the Clinical Research Division at Fred Hutch and an associate professor of medical oncology at the University of Washington School of Medicine, is also an attending physician at Seattle Cancer Care Alliance. His laboratory and clinical research focus on developing new immunotherapeutic approaches to treat — and ultimately eradicate — multiple myeloma and lymphoma.
— Kristen Woodward / Fred Hutch News Service