Metastatic breast cancer researcher Dr. Cyrus Ghajar has received a $4.1 million Department of Defense Breast Cancer Research Program (BCRP) “Era of Hope” Scholar Award.
The Department of Defense’s BCRP is the second biggest funder of breast cancer research in the U.S. Its Era of Hope award encourages high-impact, collaborative research, particularly among innovative young researchers. For this work, Ghajar has teamed with Fred Hutch researchers Drs. Julie Gralow, Jason Bielas, Eric Holland and Cecilia Moens, as well as investigators at Harvard Medical School and at the University of Colorado, Denver. Ghajar also has involved two local breast cancer patient advocates on this project.
Ghajar is the director of the Laboratory for the Study of Metastatic Microenvironments (LSM2), which is housed within the Translational Research Program in Fred Hutch’s Public Health Sciences Division. The LSM2 studies how microenvironments within distant tissues influence dormancy, drug resistance and the re-emergence of disseminated tumor cells. He will use the funds to research ways to prevent breast cancer metastasis by treating dormant disseminated tumor cells.
Metastatic breast cancer claims 40,000 lives a year; it’s estimated that 30 percent of all breast cancer cases will become metastatic. Interestingly, 20 percent of these cases will not emerge until a decade following therapy.
“The hypothesis is that these cells – which have left the breast and are in other organs basically sleeping – eventually wake up,” he said. “When women relapse seven or 10 years after treatment, these dormant cells are likely the root of recurrence.”
Ghajar is investigating two different paths for dealing with these dormant disseminated tumor cells: keeping them asleep and inactive, or destroying them altogether.
“Basically, we are hedging our bets. You might be able to keep these cells asleep forever, but this carries an inherent risk because you are leaving these ticking time bombs in your body. Perhaps we can mitigate this with a strong enough ‘sedative,’” he said. “But just in case, we also have ways we think will allow us to specifically get rid of them.”
According to Ghajar, the phenomenon of tumor dormancy has not been the subject of much study over the years. As a result, “we don’t really know a whole lot about these cells in terms of what puts them to sleep and what wakes them up,” he said.
Before joining Fred Hutch in 2013, Ghajar studied with Dr. Mina Bissell at the Lawrence Berkeley National Laboratory. Bissell did pioneering work in microenvironments and how they can impact dormant tumor cells.
“You can have a cell with oncogenic mutations, but if the microenvironment around the cell is telling it to behave, it will,” he said.
Ghajar found that single breast cancer tumor cells can exist peacefully on the blood vessels of various organs for months. However, if the blood vessel is disrupted – which can be brought on by inflammation and other processes – the cells will wake up and begin to form tumors.
“This grant is leveraging that finding,” he said. “We want to identify factors that keep the cells asleep and we’re going to try to systematically reinforce those cues in an attempt to prevent metastasis. We’re also going to profile the outside of the blood vessel and figure out if there are molecules that uniquely mediate chemo resistance. We want to see if there are interactions we can disrupt that would make dormant cells die when patients are given chemo.”
Finally, Ghajar has created 3-D, lab-based breast tumor model that will allow his team to target sleeping tumor cells in hopes of destroying them – and provide a lasting cure for cancer patients.
“There are thousands of approved compounds that we can apply to these tissues one by one and look for something that kills sleeping tumor cells without harming the rest of the tissue,” he said. “These are compounds that have been used in people before but not necessarily for cancer and not assayed for their ability to kill dormant tumor cells. It’s ambitious, but that’s what makes it so fun. And if we can find something that works, it would really be something.”
Dr. Chris Peterson of Fred Hutchinson Cancer Research Center’s Clinical Research Division will receive the Young Investigator Award Special HIV Cure Prize from the International AIDS Society, or IAS, and the French National Agency for AIDS Research, or ANRS, next month at an IAS conference in Vancouver, B.C.
His abstract was chosen from more than 2,500 submissions and singled out by judges for its “originality and vigor.”
His research involves removing blood stem cells from a preclinical model and using a gene editing technique involving zinc-finger nucleases, or ZFNs, to disrupt a receptor used as a doorway by most forms of HIV. The modified stem cells were returned to repopulate the immune system.
“This is the first time that engraftment of gene-edited blood stem cells has been shown in an autologous transplantation setting in a clinically relevant model,” said Dr. Hans-Peter Kiem, a Fred Hutch stem cell transplant researcher who was senior author of the study. “This will have significant implications not only for the HIV field but also for gene editing in genetic blood disorders such as sickle cell disease.”
Current studies are using viruses to target genes to replace the receptor. This strategy would allow an even greater proportion of the HIV-resistant cells to be present to fight infection, the abstract stated.
Peterson is a staff scientist in Kiem’s laboratory, where his work is part of the Fred Hutch-based defeatHIV, one of three federally funded consortia nationwide investigating different strategies for an HIV cure. Led by Kiem and Fred Hutch virologist Dr. Keith Jerome, defeatHIV seeks to modify an HIV patient’s own stem cells to mimic a genetic mutation called the CCR5 delta-32 deletion, which confers natural resistance to HIV. The mutation prevents CD4 cells – infection-fighting white blood cells that HIV targets – from expressing a receptor, called CCR5, on their surfaces. Without this receptor, it’s as though HIV is left standing at the door without a key to get in.
The approach is based on the only known case in which HIV has been cured, that of Timothy Ray Brown. In 2008 in Berlin, Brown received a bone marrow transplant to treat leukemia. His doctor sought out a donor with two copies of the CCR5 mutation in what turned out to be a successful effort to also cure Brown’s HIV infection.
Peterson will present his paper at both the biennial IAS Conference on HIV Pathogenesis, Treatment and Prevention and the Towards an HIV Cure Symposium that precedes it. The meetings take place July 18-22. In addition to Peterson and Kiem, other authors include researchers from the University of Washington and Sangamo Biosciences in Richmond, California.
Dr. Stephen Schwartz, an epidemiologist in Fred Hutch’s Public Health Sciences Division, has been appointed to the National Cancer Institute’s Board of Scientific Counselors – Clinical Sciences and Epidemiology.
The main function of the board is to advise NCI leadership on its Intramural Research Program, which consists of two divisions: the Center for Cancer Research and the Division of Cancer Epidemiology and Genetics.
The board provides advice on clinical/translational research programs as well as epidemiology and biostatistics programs.
In addition to attending several annual meetings, Schwartz’ board duties will include evaluating site visit reports to help determine the research undertaken by the NCI Intramural Research Program.
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