read-more
Read more about Fred Hutch achievements and accolades.
Six Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium scientists received new funding from the Breast Cancer Research Foundation to launch or continue studies aimed at improving outcomes in breast cancer, the second leading cause of cancer death in women.
Fred Hutch physician-scientists funded for another year include Executive Vice President for Clinical Affairs Nancy E. Davidson, MD, holder of the Raisbeck Endowed Chair for Collaborative Research; epidemiologist Christopher Li, MD, PhD, associate director of Diversity, Equity and Inclusion of the Cancer Consortium and epidemiologist and internist Anne McTiernan, MD, PhD, of Fred Hutch’s Public Health Sciences Division.
Hannah Linden, MD, associate program director of the Medical Oncology and Hematology Fellowship Program at Fred Hutch and UW Medicine, also received funding, as did University of Washington School of Medicine physician-researchers Nora Disis, MD, and breast cancer geneticist Mary-Claire King, PhD. Disis and King are also faculty members in Fred Hutch’s Clinical Research Division. All are part of the Cancer Consortium’s Breast and Ovary Cancer Research Program, long supported by BCRF.
Ongoing projects will explore the cancer-busting benefits of exercise, a potential vaccine to prevent breast cancer in women who are obese and the efficacy of a new imaging tracer. A brand new research project aims to engineer more effective responses to immune checkpoint inhibitors. Read on for more details.
Priming the tumor immune microenvironment
Davidson, a medical oncologist, received $225,000 in funding for a new research project aimed at expanding the use of immune checkpoint inhibitors to treat breast cancers. Partnering with her on the study is Fred Hutch cancer cell biologist James Alvarez, PhD, who studies metastatic recurrence in breast cancer.
Immune checkpoint inhibitors are used in metastatic triple-negative breast cancer and other contexts, but the response rate is low, only around 20%. Alvarez and Davidson plan to conduct a thorough high-resolution investigation of the tumor immune microenvironment, or TIME, in order to predict and engineer more effective responses to immune checkpoint inhibition.
Nuclear factor erythroid 2-related factor 2, or NRF2, is a transcription factor that regulates the cellular defense against toxic and oxidative insults through the expression of genes involved in oxidative stress response and drug detoxification.
NRF2 is associated with tumor recurrence, metastasis and poor prognosis in patients with NRF2-high cancers, which can include colorectal, esophageal, lung, ovarian, breast and other cancers. Preliminary research on NRF2 shows it may also have another role: regulating the tumor immune microenvironment.
“NRF2 has mainly been studied for its effect on tumor cell metabolism and redox homeostasis,” Alvarez said. “A role for NRF2 in suppressing inflammatory signaling and in regulation of the tumor immune microenvironment in cancer has not been documented.”
The Fred Hutch investigators hope to do just that with their new BCRF-funded project.
Preliminary work has shown NRF2 suppresses pro-inflammatory signaling in human and mouse breast cancer models. Consistent with this, NRF2 knockdown — a process that squelches its expression — leads to slowed tumor growth and increased immune cell infiltration.
“Our findings suggest that NRF2 inhibition may sensitize breast cancers to immune checkpoint inhibition by remodeling the tumor immune microenvironment,” Davidson said.
The investigative team will test this out by first performing high-resolution spatial and temporal analysis of the effects of NRF2 inhibition on the tumor microenvironment and then, determining whether NRF2 inhibition sensitizes breast cancers to immune checkpoint inhibition through altering the tumor immune microenvironment.
“We hypothesize that NRF2 inhibition sensitizes tumors to immunotherapies,” Davidson said. “If true, this would identify NRF2 as a previously unappreciated link between tumor cell metabolism and the immune microenvironment and NRF2 inhibition as a strategy for improving immune checkpoint inhibition responses in breast cancer.”
Davidson said this newly funded research will provide an important proof-of-principle.
“NRF2 inhibitors are in clinical development now,” she said. “So this work will set the stage for testing NRF2 inhibition as a clinical approach in NRF2-high breast cancers.”
Fred Hutch/UW/Seattle Children's Cancer Consortium members (from left) Drs. Anne McTiernan, Nora Disis and Mary-Claire King all received grants from the Breast Cancer Reseach Foundation (BCRF).
Fred Hutch/UW file photos
Building breast cancer recurrence prediction models
Li, holder of the Helen G. Edson Endowed Chair for Breast Cancer Research, received another year’s worth of funding — $225,000 — to continue creating risk prediction models for metastatic breast cancer. Li will partner with Fred Hutch’s Jeroen Huyghe, PhD, a computational geneticist with hands-on experience in the analysis of spatial and single cell omics data for this work.
Last year, Li and his team integrated genomic, transcriptomic, and clinical/epidemiologic data to develop and validate a risk prediction model for metastatic recurrence among patients with luminal B breast cancer. Luminal B cancers tend to have a poorer prognosis than luminal A breast cancers, which grow more slowly and are positive for estrogen and progesterone and negative for HER2 expression, or ER+/PR+/HER2-.
The researchers’ ultimate aim is to create assays that can predict recurrence for other subtypes including basal-like, often referred to as triple negative, and luminal A disease.
Patient data and samples for this project come from a large, population-based cohort known as BRAVO (Breast Cancer Risk Factors And Various Outcomes), which contains 1,216 luminal A, 607 luminal B, 487 HER2-overexpressing and 1,267 triple-negative breast cancer patients.
So far, the team has collected baseline demographic, clinical, and epidemiologic risk factors and prospectively followed patients for various clinical outcomes including recurrence and mortality. They have formalin-fixed paraffin-embedded (FFPE) tumor tissue from almost all patients along with germline DNA from saliva samples. Additionally, they’ve conducted bulk DNA and RNA sequencing on matched sets of 65 patients with (and without) basal-like recurrences as well as matched sets of 65 patients with (and without) luminal B recurrences.
The new funding will be used to perform deep immune cellular profiling of tumor tissue biospecimens from all 260 of these patients at single cell resolution, which will then be used to develop novel spatial predictors of recurrence to guide clinical decision making.
“We hypothesize that there will be important topographical differences in immune and cancer cells that will have clinical utility with respect to predicting risk of recurrence for each of the three breast cancer subtypes studied,” Li said.
The researchers will then use machine learning and artificial intelligence to develop and validate multi-omic predictors of cancer recurrence for the three subtypes.
“At present, there are no recurrence risk prediction models specific for luminal B or basal-like breast cancer patients that have sufficient performance to be clinically useful,” Li said. “Developing such models is of clinical value as demonstrated by the utility of Oncotype DX and other molecular panels, and there is a particular need for a panel tailored to luminal B and basal-like patients given their poorer prognosis compared to luminal A patients.”
Results of this work will help identify patients at high risk of recurrence who may benefit from advanced monitoring or alternative first line treatments.
“We aim to identify patients who will rapidly fail standard first line therapy,” Li said.
Results should also have longer-term translational potential through comprehensively studying the tumoral immune response and mechanism of immune evasion which can lead to novel therapeutic approaches relevant for particular breast cancer subtypes.
The hope is to improve the delivery of tailored treatments for patients at a high risk of recurrence “while at the same time being able to identify low risk patients who may be able to avoid more toxic/invasive breast cancer treatments," Li said.
How exercise can help prevent breast cancer
BCRF awarded McTiernan $225,000 to continue her investigations into the relationship between exercise and cancer development and progression.
McTiernan’s previous trial of ACute Effects of Exercise in Women (ACE), also funded by BCRF, examined changes in biomarkers related to inflammation and blood vessel growth in blood and muscle tissue of 102 women without breast cancer. Samples were taken both before and after 45 minutes of acute exercise (riding a stationary bike) or 45 minutes of rest (sitting down).
After analysis, McTiernan and colleagues found evidence that exercise changes muscle cell proteins involved in the regulation of gene expression, which are important in the development of breast cancer.
Her new study, Exercise-Stimulated Signaling Pathways Associated with Cancer Development and Progression, will continue to analyze the effects of exercise on various biomarkers of breast cancer risk and prognosis, using multi-omics analysis.
“By integrating proteomic, metabolomic and phospho-proteomic data in the context of a randomized control trial, we expect to identify tissue specific pathways that are altered in response to exercise,” McTiernan explained. “We also have the ability to test other biomarker effects of exercise using additional stored blood, and muscle samples.”
Looking ahead, McTiernan hopes this highly novel approach will help to provide answers to questions on how exercise affects biology so that “precise prescriptions can be provided to women to change lifestyle to reduce risk for developing breast cancer.”
McTiernan will partner with Fred Hutch co-investigators Catherine Duggan, PhD, Taran Gujral, PhD, Jean de Dieu Tapsoba, PhD, and Ching-Yun Wang, PhD, for the new work, and laboratory analysis will be carried out at Fred Hutch’s Proteomics and Metabolomics Shared Resource Labs. Additional analysis of protein levels and signaling pathways will be provided by Gujral, a systems biologist within the Fred Hutch Human Biology Division.
According to McTiernan, this is one of only a handful of studies to use multi-omics to analyze the impact of exercise on human biology.
“We anticipate that this integrative analysis using blood and muscle tissue samples from participants enrolled in our completed ACE trial will provide a more complete understanding of biological processes that occur in response to exercise,” she said. “We also believe the results will give women hope that they can do something to improve their health.”
‘For many families severely affected with breast cancer, no genetic reason for their illness has been discovered. Our goal is to understand inherited breast cancer in these families.’
— Fred Hutch/University of Washington clinical researcher and breast cancer geneticist Dr. Mary-Claire King
Targeting the obesity-breast cancer connection
Disis, director of the UW Medicine Cancer Vaccine Institute and associate dean of the UW School of Medicine, was again funded to continue her work on ADVac, an adipose directed vaccine to address the role of obesity in promoting breast cancer.
Obesity is a risk factor for breast cancer, especially in postmenopausal women, where the risk is 20-40% higher than for women who are not obese. Those with metabolic syndrome (obesity, type 2 diabetes and high blood pressure) are also at risk.
Obesity promotes the infiltration of CD8+ T-cells into fat early on, which triggers an adaptive immune response that causes sustained inflammation. Over time, this inflammation results in metabolic dysfunction in the fat tissue and in the T cells themselves, a dysfunction that can’t be eliminated simply by losing weight.
“These inflammatory T cells persist even after weight loss,” Disis said.
To combat this type of adipose-driven inflammation and its associated health risks, Disis and her team developed an anti-inflammatory vaccine that elicits a response from Type II anti-inflammatory T cells.
Previous funding from BCRF was used to conduct a year-long pre-clinical study of ADVac in preclinical models to determine to what extent the vaccine reversed metabolic dysfunction at the tumor site and prevented development of breast cancer. Disis and colleagues used mass spectrometry to analyze the metabolic changes in the adipose tissue of mice after vaccination. The results showed “a metabolic reprogramming in adipose tissue of obese mice to resemble the metabolic profile seen in lean mice,” Disis said, a shift that “may discourage breast cancer growth.”
With the new funding, researchers will continue to use preclinical models to investigate optimal vaccine dosing and delivery as well as assess the best timing between vaccine doses (14 versus 30 days). They’ll also evaluate the number of vaccine boosters that are necessary after the initial “priming dose.”
Once they’ve determined the vaccine formulation, dose and regimen, they will launch another preclinical study, vaccinating obese mice with the defined regimen, then testing for metabolic function, changes in immune cell composition, particularly T cells and macrophages, the major contributors to adipose inflammation and metabolic dysregulation.
“We’re first trying to identify the optimal vaccine formulation and dosing schedule,” Disis said. “Then we’re going to use it to improve measures of metabolic dysfunction by 60% or better in obese mice, with or without the additional short course of metformin. Then, we’ll see if the toxicity profile allows us to translate this to clinical use. If so, the research will form the basis of an Investigational New Drug Application to the FDA for a clinical trial.”
ADVac, which treats the actual inflammation itself, not just the symptoms of inflammation, could eventually be used to help those with metabolic syndrome, type 2 diabetes, fatty liver disease and other disorders associated with adipose inflammation.
“Our long-term goal is to bring ADVac to the clinic as a risk reducing agent that can be given to women with metabolic obesity,” Disis said, adding that the vaccine is not meant to replace the need for weight loss.
Instead, immunization with ADVac would be used to eliminate the risk of chronic inflammation and the development of metabolic dysfunction that leads to breast cancer. And at more affordable price than other weight-loss therapies.
“This type of vaccine would be much less expensive — and therefore more accessible — than any of the current drugs used to treat obesity and its resultant diseases,” she said.
Investigating a new imaging tracer
Linden, who received $1.5 million in funding in 2022, will continue investigating whether a PET/CT progesterone tracer known as FFNP (short for 21 [18F] fluorofuranylnorprogesterone) can better predict response to endocrine therapy coupled with the CDK4/6 inhibitor abemaciclib, or Verzenio.
A breast cancer oncologist and clinical researcher, Linden holds the Athena Distinguished Professorship of Breast Cancer Research at UW Medicine.
Her clinical trial, funded by BCRF along with the Translational Breast Cancer Research Consortium and run in conjunction with Washington University in St. Louis, Missouri, will be the first multi-center study to test the accuracy of FFNP-PET for predicting response.
Study participants will receive baseline PET/CT scans using the intravenous FFNP tracer, then will take estradiol for 24 hours, followed again by another scan with the FFNP tracer. Participants will then receive abemaciclib as a twice-daily oral medication for 28 days. Participants will also receive an endocrine therapy of the physician’s choice. This cadence will repeat every 28 days until the patient’s disease progresses or the toxicity levels become intolerable.
Participants will also have PET/CT scans using an intravenous glucose tracer known as FDG. These scans will be taken at baseline with additional diagnostic imaging for tumor assessment taken every three cycles.
“We’re hoping that the use of FFNP as an imaging agent will provide more precise information about the location of tumors than a PET scan alone can provide,” said Linden, who previously investigated an estrogen tracer for ER+ breast cancer patients known as FES-PET, approved by the U.S. Food & Drug Administration in 2020.
Searching for undiscovered mutations
King, a professor of medical genetics at the University of Washington School of Medicine and the first person to determine breast cancer could be inherited, will continue her research projects focused on inherited breast cancer. King received $225,000 in BCRF funding.
“For many families severely affected with breast cancer, no genetic reason for their illness has been discovered,” King said. “Our goal is to understand inherited breast cancer in these families.”
Funding will support two ongoing projects, one of which involves a new technology platform that enables researchers to sequence large swaths of DNA in single very long strands, rather than thousands of short bits.
“This approach enables us to discover complex mutations in DNA that could not otherwise be detected,” King said.
The second project will be an exploration of dysregulation of gene expression as a basis for inherited breast cancer.
“We are focusing particularly on inherited genetic variation that subtly alters expression of the estrogen receptor,” King said. “These subtle effects are not mutations, but simply changes in level of expression of the gene, all within a normal range. We have very preliminary evidence that these effects may influence breast cancer risk.”
King also received a small grant to work with Israeli and Palestinian researchers on a project aimed at analyzing the inherited bases of breast cancer in Palestinian women and to create an infrastructure that provides the entire arc of cancer genetics services, from genetic diagnosis to follow-up and surveillance.
Founded in 1993 by Evelyn H. Lauder, the Breast Cancer Research Foundation is the largest private funder of breast cancer research in the world. By investing in the best minds in science to examine every aspect of the disease from prevention to metastasis — and fostering cross-disciplinary collaboration — BCRF is accelerating the entire field and moving us closer to the answers we urgently need to end breast cancer. Learn more and get involved at BCRF.org.
