New funding boosts breast cancer research

Targeting the link between obesity and breast cancer

Disis, director of the UW Cancer Vaccine Institute and associate dean of the UW School of Medicine, has again received funding to continue work on ADVac, an adipose tissue-targeted vaccine aimed at addressing the role of obesity in breast cancer.

Obesity is a risk factor for breast cancer, especially in postmenopausal women, where the risk is 20-40% higher than in non-obese women. People with metabolic syndrome (obesity, type 2 diabetes and high blood pressure) are also at risk.

Obesity promotes early entry of CD8+ T cells into fat, which triggers an adaptive immune response that causes sustained inflammation. Over time, this inflammation leads to metabolic dysfunction in fat tissue and the T cells themselves, dysfunction that cannot be reversed by simple weight loss.

“These inflammatory T cells persist even after weight loss,” Disis said.

To combat this type of inflammation caused by fat tissue and its associated health risks, Disis and her team developed an anti-inflammatory vaccine that induces a type II anti-inflammatory T cell response.

Previous funding from BCRF was used to conduct a year-long preclinical study of ADVac in preclinical models to determine the extent to which the vaccine reversed metabolic dysfunction at the tumor site and prevented the development of breast cancer. Disis and colleagues used mass spectrometry to analyze metabolic changes in the adipose tissue of mice after vaccination. The results showed that “metabolic reprogramming in the adipose tissue of obese mice resembles the metabolic profile observed in lean mice,” Disis said, a shift that “may inhibit the growth of breast cancer.”

With the new funding, researchers will continue to use preclinical models to study optimal vaccine dosing and delivery, as well as to evaluate the best time between vaccine doses (14 versus 30 days). They will also estimate the number of booster shots needed after the initial “prime dose.”

Once they determine the vaccine composition, dose and treatment regimen, they will begin another preclinical study: vaccinate obese mice according to a specific schedule, then test metabolic function, changes in the composition of immune cells, especially T cells and macrophages, the main factors contributing to the vaccine. adipose tissue inflammation and metabolic dysregulation.

“We first try to determine the optimal vaccine formulation and dosing schedule,” Disis said. “Then we’re going to use it to improve rates of metabolic dysfunction by 60% or greater in obese mice, with or without an additional short course of metformin. We will then see if the toxicity profile allows this to be translated into clinical use. If so, the study will form the basis of an investigational new drug application submitted to the FDA for clinical trials.”

ADVac, which treats inflammation itself rather than just the symptoms of inflammation, could eventually be used to help people with metabolic syndrome, type 2 diabetes, fatty liver disease and other disorders associated with fatty inflammation.

“Our long-term goal is to bring ADVac into the clinic as a risk-reducing treatment that can be given to metabolically obese women,” Disis said, adding that the vaccine is not intended to replace the need for weight loss.

Instead, ADVac immunization will be used to address the risk of chronic inflammation and the development of metabolic dysfunction leading to breast cancer. And at a more affordable price than other weight loss methods.

“This type of vaccine will be much cheaper—and therefore more accessible—than any of the current drugs used to treat obesity and related diseases,” she said.

Exploring a new image tracing tool

Linden, which received $1.5 million in funding in 2022, will continue to investigate whether the PET/CT tracer of progesterone, known as FFNP (abbreviation for 21(18F)fluorofuranylnorprogesterone) may better predict response to endocrine therapy in combination with the CDK4/6 inhibitor abemaciclib or Verzenio.

Linden, an oncologist and breast cancer clinical researcher, holds the Athena Distinguished Professorship in Breast Cancer Research at UW Medicine.

Her clinical trialfunded by BCRF in collaboration with Breast Cancer Translational Research Consortium and conducted in collaboration with Washington University in St. Louis, Missouri, will be the first multicenter study to test the accuracy of FFNP-PET for predicting response.

Study participants will receive baseline PET/CT scans using an intravenous FFNP tracer, then take estradiol for 24 hours, followed by another scan with an FFNP tracer. Participants will then receive abemaciclib orally twice daily for 28 days. Participants will also receive endocrine therapy as chosen by their physician. This frequency will be repeated every 28 days until the patient’s disease progresses or the level of toxicity becomes intolerable.

Participants will also undergo a PET/CT scan using an intravenous glucose tracer known as FDG. These scans will be performed at baseline, and additional diagnostic imaging to evaluate the tumor will be performed every three cycles.

“We hope that using 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 has previously researched estrogen tracer detection. ER+ breast cancer patients, known as FES-PETapproved by the US Food and Drug Administration in 2020.

In search of undiscovered mutations

King, a professor of medical genetics at the University of Washington School of Medicine and the first person to determine that breast cancer can run in families, will continue his research projects focusing on hereditary breast cancer. King received $225,000 in BCRF funding.

“For many families severely affected by breast cancer, no genetic cause of the disease has been identified,” King said. “Our goal is to understand the heritability of breast cancer in these families.”

The funding will support two ongoing projects, one of which includes a new technology platform that will allow researchers to sequence large stretches of DNA as individual, very long strands, rather than thousands of short bits.

“This approach allows us to detect complex mutations in DNA that would otherwise be undetectable,” King said.

The second project will explore dysregulation of gene expression as the basis of hereditary breast cancer.

“We’re paying particular attention to inherited genetic variations that subtly alter estrogen receptor expression,” King said. “These subtle effects are not mutations, but simply changes in gene expression levels, all within normal limits. “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 hereditary causes of breast cancer in Palestinian women and creating an infrastructure to provide a full range of cancer genetics services, from genetic diagnosis to follow-up. and observation.

Founded in 1993 by Evelyn H. Lauder, the Breast Cancer Research Foundation is the world’s largest private funder of breast cancer research. By investing in the best scientific minds to study all aspects of the disease, from prevention to metastasis, and by fostering interdisciplinary collaboration, BCRF is accelerating the entire field and bringing us closer to the answers we urgently need to end breast cancer. Find out more and get involved at BCRF.org.