Fred Hutch/UW Cancer Consortium Breast Cancer Researchers Receive Grants

Fred Hutch/UW Cancer Consortium Breast Cancer Researchers Receive Grants

Can a progesterone tracer predict treatment response?

Breast cancer oncologist Linden, Athena Emeritus Professor of Breast Cancer Research at UW School of Medicine, and nuclear medicine physician Delphine Chen, received funding from the BCRF, as well as the breast cancer translational research consortium and drugmaker Eli Lilly, to lead a multicenter collaborative study with partner institutions, Washington University in St. Louis, Missouri, University of Illinois in Urbana- Champaign and the University of North Carolina.

“This study will build on our experience with FES PET — a PET scan that uses an estrogen-based tracer — and our nationwide collaboration with the exceptional group at the University of Washington,” Linden said. “We are currently working on FFNP, a radiotracer that images the progesterone receptor.”

In recent years, Linden has studied the clinical utility of FES-PET, which illuminates estrogen receptors and can be used to predict whether hormone therapy will be effective in patients. Now she is leading a study to determine if a progesterone tracer known as FFNP-PET (short for 21 [18F] fluorofuranylnorprogesterone) can be used as a better predictive marker of the effectiveness of hormone therapy.

“While FES-PET is able to quantify the presence of estrogen receptors and assess tumor heterogeneity, it does not appear to be as accurate as FFNP-PET in predicting which patients will or will not respond to hormone therapy” , Linden wrote in the proposal.

This will be the first multicenter study to test the accuracy of FFNP-PET in predicting response to hormone therapy.

“If we are successful,” she writes, “it will allow future studies of FFNP-PET as an integral and predictive imaging biomarker to inform physicians when it is reasonable to use hormone therapy with or without new targeted therapy that relies on an active estrogen pathway.

The Phase 2 multi-site study will enroll 60 patients with hormone receptor-positive, HER2-negative metastatic breast cancer to assess the accuracy of FFNP-PET imaging in predicting response to abemaciclib (also known as Verzenio’s name) plus hormone therapy.

“The trial is not open yet, but we hope to be able to enroll a patient before the end of the year,” Linden said.

A breast cancer vaccine that targets obesity?

Disis, director of the UW Cancer Vaccine Institute and clinical researcher Fred Hutch, will continue her work on a vaccine designed to fight obesity, a major risk factor for breast cancer, especially in women with metabolic syndrome and of metabolic dysfunction.

Previous research has shown that obesity triggers the infiltration of CD8 T cells into fat, which in turn secretes type I (inflammatory) cytokines. This change in fat leads to an immune response that leads to metabolic dysfunction in both adipose (fat) tissue and the T cells themselves. Once this happens, the T cells are no longer able to maintain immune surveillance of the tumor. In addition, the secretion of adipokines promotes malignant or harmful cell transformation.

“Losing weight will not solve this problem,” Disis wrote in her proposal. “Immunological memory prevents T cell-associated inflammation from resolving even if an individual reaches a normal weight.”

The team therefore focused on strategies to increase type II (anti-inflammatory) T cells in inflammatory adipose tissue, with particular emphasis on creating an inflammatory vaccine directed against adipocytes (AD).

In a preliminary experiment, ten-week-old mice were fed a high-fat, high-sucrose diet and then once obese, randomized into two cohorts. One received the ADVac, the other received only an adjuvant. Significantly, fewer CD8+ cells were observed in the mammary adipose tissue of ADVac-immunized mice compared to control obese mice. There was also significantly less leptin detected in the serum of ADVac vaccinated mice compared to controls. Additionally, 60% of vaccinated mice were tumor-free at the end of the study, while 100% of control mice had developed tumors.

With the new one-year grant of $225,000, Disis and her team aim to determine the extent to which ADVac immunization can restore metabolic function at the tumor site and prevent the development of breast cancer and identify the systemic effects of ADVac immunization.

“We don’t want ADVac to replace the need to lose weight, but immunization with ADVac, if the vaccine proves safe, could eliminate the risk of chronic inflammation and the development of metabolic dysfunction. which leads to breast cancer,” Disis wrote in her proposal. “The systemic effects of the vaccine could provide important additional health benefits for men and women struggling with obesity, such as restoring insulin sensitivity.”

Digging deeper into hereditary breast cancer

Finally, Lasker Prize-winning King, the first person to determine that breast cancer could be hereditary, will continue to work to understand hereditary breast cancer in families where genetic mutations have not yet been found. Its BCRF funding will go towards two projects.

The first concerns new technologies. King and his team adapted rapidly evolving genomics technology to sequence large swaths of DNA into a single, very long strand, rather than thousands of short pieces.

“This approach allows us to discover complex mutations in DNA that otherwise could not be detected,” King said.

With the funding, they will use this long-read sequencing approach to evaluate families in the New York Breast Cancer Study. The NYBCS aims to identify all genes responsible for hereditary breast cancer in women of Ashkenazi Jewish ancestry.

The second project will be an exploration of the dysregulation of gene expression as the basis of hereditary breast cancer.

“We are particularly focused on inherited genetic variation that subtly alters the expression of genes important for breast cancer,” King said. “These subtle effects are not mutations, but simply changes in gene expression level, all within a normal range.”

King will study this variation in more detail and explore its effects on age at breast cancer diagnosis.

The Breast Cancer Research Foundation, founded in 1993 by Evelyn H. Lauder, is dedicated to “being the end of breast cancer” by advancing the world’s most promising research.

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