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Grantee: Katherine Varley, PhD
Institution: Huntsman Cancer Institute, University of Utah
Area of Focus: Breast Cancer Genomics, Epigenetics, and Biomarkers
Grant Term: 1/19-12/22
“When my mother’s breast cancer recurred shortly after she finished treatment, we were both shocked. We wanted to know why the chemotherapy she endured didn’t work for her when it had worked for so many other women. This question has led me on a career path focused on identifying differences in the genome between patients’ tumors and on understanding how these differences affect response to treatment.
"I work with a wonderful team of scientists in my lab to compare the genomes of hundreds of breast tumors. We have discovered drivers of tumor-cell growth that are unique to a subset of breast cancer patients and that can be targeted with new combinations of existing drugs. We’ve also identified genomic differences between patients who respond to treatment and those whose cancers recur.
"I think my mother would appreciate that her struggle with cancer recurrence has inspired our work to identify new therapies to stop tumor-cell growth and determine which treatment is best for each patient.”—Katherine Varley, PhD
The Challenge: About 10% to 15% of people diagnosed with breast cancer have the triple-negative subtype. There are few FDA-approved targeted therapies to treat triple-negative breast cancer (TNBC), and even after treatment, almost half of people with TNBC have a recurrence within 3 years. Development of new treatment strategies for this deadly cancer is crucial.
The Research: With support from a research grant from the American Cancer Society (ACS), Katherine Varley, PhD, recently published a study about her lab’s work on the basal-like subtype of TNBC. Most people with TNBC have this aggressive subtype, which is more common in women who are younger than age 40, African American, or have the BRCA1 mutation.
Research has shown that each of the many different subtypes of breast cancer has a unique driver of cancer-cell growth, which requires a unique treatment. Development of targeted therapies for the basal-like triple-negative cancer subtype has been slowed because it’s been challenging to identify its unique driver.
In a recent study, Varley’s lab found that this subtype has not just one driver, but two. Her team was the first to discover that two cancer-promoting proteins cooperate to “turn on” (express) hundreds of genes that drive the aggressive behavior of TNBC cells.
These proteins (glucocorticoid receptors [GR] and STAT3) are transcription factors, which are involved in the process of converting, or transcribing, DNA into RNA. Transcription factors help determine which genes are active in each cell of the body.
Drugs have already been developed to target each of these proteins separately, but their cooperative role hasn’t previously been described.
Varley’s team found that combining the drugs to block both proteins at the same time decreased the growth of the breast cancer cells more than blocking either protein alone. This suggests a new combination targeted treatment strategy—using drugs to block both GR and STAT3—could be effective for treating basal-like TNBCs.
Why Does It Matter? There’s a precedent for cancer drugs that target a transcription factor. For instance, certain breast cancers that aren’t the triple-negative subtype are often dependent on estrogen to grow. These are treated most effectively with hormone therapy that targets the estrogen receptor alpha transcription factor and blocks estrogen to help slow or stop tumor growth.
Current clinical trials are separately testing a variety of STAT3 inhibitors and GR inhibitors. Varley’s findings support this line of investigation and offer promising opportunities for future studies to learn if combination treatment with STAT3 and GR inhibitors improves efficacy, or if combination treatment can provide similar efficacy with a lower, better tolerated, dose of each drug.
“We’re excited to work with colleagues across the country to determine if this combination treatment strategy improves outcomes for women with this type of breast cancer,” Varley says.