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Pathways to Discovery: Summer 2012

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Laboratory Finding May Lead to Improved Chemotherapy Response in Breast Cancer

This study is really exciting to us because it’s based on groundbreaking work that has been done by Dr. Conzen here at UChicago, and we’re finally seeing the laboratory work come to fruition.
–– Rita Nanda, MD

A novel approach to breast cancer therapy may soon help patients overcome cancer that is resistant to chemotherapy. By turning off a stress signaling pathway that stimulates tumor growth, a drug paired with chemotherapy may attack cancer cells more effectively. Suzanne Conzen, MD, professor of medicine, made the discovery through her ongoing research on signaling pathways and their contribution toward cancer. In 2000, she observed that the stress hormone cortisol activates the glucocorticoid receptor pathway in chemotherapy-resistant breast tumor cells.

To further explore this mechanism, Dr. Conzen analyzed gene expression data in early stage tumors from more than 1,000 breast cancer patients and found that high glucocorticoid receptor expression was associated with a faster relapse in patients with breast cancers lacking estrogen receptor expression. This finding suggested that the glucocorticoid receptor activates a tumor cell survival pathway, making it resistant to cell death induced by chemotherapy. Dr. Conzen hypothesized that targeting this receptor with a neutralizing agent would increase the effectiveness of chemotherapy.

In preliminary studies, Dr. Conzen combined the chemotherapy agent paclitaxel with mifepristone, a drug that targets the glucocorticoid receptor and interrupts the receptor’s signaling pathway. This combined regimen slowed the growth of breast cancers in a mouse model by about 50% when compared with chemotherapy alone.

Putting It to the Test
Dr. Conzen’s novel approach to breast cancer therapy is being tested in a Phase I clinical trial, which is currently enrolling patients at The University of Chicago Medicine and NorthShore University HealthSystem. The process is moving quickly, since the individual pharmaceutical agents being tested are already approved by the Food and Drug Administration for use in humans. If the trial demonstrates the combined therapy is safe, a Phase II clinical trial will be initiated to test the therapy’s effectiveness.

Rita Nanda, MD, assistant professor of medicine, who is working with Dr. Conzen to translate the research to the clinical setting, said, “This study is really exciting to us because it’s based on groundbreaking work that has been done by Dr. Conzen here at UChicago, and we’re finally seeing the laboratory work come to fruition.” She added, “We’re optimistic that it will soon be an effective treatment for women.”

Future Implications
Although the clinical trial aims to improve chemotherapy responses for all types of breast cancer, Dr. Conzen’s research predicts that the approach may provide a significant benefit for so-called “triple-negative” breast cancer, which lacks HER2, estrogen, and progesterone receptor expression. This particularly aggressive subtype of breast cancer is found at a higher rate in young women, especially women of African ancestry.

“This first study is just the tip of the iceberg,” said Dr. Nanda. “I imagine that this concept of blocking a tumor cell stress receptor pathway with the goal of improving chemotherapy effectiveness holds true for a variety of chemotherapy agents and has the potential to be more broadly applicable for other cancers, too.”

Ernst Lengyel

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