Researchers studying tamoxifen-resistant breast-cancer cells have discovered how the cells grow and proliferate and revealed that a new targeted experimental drug can be used in treating the condition.
Like a second door that opens after the first door closes, a signaling pathway called hedgehog (Hhg) can promote the growth of breast-cancer cells after tamoxifen shuts down the pathway activated by the hormone estrogen. A second signaling pathway, called PI3K/AKT, is also involved.
Activation of the Hhg pathway renders tamoxifen treatment ineffective and enables the tumor to resume its growth and progression.
As part of the study, researchers at the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) analysed over 300 human tumors and found that the tumors with an activated Hhg pathway had a worse prognosis.
Finally, the researchers showed that an experimental drug called vismodegib, which blocks the Hhg pathway, inhibits the growth of tamoxifen-resistant human breast tumors in an animal model. The drug is in clinical trials testing for other types of cancer.
Currently, chemotherapy is used to treat hormone-resistant breast cancers, but this is associated with significant side effects. This study has identified targeted therapies that could be an alternative to chemotherapy for these resistant tumors.
"Our findings suggest that we can target this pathway in patients with estrogen-receptor breast cancers who have failed tamoxifen therapy," said first author Dr. Bhuvaneswari Ramaswamy, a medical oncologist specializing in breast cancer at the OSUCCC - James.
In 2008, Ramaswamy was awarded pilot funding from the Ohio State Center for Clinical and Translational Science (CCTS) and the Center for Women's Health to compare the microRNA of tissue from tumors treated with tamoxifen with those that have not been treated.
The data from this early study provided critical information on how microRNA, a regulator of genetic expression, reflects a tumor's response to tamoxifen. The research team used these findings to help focus their current phase of research.
"We describe a link between the hedgehog signaling pathway, which promotes tamoxifen resistance, and the PI3K/AKT pathway. Targeting the hedgehog pathway alone or in combination with the PI3K/AKT pathway could be a novel therapeutic option for treating tamoxifen-resistant breast cancer," said principal investigator Sarmila Majumder, research assistant professor in molecular and cellular biochemistry at the OSUCCC - James.
Ramaswamy, an assistant professor of internal medicine at Ohio State, emphasizes that novel options are needed for these patients.
"A combined targeted therapy using both hedgehog and PI3K inhibitors could lead to a novel treatment for endocrine-resistant tumors in the future without use of chemotherapy," she said.
"Our next step is to organize a clinical trial to evaluate vismodegib in patients with tamoxifen-resistant breast cancer," she added.
The finding has just been published in the journal Cancer Research.