New drug holds promise for therapy-resistant breast cancer
Scientists have identified a first-in-class molecule that shuts down estrogen-sensitive breast cancer.
First-in-class drugs are drugs that work by a unique mechanism, in this case a molecule that targets a protein on the estrogen receptor of tumour cells. The potential drug offers hope for patients whose breast cancer has become resistant to traditional therapies.
All breast cancers are tested to determine if they require estrogen to grow and about 80% are found to be estrogen-sensitive. These cancers can often be effectively treated with hormone therapy, such as tamoxifen, but as many as a third of these cancers eventually become resistant. The new compound is a potential highly effective, next-line treatment for these patients, said Dr Ganesh Raj, Professor of Urology and Pharmacology at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center.
Traditional hormonal drugs, such as tamoxifen, work by attaching to a molecule called the estrogen receptor in cancer cells, preventing estrogen from binding to the receptor, a necessary step for cancer cells to multiply. But the estrogen receptor can mutate and change its shape over time so that the treatment drug no longer fits neatly with the receptor. When this happens, the cancer cells start multiplying again.
“There has been intense interest in developing drugs that block the ability of the estrogen receptor — the prime target in most breast cancers — from interacting with the co-regulator proteins that cause a tumour’s growth. Blocking such “protein-protein interactions” has been a dream of cancer researchers for decades. Dr Raj and his colleagues have done the remarkable by discovering what could be the first in class of a therapeutic that realises this dream,” said Dr David Mangelsdorf, Professor and Chairman of the Department of Pharmacology, who holds the Alfred G. Gilman Distinguished Chair in Pharmacology, and the Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology in Honor of Harold B. Crasilneck, PhD.
The drug works by blocking other molecules — proteins called co-factors that also must attach to the estrogen receptor for cancer cells to multiply. The new molecule, dubbed ERX-11, mimics a peptide, or protein building block. The drug has been tested in mice and in cancer cells removed from patients and it has worked well in both models, and there have been no signs of toxicity in the tests.
If successfully translated to a human therapy, another advantage of ERX-11 is that it could be taken orally by patients, rather than as an infusion. Dr Raj said the group is hoping to get a clinical trial underway in about a year. The notion of blocking protein co-factors has implications for treatment of other cancers as well. The research appears in the online journal eLife.
Other UT Southwestern researchers who participated in the study are Dr Shihong Ma, senior research associate; Dr Rui Li, senior research associate; Dr Xihui Liu, Instructor in Urology; Shino Murakami, graduate student researcher; Dr Wan-Ru Lee, research scientist; Dr Vijay Gonugunta, research scientist; and Dr Douglas Strand, Assistant Professor in Urology.
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