Enzalutamide shows promise in treating triple-negative and estrogen-positive breast cancer

Published on December 3, 2012 at 11:43 PM · No Comments

Breast cancers are defined by their drivers - estrogen and progesterone receptors (ER and PR) and HER2 are the most common, and there are drugs targeting each. When breast cancer has an unknown driver, it also has fewer treatment options - this aggressive form of breast cancer without ER, PR or HER2, which was thought not to be driven by hormones, is known as triple negative. A decade ago, work at the University of Colorado Cancer Center added another potential driver to the list - the androgen receptor - and this week marks a major milestone in a clinical trial targeting this cause of breast cancer growth.

In fact, 75 percent of all breast cancers and about 20 percent of triple negative cancers are positive for the androgen receptor. Blocking the androgen receptor may stop the growth of some triple negative breast cancers - these aggressive cancers for which chemotherapy, radiation, surgery and hope have long been the only treatments.

"This work is a concise example of modern cancer science in action. We noticed something in the clinic, worked on it in the lab, and now are happy to report the lab work is once again back in the clinic where it has the very real potential to benefit patients," says Anthony Elias, MD, breast cancer program director at CU Cancer Center.

The work started in 2001 when Elias took the clinical observation of estrogen-positive breast cancers that responded poorly or only very temporarily to estrogen-blocking treatments, to colleague Jennifer Richer, PhD, co-director of the CU Cancer Center Tissue Processing and Procurement Core. In these cases, something else was driving the cancer. What was the pathway? Richer showed that it was the androgen receptor.

Androgens including testosterone have long been implicated as a driver of prostate cancer and so drugs targeting both the body's production of androgens and cancer cells' ability to use the hormone were already in the development pipeline. Richer started with cell culture and animal model work on a then-experimental drug by the company Medivation known as MDV-3100.

"Normally, the way these hormones work is by attaching to receptors in the cell cytoplasm, at which point the receptor draws itself and the hormone molecule inside the nucleus where it regulates genes," Richer says. The genes regulated by these hormones tell breast cancer cells to survive and reproduce beyond control. The drug MDV-3100, now known as Enzalutamide, which recently gained FDA approval for use with prostate cancer, makes androgen receptors unable to go into a cell's nucleus - and so the message of growth never gets delivered.

"Interestingly, it seems that estrogen-positive breast cancers are susceptible to the same drug," Richer says, explaining that something about the way the signal of estrogen is transmitted inside a cell's nucleus requires the (counterintuitive) presence of androgen receptors in the nucleus, too.

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