Fighting Triple Negative Female Breast Cancer by Blocking Androgen (Male) Receptors
It may seem counter-intuitive, a potentially powerful treatment for breast cancer based on blocking receptors for the male hormone androgen; but that’s what turns out to be the case. Researchers at the University of Colorado Cancer Center recently completed a Phase I clinical trial of Enzalutamide, which provided evidence of the safety and possible effectiveness of the approach.
How did the researchers arrive at the notion that dealing with a male hormone would be effective against (mostly female) breast cancer? It’s a story that begins in 2001, when lead researcher Anthony Elias looked at clinical observations of estrogen-positive (female hormone) breast cancers that responded poorly or very temporarily to estrogen blocking treatments. It seemed that something else was driving the cancer.
Over the past decade or so, breast cancer research focused on the apparent ‘drivers’ of cancer development – the hormones estrogen and progesterone along with their receptors, like gateways keyed for the hormones’ specific molecular structure, on the cells of breast tissue. Identified as ER and PR, along with the gene HER2, they seemed to be the most common drivers and many research programs kept busy exploring their biochemistry and looking for treatments.
Normally, the hormones work by attaching themselves to the specific receptors on the outer surface of cells (the cytoplasm), where the receptor in turn passes the hormones into the cell interior. The hormones then go on to the nucleus where they regulate genes in the DNA. What these hormones do, however, is in effect tell the genes regulating breast cancer cells to survive and reproduce without control. In this way, estrogen and progesterone link to the development of breast cancer.
Treatment for these types of cancer focused mainly on blocking the hormones at the receptors – before they had a chance to penetrate the cell to the nucleus. This approach worked reasonably well and a number of new drug treatments were the result. However, there remained a class of breast cancers where the combination of ER-PR-HER2 drug targets was ineffective. Known as “triple negative” breast cancers, they comprise 75% of all breast cancers and are among the most aggressive. Treatments with surgery, heavy chemotherapy and radiation proved to be only somewhat effective and, of course, exacted a heavy toll on the health of the patient.
This brings it back to Dr. Elias’ observation about the ineffectiveness of blocking estrogen receptors. He knew that among hormone drivers for cancer, androgens including the male hormone testosterone, linked very closely to prostate cancer. Already in 2001 there were many research programs developing drugs to control the action of androgens and their receptors, including one drug, MDV-3100 (now Enzalutamide) produced by Medivation. He also knew that cells have many kinds of receptors and it was possible that breast cells might include those for androgen.
To test the presence of androgen receptors, Elias and co-researchers began working with laboratory and animal models of breast cancer cells. They demonstrated that these cells did indeed have androgen receptors. Then they applied MDV-3100 in a series of controlled tests to see if this form of androgen blocker had any effect. It did.
In moving to the next step, a Phase I clinical trial with cancer patients, it helped the researchers that MDV-3100, which by then was renamed as Enzalutamide, was already FDA approved – for prostate cancer treatment. It turns out that blocking androgen receptors has an effect on the transmission of female estrogen into the cell.
As the Phase I clinical trial demonstrated no undue toxicity, the researchers are rolling the program into a Phase II trial to find the right dosage (or combination of drugs) to test the effectiveness of Enzalutamide. If it works and continues to prove safe, Enzalutamide could be a first line of treatment for androgen positive breast cancers, and a second line of treatment for tumors that form from mutated ER or HER2 dependence.
In short, Enzalutamide may add significantly to the treatment of triple negative breast cancer – a major milestone in breast cancer treatment.