New drugs, new ways to target androgens in prostate cancer therapy

June 20, 2012

Prostate cancer cells require androgens including testosterone to grow. A recent review in the British Journal of Urology International describes new classes of drugs that target androgens in novel ways, providing alternatives to the traditional methods that frequently carry high side effects.

"In many ways, therapies for have led the way in the fight against the disease," says E. David Crawford, MD, investigator at the University of Colorado Cancer Center and review co-author. "The first effective oral therapy for any cancer was estrogen which was described in 1941. The first cancer biomarker that allowed diagnosis and staging was prostatic acid phosphatase back in 1938. Then there was little progress for over four decades."

During those 40 years, in which early work in prostate cancer led to Nobel prizes for researchers Charles Huggins and Andrew Schally, other capitalized on this research, notably developing hormone therapies targeting estrogen in . But work in prostate cancer stalled.

"What we realized is that production of androgens like testosterone depends on an intact system in which the brain recognizes hormone levels, signals the pituitary to increase or decrease production, and the pituitary in turn sets the testes in motion. Additionally, by targeting the production of androgens by the testes, we could break that system at many other points," Crawford says.

For example, estrogen is similar enough to testosterone that administering estrogen to patients tricked the brain into thinking testosterone hormone levels were high – with high presumed , the brain sent no production signal to the pituitary. But estrogen therapy led to side effects including breast enlargement.

The next class of drugs, known as luteinizing hormone releasing hormones or LHRHs, intervened in this signaling chain at the level of the pituitary. Just as keeps the brain from signaling for more testosterone, LHRHs keep the pituitary from passing messages to the testes.

"Because the effects of LHRHs are reversible, this allowed us to use hormone-targeting therapies much earlier in the disease," Crawford says. "But LHRHs lead to an initial spike in testosterone, before it decreases." Most patients can withstand this spike, but for some, for example those with bone metastasis in the back, a spike in testosterone could flare the disease and lead to spinal complications.

"It was only about ten years ago that somebody was able to make a usable antagonist," Crawford says. Instead of first spiking and then lowering testosterone, these LHRH antagonists lead to an immediate drop.

And instead of targeting the signaling pathway that leads to the production of androgens including testosterone, androgen antagonists like Enzalutamide (formerly known as MDV3100), currently in phase III clinical trials, target cells' ability to trap testosterone that exists in the body – it doesn't matter how much testosterone is floating around, as long as are unable to grab it. Specifically, Enzalutamide and other androgen antagonists are easier to "catch" than the androgens themselves, and so cells grab Enzalutamide and are then unable to grab .

Also new to the field are drugs that block the production of androgens from all sources which of course includes the testes, but also includes blocking the smaller amounts produced by the adrenals and even by the cancer itself. This class of drugs is called androgen biosynthesis inhibitors, and the first approved is a drug called abiraterone or Zytiga.

"Targeting cells' androgen receptors is a new and exciting development in the field of prostate cancer therapy," Crawford says. "As these new drugs make their way from the lab to clinic, we expect the ability to offer androgen antagonists to patients whose cancers have resisted other treatments."

Explore further: Four new drugs will change prostate cancer care

Related Stories

Four new drugs will change prostate cancer care

February 16, 2012
After a decade and a half of near stagnation, four new drugs could help make advanced prostate cancer a chronic illness instead of a terminal disease, a leading Colorado prostate cancer expert says.

Elevated hormone levels add up to increased breast cancer risk

October 21, 2011
Post-menopausal women with high levels of hormones such as estrogen or testosterone are known to have a higher risk of breast cancer. New research published in BioMed Central's open access journal Breast Cancer Research looked ...

New target, new drug in breast cancer

June 4, 2012
Many breast cancers depend on hormones including estrogen or progesterone for their survival and proliferation. Eight years of lab work at the University of Colorado Cancer Center and elsewhere suggest that the androgen (AR) ...

Recommended for you

What does hair loss have to teach us about cancer metastasis?

December 15, 2017
Understanding how cancer cells are able to metastasize—migrate from the primary tumor to distant sites in the body—and developing therapies to inhibit this process are the focus of many laboratories around the country. ...

Cancer immunotherapy may work better in patients with specific genes

December 15, 2017
Cancer cells arise when DNA is mutated, and these cells should be recognized as "foreign" by the immune system. However, cancer cells have found ways to evade detection by the immune system.

Scientists pinpoint gene to blame for poorer survival rate in early-onset breast cancer patients

December 15, 2017
A new study led by scientists at the University of Southampton has found that inherited variation in a particular gene may be to blame for the lower survival rate of patients diagnosed with early-onset breast cancer.

Scientists unlock structure of mTOR, a key cancer cell signaling protein

December 14, 2017
Researchers in the Sloan Kettering Institute have solved the structure of an important signaling molecule in cancer cells. They used a new technology called cryo-EM to visualize the structure in three dimensions. The detailed ...

'Bet hedging' explains the efficacy of many combination cancer therapies

December 14, 2017
The efficacy of many FDA-approved cancer drug combinations is not due to synergistic interactions between drugs, but rather to a form of "bet hedging," according to a new study published by Harvard Medical School researchers ...

Liquid biopsy results differed substantially between two providers

December 14, 2017
Two Johns Hopkins prostate cancer researchers found significant disparities when they submitted identical patient samples to two different commercial liquid biopsy providers. Liquid biopsy is a new and noninvasive alternative ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.