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Castration Resistant Prostate Cancer

Castration resistant of prostate cancer


Most hormone dependent cancers become refractory after one to three years and resume growth despite hormone therapy. Previously considered "hormone-refractory prostate cancer" or "androgen-independent prostate cancer", the term castration-resistant has replaced "hormone refractory" because while they are no longer responsive to castration treatment (reduction of available androgen/testosterone/DHT by chemical or surgical means), these cancers still show reliance upon hormones for androgen receptor activation.

Before 2004, all treatments for castration-resistant prostate cancer (CRPC) were considered palliative and not shown to prolong survival. However, there are now several treatments available to treat CRPC that improve survival.


The cancer chemotherapic docetaxel has been used as treatment for CRPC with a median survival benefit of 2 to 3 months. A second-line chemotherapy treatment is cabazitaxel. A combination of bevacizumab, docetaxel, thalidomide and prednisone appears effective in the treatment of CRPC.
The immunotherapy treatment with sipuleucel-T in CRPC increases survival by 4 months.

The second line hormonal therapy abiraterone increases survival by 4.6 months when compared to placebo. Enzalutamide is another second line hormonal agent with a 5 month survival advantage over placebo. Both abiraterone and enzalutamide are currently being tested in clinical trials in those with CRPC who have not previously received chemotherapy.

Castration Resistant Prostate CancerOnly a subset of a people respond to androgen signaling blocking drugs and certain cells with characteristics resembling stem cells remain unaffected. Therefore, the desire to improve outcome of people with CRPC has resulted into the claims of increasing doses further or combination therapy with synergistic androgen signaling blocking agents.

But even these combination will not affect stem -like cells that do not exhibit androgen signaling. It is possible that for further advances, a combination of androgen signaling blocking agent with stem-like cell directed differentiation therapy drug would prove ideal.

Genetic Mutation Found in Castration-Resistant Prostate Cancer

A Cleveland Clinic researcher has discovered a genetic mutation in a drug resistant and often deadly form of prostate cancer.

The mutation occurs in the androgen-synthesizing enzyme 3βHSD1 in castration-resistant prostate cancer (CRPC), according to research published online today in Cell. This mutation enables the tumor to make its own supply of androgens, a hormone that fuels the growth of the prostate cancer.

Prostate cancer requires a constant supply of androgens in order to sustain itself. The current standard of care for patients with metastatic prostate cancer is medical castration, the ability to interfere with the body's production of testosterone (androgens) using medications that disrupt the process.

Oftentimes, metastatic prostate cancer flourishes despite the lack of testosterone in the bloodstream, creating CRPC. These tumors are able to exist without the body's supply of testosterone by creating androgens within the tumor cell; however, increased androgen synthesis has not yet been attributable to any known mutations. The Cleveland Clinic discovery shows that the 3βHSD1 mutation makes this enzyme hyperactive to create androgens.

"This discovery gives us the ability to identify molecular subtypes of prostate cancer known to resist treatment. By finding the mutated enzyme, we can now investigate treatments that block it. This kind of strategy is the crux of personalized medicine which is currently used as the standard of care for some forms of lung cancer and melanoma," said Nima Sharifi, MD, Kendrick Family Chair for Prostate Cancer Research at Cleveland Clinic, who led the research.

The 3βHSD1 mutation can occur within CRPC tumors and it can also come from germline DNA, which is inherited from maternal and paternal sources.

The research found that laboratory models of human prostate cancer fall into two categories of androgen synthesis: those that make androgens slowly and those that do so rapidly. Next, they found that the 3βHSD1 mutation explains the difference between these two categories and that DNA from some patient tumors also contains this mutation. The mutation works by opening the floodgates to androgen synthesis, essentially throwing fuel on the fire that promotes tumor progression.

In an era of personalized cancer care, there is increased focus on defining and treating cancer by its genetic abnormalities. Tumor-promoting enzyme mutations in several cancers have been identified and, subsequently, have led to the development of targeted drug therapies, improving outcomes for patients.

"The past decade has seen an explosion of molecularly targeted therapies that are matched to specific mutations in a given patient's tumor," says Dr. Sharifi. "However, no drug-targeting based on enzyme mutations exists for the standard treatment of metastatic CRPC. With this finding, we have the opportunity for matching a mutant disease-driving biomarker with a pharmacologic inhibitor."

Prostate cancer is the most common cancer in men, with nearly 240,000 new cases diagnosed each year in the United States. According to the American Cancer Society, there will be an estimated 30,000 deaths due to prostate cancer in 2013. Almost every man who dies of prostate cancer dies with castration-resistant prostate cancer.

This research was funded by Prostate Cancer Foundation, American Cancer Society, Department of Defense, Howard Hughes Medical Institute and National Cancer Institute.

New Medication Treats Drug-Resistant Prostate Cancer in the Laboratory

A new drug called pyrvinium pamoate inhibits aggressive forms of prostate cancer that are resistant to standard drugs, according to a study conducted in an animal model.

The results will be presented Monday at The Endocrine Society's 95th Annual Meeting in San Francisco.

"Our novel prostate cancer drug works by a unique mechanism of action," said study lead author Jeremy Jones, PhD, assistant professor of molecular pharmacology at City of Hope, Beckman Research Institute, in Duarte, CA. "Thus, it has the potential to treat cancers resistant to currently approved therapies."

Prostate cancer is the second-leading cause of cancer death, after lung cancer, among men in the United States, according to the American Cancer Society. The disease affects about one out of every six men, and more than 29,000 will die of prostate cancer this year alone.

An age-related disease, prostate cancer usually affects men who are 65 or older. In addition to advanced age, genes and certain environmental factors influence the development of prostate cancer, although the exact causes remain unknown.

In a healthy prostate gland, cells express a protein called androgen-receptor, or AR, which is activated by male sex hormones, or androgens, including the primary male hormone testosterone. These same receptors also play a role in promoting the growth of the abnormal cells of prostate cancer.

The drugs that are currently available to treat prostate cancer work by preventing androgen from binding to the AR. Specifically, the drugs block androgen from attaching to a certain part of the AR known as the ligand-binding domain. This domain is the part of the receptor that hormones bind to when they activate the receptor. By blocking all androgen activity, these drugs induce chemical castration.

The problem is that prostate-cancer cells usually become resistant to androgen blockage. After initially responding, these aggressive cancers develop mutations that enable them to spread, or metastasize, without the influence of androgens. For this reason, these aggressive prostate cancers are called castration-resistant.

In contrast, the study drug binds to a different part of the AR that does not require androgen, according to Jones. "Our new lead compound, pyrvinium pamoate, works by a unique mechanism that involves binding to a different site on the AR and inhibiting its activity without preventing androgen binding," he said. "We are hopeful that an optimized derivative of pyrvinium will be able to inhibit all AR activity and inhibit the growth of human prostate cancers that become resistant to other AR-targeted therapies and perhaps result in a curative metastatic prostate cancer therapy."

Investigators conducted this pre-clinical study using prostate-cancer cells in an animal model.
The National Institutes of Health's National Cancer Institute supported part of this study.


Source: http://www.sciencedaily.com/releases/2013/06/130617160730.htm
Source: http://www.sciencedaily.com/releases/2013/08/130829124349.htm
Source: http://en.wikipedia.org/wiki/Prostate_cancer

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