Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New medications show promise in treating drug-resistant prostate cancer

09.04.2009
A new therapy for metastatic prostate cancer has shown considerable promise in early clinical trials involving patients whose disease has become resistant to current drugs.

Of 30 men who received low doses of one the drugs in a multisite phase I/II trial designed to evaluate safety, 22 showed a sustained decline in the level of prostate specific antigen (PSA) in their blood. Phase III clinical trials are planned to evaluate the drug's effect on survival in a large group of patients with metastatic prostate cancer.

The drugs are second-generation antiandrogen therapies that prevent male hormones from stimulating growth of prostate cancer cells. The new compounds – manufactured by the pharmaceutical company Medivation and known as MDV3100 and RD162 – appear to work well even in prostate cells that have a heightened sensitivity to hormones. That heightened sensitivity makes prostate cancer cells resistant to existing antiandrogen therapies.

The drugs were discovered in the laboratory of Howard Hughes Medical Institute investigator Charles Sawyers at Memorial Sloan-Kettering Cancer Center in collaboration with chemist Michael Jung at UCLA. He and his colleagues described the development of the drugs and initial testing in an article posted online April 9, 2009, in Science Express, which provides electronic publication of selected Science articles in advance of print. Sawyers's team collaborated on the studies with researchers from the University of California Los Angeles, Oregon Health and Science University, University of Washington and Medivation.

About 186,000 new cases of prostate cancer are diagnosed each year in the United States. The male hormones testosterone and dihydrotestosterone -- also known as androgens -- spur the growth of prostate cells, and drugs that block the receptors for these hormones are the most common treatment for the disease in its advanced, metastatic stage. Antiandrogen drugs, such as bicalutamide, suppress the growth of cancer cells temporarily, but in most patients the cancer ultimately develops resistance to drugs. About 29,000 men in the United States die each year from the disease.

Prostate cancer becomes resistant to antiandrogen drugs when cancer cells begin to increase production of the androgen receptor, said Sawyers. When the level of androgen receptors on the cells' surface reaches a certain level, the drugs that originally suppressed the cancer actually begin to stimulate cancer growth.

Because of this backlash effect, many scientists have questioned whether blocking the androgen receptor is a wise course of action. But Sawyers and his colleagues believe that blocking the receptor is critical to successful treatment. So they set out to design a new generation of drugs that can block the androgen receptor without unwanted side effects, even when levels of the receptor are high.

Researchers in Sawyers' lab based their designs on a drug that tightly attaches to the site on the androgen receptor that binds testosterone. If that site is blocked, the hormone cannot bind to prostate cells and tell the receptor to stimulate growth. Using this molecule as a chemical scaffold, the researchers synthesized nearly 200 slightly different versions of the drug. They tested each one in the lab on prostate cancer cells that had been engineered to produce high levels of androgen receptor.

This screening yielded two molecules, RD162 and MDV3100, which tightly bind to the androgen receptor and did not show the cancer-stimulating effect of bicalutamide and other current antiandrogen drugs. The molecules were good candidates for drugs, because they are readily absorbed into the blood when taken orally and they persist in the bloodstream.

The researchers tested the new drugs' effectiveness in mice with tumors derived from drug-resistant prostate cancer cells. "To our delight, we found that these compounds caused very dramatic shrinkage of tumors in the mice," said Sawyers. "While treating these animals with bicalutamide produced a modest effect on their tumors, the new drugs caused the tumors to shrink dramatically, and in some animals almost completely," he said.

Sawyers said the new drugs bind tightly enough to the natural hormone-binding site on androgen receptors to prevent most of them from functioning – even in cells with a lot of androgen receptors. Bicalutamide interferes with the receptor through a different mechanism, which backfires, when too much androgen receptor is present, Sawyers explained.

The promising laboratory studies led Medivation to license the drugs for commercial development, said Sawyers, who serves as a consultant to the company and would receive royalties on the drug should it prove to be successful.

The company chose to use MDV3100 for clinical studies, which began in 2007. In those initial studies, 30 men with antiandrogen-resistant prostate cancer received low doses of MDV3100. Twenty-two of those men showed a sustained decline in their blood levels of prostate specific antigen (PSA), an indication that their cancer was responding favorably to the drug. This trial is still under way, and results from a total of 140 patients receiving higher doses of the drug will be reported within the next year, said Sawyers.

Medivation has received permission from the Food and Drug Administration for a large clinical trial of MDV3100 on about 1,200 patients with antiandrogen-resistant disease. This study will assess MDV3100's effect on cancer survival and will take several years.

While these preliminary results are promising, Sawyers said his laboratory will continue to seek further improvements in drug therapy for prostate cancer. "There were some men in the initial trial in which the drug didn't work at all, and we want to find out why," he said. "It may be because the drug is not potent enough to overcome resistance due to androgen receptor overexpression. Or, it may be that the cancers in these men are not driven by the androgen receptor anymore. Also, there were men who initially received benefit from the drug, but then relapsed, and their PSA levels came back up. We want to understand the mechanism of that relapse and to try to develop drugs that prevent that renewed resistance," he said.

Jennifer Michalowski | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Health and Medicine:

nachricht Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University

nachricht The first analysis of Ewing's sarcoma methyloma opens doors to new treatments
01.12.2016 | IDIBELL-Bellvitge Biomedical Research Institute

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>