Drug shows activity in men with advanced prostate cancer

A new multi-center study shows that an experimental drug lowers prostate specific antigen (PSA) levels – a marker for tumor growth – in men with advanced prostate cancer for whom traditional treatment options have failed. The study, led by researchers at Memorial Sloan-Kettering Cancer Center (MSKCC), is published today in Science Express, the online version of the journal Science.

Most men with metastatic prostate cancer eventually build up resistance to the drugs that lower or block male hormones and develop a more aggressive form of the illness called castration-resistant prostate cancer (CRPC), or hormone-refractory disease. According to the study's findings, investigators studied two novel compounds, RD162 and MDV3100, and not only gained an understanding of their novel mechanism of action, but found that these agents showed activity in CRPC cells in culture and in mice.

The study also reports on a Phase 1/2 trial of MDV3100 in 30 patients with advanced CRPC and found that 22 out of 30 men showed declining PSA levels, and 13 out of 30 men (43 percent) had PSA levels fall by more than half.

Several years ago, the senior author of the study, Charles Sawyers, MD, and his colleagues at the University of California, Los Angeles (UCLA), uncovered a potential reason why metastatic prostate cancer patients eventually relapse with CRPC. This insight was used to discover RD162 and MDV3100.

"It's gratifying to know that our hypotheses about why men develop resistance to currently available treatments are confirmed and, most importantly, that there are already patients who are benefiting from our research," said Dr. Sawyers, Chair of the Human Oncology and Pathogenesis Program at MSKCC and a Howard Hughes Medical Institute investigator.

Current treatments for men who have advanced prostate cancers inhibit the activity of male hormones that help drive tumor growth. Many of these drugs disrupt the androgen (male hormone) receptor, which helps regulate cell proliferation, but tumors eventually become resistant to the drugs by expressing higher levels of the receptor. Preclinical studies by Dr. Sawyers and others have demonstrated that CRPC cells have increased expression of the androgen receptor and that overexpression of this receptor may contribute to the progression of disease.

Based on this information, Dr. Sawyers initiated a collaboration with Michael Jung, PhD, Professor of Chemistry at UCLA, that led to the discovery of a number of nonsteroidal, small molecule antiandrogen compounds, including MDV3100, which has been shown to retain its anticancer activity, even when the receptor's expression is elevated.

"The discovery and initial development of this drug was a collaborative effort all done in the academic setting, without reliance on the engine of the pharmaceutical industry that typically drives drug development," said Dr. Sawyers. Dr. Jung's group synthesized the compounds, which Dr. Sawyers' team then evaluated using prostate cancer mouse models engineered to highly express the androgen receptor, mimic progression to castration-resistant disease, and reflect the biology of clinical drug resistance.

According to the new study, the team of researchers tested various compounds to block the androgen receptor in CRPC cells. They chose to further evaluate the drug RD162 and a closely related compound, MDV3100. According to their findings, both drugs inhibit the androgen receptor function by impairing the receptor's ability to enter a CRPC cell's nucleus (called nuclear translocation), blocking it from binding to the DNA of its target genes, and preventing the cell from growing. They found that both compounds worked well in cells in culture, shrank tumors in mice, maintained tumor shrinkage for months, and prevented the androgen receptor from activating additional genes later in the process, or "downstream." Other currently approved drugs cannot disable the receptor in such a way.

The biopharmaceutical company Medivation, Inc., licensed RD162 and MDV3100 from UCLA in 2006 and has already completed enrollment in the first human trial of oral MDV3100 – a Phase 1/2 clinical trial, which was led by investigators at MSKCC and conducted through the Prostate Cancer Clinical Trials Consortium. The Consortium is sponsored by the Department of Defense and the Prostate Cancer Foundation. The trial enrolled men with metastatic, castration-resistant prostate cancer who relapsed after treatment with conventional hormone therapy and demonstrated anti-prostate cancer effects beginning with the first patient treated with MDV3100 at the lowest dose. Further positive results from an additional 110 patients who received the drug at higher doses were recently reported at the ASCO Genitourinary Cancers Symposium in February 2009 (see abstract: http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=64&abstractID=20500).

"The declines in PSA levels observed thus far and the general tolerability of this treatment are encouraging," said Howard Scher, MD, a study co-author and Chief of the Genitourinary Oncology Service at MSKCC. "I am looking forward to continuing the study of this drug, which has the potential to be a powerful tool in a limited arsenal of treatments against this deadly form of the disease." A Phase 3 trial is planned to begin later this year.

Stem cell therapy makes cloudy corneas clear, according to Pitt researchers

PITTSBURGH, April 9 – Stem cells collected from human corneas restore transparency and don't trigger a rejection response when injected into eyes that are scarred and hazy, according to experiments conducted in mice by researchers at the University of Pittsburgh School of Medicine. Their study will be published in the journal Stem Cells and appears online today.

The findings suggest that cell-based therapies might be an effective way to treat human corneal blindness and vision impairment due to the scarring that occurs after infection, trauma and other common eye problems, said senior investigator James L. Funderburgh, Ph.D., associate professor, Department of Ophthalmology. The Pitt corneal stem cells were able to remodel scar-like tissue back to normal.

"Our experiments indicate that after stem cell treatment, mouse eyes that initially had corneal defects looked no different than mouse eyes that had never been damaged," Dr. Funderburgh said.

The ability to grow millions of the cells in the lab could make it possible to create an off-the-shelf product, which would be especially useful in countries that have limited medical and surgical resources but a great burden of eye disease due to infections and trauma.

"Corneal scars are permanent, so the best available solution is corneal transplant," Dr. Funderburgh said. "Transplants have a high success rate, but they don't last forever. The current popularity of LASIK corrective eye surgery is expected to substantially reduce the availability of donor tissue because the procedure alters the cornea in a way that makes it unsuitable for transplantation."

A few years ago, Dr. Funderburgh and other University of Pittsburgh researchers identified stem cells in a layer of the cornea called the stroma, and they recently showed that even after many rounds of expansion in the lab, these cells continued to produce the biochemical components, or matrix, of the cornea. One such protein is called lumican, which plays a critical role in giving the cornea the correct structure to make it transparent.

Mice that lack the ability to produce lumican develop opaque areas of their corneas comparable to the scar tissue that human eyes form in response to trauma and inflammation, Dr. Funderburgh said. But three months after the lumican-deficient mouse eyes were injected with human adult corneal stem cells, transparency was restored.

The cornea and its stromal stem cells themselves appear to be "immune privileged," meaning they don't trigger a significant immune response even when transplanted across species, as in the Pitt experiments.

"Several kinds of experiments indicated that the human cells were alive and making lumican, and that the tissue had rebuilt properly," Dr. Funderburgh noted.

In the next steps, the researchers intend to use the stem cells to treat lab animals that have corneal scars to see if they, too, can be repaired with stem cells. Under the auspices of UPMC Eye Center's recently established Center for Vision Restoration, they plan also to develop the necessary protocols to enable clinical testing of the cells.

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Rheumatoid Arthritis Therapeutics in China

JAKARTA, Indonesia, April 9 - Rheumatoid arthritis (RA) is a systemic disease or an autoimmune disorder in which the body's defense system attacks the joints through the thin layer of cells called the synovium that lines and lubricates the joints. The most visible symptoms of RA are swollen joints and crippling stiffness, particularly of the hands and feet. It can cause fatigue, fever, loss of appetite and also impedes mobility and quality of life.

In 2007, the prevalence of rheumatoid arthritis (RA) in China was 0.3 percent, and has remained stable. About three times as many women as men are afflicted with the disease. Earlier, NSAIDs were mainly used for treatment, and as the disease progressed to moderate and severe, DMARDs were introduced. However, with time, education, awareness, and treatment options, physicians have started to treat with a combination of NSAIDs and DMARDs in the early stages of treatment. Patients are also treated with traditional Chinese medicine (TCM) in combination with western medicine, or independently.

State health insurance funds the treatment cost for NSAIDs and some DMARDs such as Methotrexate (MTX). However, a majority of the population has no health insurance, putting pressure on out-of-pocket payment, or go without treatment.

Frost & Sullivan, Research Analyst Sushma Rajan says, "The diagnosis of RA is based on clinical examination of symptoms, patient history, as well as some blood tests. RA cannot be confirmed or excluded by any one test. The most common test is rheumatoid factor (RF). The other supporting tests are: anti-cyclic citrullinated peptide (Anti-CCP), erythrocyte sedimentation rate (ESR), and X-ray.

"Recent work productivity studies have confirmed that better disease awareness and availability of treatment options have resulted in fewer patients ceasing to work and more patients reporting lower impact of their disease on work as well as family and social activities," she further elaborates.

Methotrexate (MTX), a DMARD (disease-modifying anti-rheumatic drug) has been traditionally used to treat RA. It is also the most used form of treatment in rheumatoid arthritis, especially with generic forms available. Currently, combination therapies between DMARDs and NSAIDs (non-steroidal anti-inflammatory drugs) are commonly practiced.

DMARDs capture the majority of the RA therapeutics market owing to the availability of reimbursement for treatment with these drugs and their easy availability over the counter. DMARDs are expected to retain majority share in the forecast period as well.

According to Rajan, "Biologics are used in combination with DMARDs for moderate to severe RA patients. Some biologic drugs are currently reimbursed, if treated in government hospitals. Physicians opine that with more drugs brought into the hospital formularies, the usage of biologics would increase for treatment earlier in the disease."

Though there are new drugs available for treating RA, specialists in china are likely to continue using DMARDs as their first line therapy, as they have the most experience with this drug class, and it is seen as the most cost effective treatment option. Even though biologics are highly effective and recommended for treatment, they are likely to be the third line of treatment, due to their high cost. Physicians are willing to use biologics if they are listed in the hospital formulary and if they are affordable to their patients (current price range is seen to be out of reach of most patients). Physicians are of the opinion that more studies are required to make them feel confident in using biologics, but the cost of treatment is likely to restrain the high use of the drug class.