AUA: Statin Benefits Linked to Prostate Cancer, BPH, ED

By Charles Bankhead, Staff Writer, MedPage Today
Published: April 28, 2009
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.

CHICAGO, April 28 -- Men who were taking statins at the time of radical prostatectomy had a 30% reduction in prostate cancer recurrence, data reported here showed.

Statin users also had lower PSA values and were more likely to have T1 disease than nonusers, Robert J. Hamilton, M.D., of the University of Toronto, said at the American Urological Association meeting.

"Our findings suggest that statins may slow prostate cancer progression after radical prostatectomy," said Dr. Hamilton. However, he emphasized, "at this point we cannot say with confidence that statins reduce the risk of prostate cancer recurrence after radical prostatectomy."

He said the findings require confirmation in other studies, such as a randomized controlled trial placing men on statins who are about to undergo surgery.

Dr. Hamilton's study was one of a half-dozen statin-related abstracts featured at an AUA press briefing. Collectively, the studies suggested that statins have favorable effects on prostate cancer risk, lower urinary tract symptoms (LUTS), benign prostatic hyperplasia (BPH), and erectile dysfunction.

Dr. Hamilton reported findings from a study of 1,325 men who underwent radical prostatectomy for prostate cancer. Information collected before surgery included current statin use -- 237 (18%) men were taking one of the drugs at the time of surgery. The principal outcomes were pathologic features of the cancer and biochemical recurrence.

There were no differences between those taking statins and those not taking the drugs with respect to the frequency of positive surgical margins, seminal vesicle invasion, extracapsular extension, or lymph node metastases. However, significantly more statin users had a Gleason score of 7 (60% versus 49%, P=0.003).

Statin users presented a mixed bag of risk characteristics. They had a lower mean PSA value (6.2 ng/mL versus 6.9 ng/mL, P=0.04), and 67% of statin users had stage T1c disease compared with 58% of nonusers (P=0.009).

On the negative side, statin users were 2 years older and had a higher rate of obesity, as well as the higher proportion of Gleason 7 disease.

In a multivariate analysis, statin users had an odds ratio for recurrence of 0.70 compared with nonusers (95% CI 0.50 to 0.97, P=0.03).

Adding to statins' association with prostate cancer, Lionel Banez, M.D., of Duke University in Durham, N.C., reported findings from an analysis of obesity, statin use, and tumor inflammation.

Mounting evidence suggests inflammation may play a role in prostate cancer evolution and progression. Obesity has been associated with inflammation and more aggressive cancer, Dr. Banez said. Statins, on the other hand, have well-documented anti-inflammatory activity and have been associated with reduced cancer risk.

Dr. Banez and colleagues reviewed data on 254 men who underwent radical prostatectomy. About half of the patients reported statin use.

One pathologist graded all of the surgical specimens with respect to inflammatory infiltrates.

Significantly more statin users were overweight (48%) and obese (31%, P<0.001). p="0.07)." p="0.01).">

Dr. Banez disclosed relationships with AstraZeneca and Veridex.
Dr. Nehra disclosed relationships with GlaxoSmithKline, Pfizer, and sanofi-aventis.
Dr. Thrasher disclosed a relationship with sanofi-aventis.

Primary source: American Urological Association
Source reference:Hamilton RJ et al "Statin medication use and the risk of biochemical recurrence following radical prostatectomy: results from the SEARCH database" AUA 2009; Abstract 1598.

Additional source: American Urological Association
Source reference:Banez LL et al. "Association between statins, obesity, and prostate tumor inflammatory infiltrate in men undergoing radical prostatectomy" AUA 2009; Abstract 575.

Additional source: American Urological Association
Source reference:Loeb S et al. "Is statin use associated with prostate cancer aggressiveness?" AUA 2009; Abstract 576.

American Urological Association Counters Mainstream Recommendations With New Best Practice Statement On PSA Testing

ScienceDaily (Apr. 27, 2009) — The American Urological Association (AUA) has issued new clinical guidance – which directly contrasts recent recommendations issued by other major groups – about prostate cancer screening, asserting that the prostate-specific antigen (PSA) test should be offered to well-informed, men aged 40 years or older who have a life expectancy of at least 10 years.

The PSA test, as well as how it is used to guide patient care (e.g., at what age men should begin regular testing, intervals at which the test should be repeated, at what point a biopsy is necessary) is highly controversial; however, the AUA believes that, when offered and interpreted appropriately the PSA test may provide essential information for the diagnosis, pre-treatment staging or risk assessment and post-treatment monitoring of prostate cancer.

The new Best Practice Statement updates the AUA's previous guidance, which was issued in 2000. Major changes to the AUA statement include new recommendations about who should be considered for PSA testing, as well as when a biopsy is indicated following an abnormal PSA reading.

According to the AUA, early detection and risk assessment of prostate cancer should be offered to well-informed men 40 years of age or older who have a life expectancy of at least 10 years. The future risk of prostate cancer is closely related to a man's PSA score; a baseline PSA level above the median for age 40 is a strong predictor of prostate cancer.

Such testing may not only allow for earlier detection of more curable cancers, but may also allow for more efficient, less frequent testing. Men who wish to be screened for prostate cancer should have both a PSA test and a digital rectal exam (DRE).

The Statement also notes that other factors such as family history, age, overall health and ethnicity should be combined with the results of PSA testing and physical examination in order to better determine the risk of prostate cancer. The Statement recommends that the benefits and risks of screening of prostate cancer should be discussed including the risk of over-detection, detecting some cancers which may not need immediate treatment

"The single most important message of this statement is that prostate cancer testing is an individual decision that patients of any age should make in conjunction with their physicians and urologists. There is no single standard that applies to all men, nor should there be at this time," Dr. Carroll said. He also notes that the "panel carefully reviewed the most recently reported trials of PSA testing in both the United States and Europe before finalizing their guidelines. The strengths and limitations of these trials are reviewed in the guideline."

In regard to biopsy, a continuum of risk exists at all values, and major studies have demonstrated that there is no safe PSA value below which a man may be reassured that he does not have biopsy-detectable prostate cancer.

Therefore, the AUA does not recommend a single PSA threshold at which a biopsy should be obtained. Rather, the decision to biopsy should take into account additional factors, including free and total PSA, PSA velocity and density, patient age, family history, race/ethnicity, previous biopsy history and co-morbidities.

Additionally, the AUA statement emphasizes that not all prostate cancers require active treatment and that not all prostate cancers are life-threatening. The decision to proceed to active treatments is one that men should discuss in detail with their urologists to determine whether active treatment is necessary, or whether surveillance may be an option for their prostate cancer.

"Prostate cancer comes in many forms, some aggressive and some not," said Peter Carroll, MD, chair of the panel that developed the Statement. "But the bottom line about prostate cancer testing is that we cannot counsel patients about next steps for cancer that we do not know exist." He also notes that "the AUA is committed to the timely, expert and appropriate care for men either with or at risk of getting prostate cancer and is prepared to revise these guidelines continuously as new information becomes available."

Additionally, the Best Practice Statement clarifies a number of key points about the use of PSA in treatment selection and post-treatment follow up of prostate cancer patients:

• Serum PSA predicts the response of prostate cancer to local therapy.
• Routine use of a bone scan is not required for staging asymptomatic men with clinically localized prostate cancer when their PSA level is equal to or less than 20.0 ng/mL.
• Computed tomography or magnetic resonance imaging scans may be considered for the staging of men with high-risk clinically localized prostate cancer when the PSA is greater than 20.0 ng/mL or when locally advanced or when the Gleason score is greater than or equal to 8.
• Pelvic lymph node dissection for clinically localized prostate cancer may not be necessary if the PSA is less than 10.0 ng/mL and the Gleason score is less than or equal to 6.
• Periodic PSA determinations should be offered to detect disease recurrence.
• Serum PSA should decrease and remain at undetectable levels after radical prostatectomy.
• Serum PSA should fall to a low level following radiation therapy, high intensity focused ultrasound and cryotherapy and should not rise on successive occasions.
• PSA nadir (low point) after androgen suppression therapy predicts mortality.
• Bone scans are indicated for the detection of metastases following initial treatment for localized disease, but the PSA level that should prompt a bone scan is uncertain. Additional important prognostic information can be obtained by evaluation of PSA kinetics (velocity).
• The kinetics of PSA rise after local therapy for prostate cancer can help distinguish between local and distant recurrence.

The new AUA statement is based on panel review of all available professional literature, members' clinical experience and expert opinion.

Adapted from materials provided by American Urological Association, via EurekAlert!, a service of AAAS.

3-D Research Model Tackles Prostate Cancer Spread

ScienceDaily (Apr. 24, 2009) — One of the few research projects to study the spread of prostate cancer to the bones using three-dimensional models of tissue-engineered bone is underway at QUT's Institute of Health and Biomedical Innovation (IHBI).

Shirly Sieh, a PhD student at IHBI, is studying the way cancer cells escape from the prostate through the bloodstream to form tumour colonies, most often in the spine and long bones.

"It is an innovative study which uses a tissue engineering platform technology developed by IHBI's Professor Dietmar W. Hutmacher in order to investigate the interaction between bones and cancer cells," Ms Sieh said.

"Tissue-engineered bone provides the 3D architecture for the cancer cells which more closely resemble bone metastasis instead of growing the cancer cells and bone cells on a flat Petrie dish.

"I am growing prostate cancer cells on the tissue-engineered bone to observe the interactions between the cells and the surrounding tissue so it is a way of mimicking the cancer cells invading the bone environment."

Ms Sieh said it was still not clear to researchers how bones and cancer cells interacted.

"With this 3D method we can see if and how the cancer cells 'set up home' in the bone cells," she said.

"We want to study how the cancer cells degrade the matrix, or the mix of proteins and growth factors produced by these cells, and remodel the environment to suit the cancer cells to grow a tumour."

Ms Sieh said scientists also wanted to understand why prostate cancer cells were attracted to the bone sites. She and Amy Lubik, a PhD student supervised by Professor Colleen Nelson, are studying the effect the cancer cells in the bone have on male hormone production, particularly on the hormone, androgen.

"People with advanced cancer who have had prostate removal surgery should have low levels of androgen and the cancer cells should be suppressed. However, sometimes the cancer cells do recur," she said.

"We think it might have something to do with the fact that the cancer cells are very sensitive to androgen and even low levels of androgen in the body could promote the growth of these cancer cells."

Ms Sieh said previous research had found that when the prostate cancer cells changed the bone environment they eventually induced more bone formation.

"But it is very abnormal growth which can cause bone fractures and painful spinal compression for the person," she said.


Adapted from materials provided by Queensland University of Technology.

Colonoscopy—What to Expect

In a previous post I outlined the reasons why I have been scheduled for a colonoscopy see: Managing Chronic Radiation Proctitis .

Below, I offer some facts about the procedure for those who may find themselves in a similar situation.

A colonoscopy is a diagnostic examination that allows a doctor to look inside the entire colon and rectum. The examination is used to determine the cause of colorectal problems and is also used as a screening test for colorectal cancer in people who have no symptoms.


About the procedure

During a colonoscopy, the doctor inserts a colonoscope (a long, thin, flexible tube) into the anus. Pain medication and a sedative (medication that causes drowsiness) are given to help reduce discomfort. The tube is slowly advanced through the rectum and the full length of the colon. The doctor views the image from the colonoscope on a video monitor. If the doctor finds an abnormal growth, or polyp, in your colon, a biopsy (removal of a small amount of tissue for examination under a microscope) of a part or the entire polyp can be taken using a tool at the end of the colonoscope. When the examination is complete, the colonoscope is slowly removed from the body.


The medical team

Most colonoscopies are performed by a gastroenterologist with the help of a nurse.

A gastroenterologist is a medical doctor who has completed five to six years of specialized training in gastroenterology, the study of the function and diseases of the esophagus, stomach, small intestine, colon and rectum, pancreas, gallbladder, bile ducts, and liver.

A gastroenterologist receives specific training in endoscopy (the use of a thin, flexible tube with an attached light and view lens to look inside the body) and how to interpret the results of endoscopic studies to make treatment recommendations.


Questions to ask your doctor

Before your colonoscopy, consider asking your doctor the following questions:

• Why do you recommend that I have a colonoscopy?
• Who will perform the colonoscopy, and who else will be in the room?
• What will happen during the colonoscopy?
• How long will the procedure take?
• Will it be painful?
• Will I receive anesthesia (drugs that cause loss of feeling or put a person to sleep)?
• What are the risks associated with having a colonoscopy?
• What if I don't have this examination?
• Will I need to avoid any activities after the colonoscopy?
• When will I learn the results?
• Who will explain the results to me?
• What other tests will be necessary if the test results show cancer?
  

Preparing for the procedure

When you schedule the examination, you will get detailed instructions on how to prepare for your colonoscopy.

Review with your doctor or nurse what you need to do to prepare for your colonoscopy, and whether you should take your regular medications that day. In addition, tell your doctor about all medications you are taking and any drug allergies or medical conditions you have.

Because your colon must be empty, you will need to be on a diet of clear liquids for one to three days before the procedure. This diet means eating only foods such as fat-free bouillon or broth, black coffee, strained fruit juice, and gelatin.

In addition to the liquid diet, you will need to take a laxative or give yourself an enema the day or night before the colonoscopy. If your doctor prescribes a laxative, it will either be given as a pill or as a powder that you will mix with water before drinking. In either form, the laxative will make you use the bathroom frequently so that your bowel will be cleansed before the examination.

You will be asked to review and sign a consent form that states you understand the risks of having the colonoscopy and agree to have the test done. Talk with your doctor about any concerns you have about the colonoscopy.

During the procedure

A colonoscopy usually takes 30 to 60 minutes to complete. Before the procedure begins, you will need to change into a hospital gown. You will be given pain medication and a sedative through an intravenous (IV) line in your arm. This will help you relax and reduce the discomfort you might otherwise feel from the colonoscopy. You may feel a slight stinging where the IV needle is inserted.

You will lie on your side on an examining table in a private room with a sheet draped over your body. As the doctor guides the colonoscope through the curves of your colon, you may need to change your position slightly to allow better access. The colonoscope inflates your colon by blowing air into it; this provides the doctor a better view of the colon lining. Though rare, there is a risk of the colonoscope puncturing the colon wall and surgery may be required to repair the perforation (hole).

Removing a polyp or taking a biopsy from the colon usually does not cause pain. However, bleeding may occur at the site of a biopsy or where a polyp is removed. The doctor can stop the bleeding using tools passed through the colonoscope.

Generally, the pain medicine and sedative you receive before the colonoscopy should limit pain you may feel during the procedure. However, you may feel cramping; taking slow, deep breaths may ease this discomfort. You may also feel discomfort from lying still for an extended time.

After the procedure

You will stay at the facility where you had the colonoscopy for up to two hours while the effects of the sedative wear off. You will need a ride home, so bring someone with you or make arrangements for a ride before the procedure. You can expect to resume your normal activities the day after your colonoscopy. If you feel severe abdominal pain or have a fever, bloody bowel movements, dizziness or weakness, call your doctor immediately.

AACR: Designer T Cells Attack Prostate Cancer

DENVER, April 21 -- Reprogrammed immune cells could become targeted "killing machines" against prostate cancer, a researcher said here.

In the early stages of a phase I study, these reprogrammed T cells sharply reduced the levels of prostate specific antigen (PSA) in two patients with metastatic prostate cancer, according to Richard Junghans, M.D., Ph.D., of the Roger Williams Medical Center in Providence, R.I.

Within a few weeks of the infusion of the engineered cells, one patient's PSA level had fallen by half and the other's by 75%, Dr. Junghans reported at the annual meeting of the American Association for Cancer Research.

T cells, Dr. Junghans told reporters, are the "perfect killing machines" when faced with a cell infected with a virus. "We have to fool the T cells into thinking that the cancer has a virus infection," he said.

To do that, he and colleagues isolate a patient's T cells from a blood sample and use genetic engineering techniques to make them sensitive to a molecule that only occurs in prostate cancer -- prostate specific membrane antigen, or PSMA.

Over a period of weeks, the modified cells are amplified in culture. Meanwhile the patient undergoes chemotherapy to knock down his remaining lymphocytes, creating "hematopoietic space" for the engineered T cells.

Finally, he said, the cells are infused into the patient and begin attacking cells that express PSMA. A marker for that activity, Dr. Junghans said, is the level of prostate specific antigen.

The falling levels of PSA in the two patients treated so far were obtained despite the low dose of cells they were given -- about a billion each.

The researchers plan to test that dose in one more patient and then escalate the dose -- first to 10 billion in six patients and then to 100 billion in another six.



In the two patients treated so far, the falling PSA levels appeared to have bottomed without reaching zero -- possibly because the methods used to activate them caused them to enter a resting state without completely eradicating the cancer cells, Dr. Junghans said.

With the higher doses, he said, he hopes to see PSA levels fall all the way to zero.

"We are very hopeful that when we get to higher doses," he said, "all those activated (cells) may get us to 100% suppression before they go to the resting state."

Dr. Junghans said the redirected T cells are a "brave new world" for cancer treatment. "I predict the FDA will have approved one of these designer T-cell constructs -- if not this one, then another one -- as standard therapy in the next five or so years," he said.

Dr. Junghans' approach is a new twist on ideas that have been around for "two decades or more," said Louis Weiner, M.D., of Washington's Lombardi Cancer Center, who was not part of the research.

"What Dr. Junghans and colleagues have done is to really combine two critical elements" -- redirecting the T cells and creating space for them by chemotherapy, Dr. Weiner said.

He said while the idea is intriguing and the early results promising, "at the end of the day, we will need properly conducted efficacy trials."

But "the early returns are sufficiently encouraging that I certainly hope they continue doing the work," he said.

Note: This study was published as an abstract and presented orally at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Dr. Junghans did not report support or conflicts.

By Michael Smith, North American Correspondent, MedPage Today
Published: April 21, 2009
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.

Primary source: American Association for Cancer Research
Source reference: Junghans RP, et al "Phase I trial of anti-PSMA designer T cells in prostate cancer" AACR 2009; Abstract 5662.

Science Makes Inroads Against Prostate, Other Cancers

In studies, an immune boost fights prostate tumors, and better drugs outwit brain, pancreatic malignancies


SUNDAY, April 19 (HealthDay News) -- Harnessing cutting-edge techniques, a variety of human, animal and laboratory studies are suggesting innovative new ways to beat cancer.

Brain, prostate, and pancreatic cancer are some of the specific targets of the new research described Sunday in Denver at the annual meeting of the American Association for Cancer Research.

"This is an extremely exciting time in cancer research," observed Dr. David Carbone, director of the thoracic oncology center at the Vanderbilt-Ingram Cancer Center in Nashville. "Even in the kinds of cancers that traditionally have been very resistant to therapy, we're starting to see clues of amazing responses and clinical benefits for patients."

Carbone, himself a cancer survivor, was not engaged in any of the investigations under discussion in Denver.

One of the studies involved a clinical trial into a new therapy for prostate cancer. That study's lead author, Dr. Richard Junghans, described his team's effort as an attempt "to find a cure for patients who will ultimately die, because standard therapies don't really work".

"Prostate cancer kills about 3,000 [men] every month," observed Junghans, an associate professor in the department of surgery and medicine at Boston University School of Medicine, as well as chief of the division of surgical research at Roger Williams Medical Center in Providence, R.I.

"Chemotherapy doesn't work, and hormone treatment can keep the prostate under control for one to two and maybe even three years. But after that, there's very little left. So almost all patients who've had their cancer spread to the bones will die, and it can be a miserable way to go."

"So, what we've done is to go in a radical new direction to develop a therapy that is not a chemical, not an inert drug, not a hormone," he explained. "It's almost a living organism. It's actually the patient's own T-cells -- white blood cells that exist in everyone's body -- that have been modified and engineered to be 'fooled' into attacking the cancer."

Junghans said that the first two patients to receive a single infusion with the new treatment experienced a 50 percent to 75 percent reduction in their blood level of prostate-specific antigen (PSA), a measure of prostate cancer activity, over the following two months.

"So, I'm very excited, because this achievement was with the lowest dose of the therapy, which we now plan to try out at a level ten times as high," he noted. Junghans said he and his team hope to "achieve a 100 percent reduction (in PSA)."

Another of the four studies included work led by Florence Hofman, a professor of pathology at the University of Southern California, Keck School of Medicine, in Los Angeles. Her team targeted brain cancer with an inhibitor called "dimethyl-celecoxib".

Celecoxib may sound familiar: It's the more scientific name for the cox-2 inhibitor drug, Celebrex, which has been used as a pain reliever and cancer-fighter but also has some cardiovascular side effects. The new drug is "similar to a cox-2, but not quite the same," Hofman noted. "It's like a key in a lock. You just change one of the little teeth in the key -- a molecule for example -- and it does one thing but not another, even if it looks very much the same. So then, we get the very great advantage of avoiding some known and dangerous side effects."

The therapy appears to inhibit new blood vessel growth as part of its strong anti-tumor effect, Hofman said. Specifically, in animal studies, this cox-2-like agent achieved a 35 percent to 45 percent reduction in the density of tumor blood vessels without the development of any potentially damaging long-term side effects.

Hofman and her colleagues noted that though their current focus was on brain cancer, the therapy could have applications for other types of cancer, including breast cancer.

However, "this is not a wonder-drug," Hofman cautioned. "We don't have a cure for cancer here. But the approach we've taken and tested in lab and with rodent models looks very promising for future therapy with brain tumors."

Another study, led by researchers at the Mayo Clinic in Rochester, Minn., looked at inhibiting pancreatic cancer at the cellular level with a combination of two new agents: a histone deacetylase inhibitor called LBH589 and a mTOR inhibitor called rapamycin.

When used together, the two drugs appeared to provide more anti-cancer punch than they would have singly, the team said. While treatment with rapamycin alone only resulted in a tumor cell death rate of about 10 percent, the two drugs in combination elicited a 60 percent to 70 percent death rate. Any improvement in outcomes is welcome for patients battling pancreatic cancer, a malignancy that, because it is often detected late, has a very high mortality.

A fourth study was conducted by the biotech company Genentech. Researchers there honed in on specific proteins generated by a key player in cancer development, known as the "ras" oncogene.

In lab work, the study authors found evidence that by interrupting the pathways by which these proteins signal and trigger tumor growth, they were able to produce "significant" tumor cell death.

At this point in cancer research, "we obviously have a long way to go," remarked Vanderbilt's Carbone. "But this is all about more than just hope. I've been practicing for 18 years now, and I can say that we now are developing a new reality, as we learn more and more about cancer. And this will translate into real people having real responses and real improvements in their quality of life as they battle cancer. And that is what's so exciting."

More information

There's more on the effort to beat cancer at the American Association for Cancer Research.

Molecular Fingerprints Point The Way To Earlier Cancer Diagnosis And More Targeted Treatment

ScienceDaily (Mar. 27, 2009) — Metabolites are molecular fingerprints of what your cells are up to and Dr. Arun Sreekumar wants to know the impression made by cancer.

You've likely heard about metabolites; your physician probably screens for some known ones such as triglycerides or cholesterol at your annual physical. Scientists suspect we have about 3,000 metabolites that come from our food or are synthesized from different compounds in our bodies.

Dr. Sreekumar, a cancer researcher at the Medical College of Georgia Cancer Center, wants those screens of the blood or urine to also detect early signs of cancers such as leukemia, bladder, kidney and breast when the chance for cure is best.

He's already begun to identify metabolites that indicate not only the presence of prostate cancer, but its aggressiveness, a tool that could help tailor optimal treatment. The search began in men at risk: those with elevated prostate specific antigen, or PSA, levels. A PSA test along with a digital rectal exam is today's standard for prostate screening so physicians typically do both in men age 50 and older. But PSA levels are actually better at helping determine if prostate cancer has returned, Dr. Sreekumar says.

Elevated levels of PSA, a protein, are not always predictive of cancer, which means a lot of men get unnecessary biopsies. PSA measurements also can't distinguish between tumors that have a good outcome versus those with a poor one.

"The physician does not really have the tools in hand to really say that this tumor will spread to other organs or not." says the Georgia Cancer Coalition Distinguished Cancer Scholar. "We want to find clinical markers that supplement PSA."

Aggressiveness is a major factor in prostate cancer treatment. In fact some men with slow growing disease likely won't even need treatment. So he wants to provide a complement of biomarkers that accurately diagnose and categorize the disease then help monitor success of treatment. These early studies indicate a urine test may one day be possible to do just that.

He and colleagues at the University of Michigan reported in the Feb. 12 issue of Nature what appears to be one of the first metabolites implicated in cancer invasion. They looked at 1,126 metabolites in 262 samples taken from men with high PSA levels. They consistently found elevated levels of the amino acid sarcosine in the prostate tissues of men with cancer; levels were highest in what appeared to be the most aggressive tumors.

Sarcosine, a modified form of the amino acid glycine, was a known entity but its function was unclear. Scientists thought it might be a dumping ground for excess methyl groups needed to enable chemical changes of genes, proteins and other body components that can affect what and how much they do.

This process called methylation can be a good thing – like when it's helping an embryo develop – but when it goes badly, it can cause disease such as cancer. While sarcosine's dumping role seemed to protect from cancer, the Michigan scientists found its action actually helps induce tumors. In fact, when they added it to prostate cancer cells, the cells became more aggressive. Exactly how that process works is still under study but the findings were pretty consistent.

"When we looked at patients with metastatic disease, sarcosine levels were sky high compared to patients with localized tumors," says Dr. Sreekumar. "It's enabling invasion."

Because cancer and people are both very heterogenous, measures need to be taken in larger population samples, he says. Also, they found a small group of patients with negative biopsies and high sarcosine levels. "We don't know how many of them have missed cancer," says Dr. Sreekumar who joined the MCG faculty in February.

These are among the reasons he believes in strength in numbers. "In the real world of biomarkers, you want 100 percent sensitivity. If the patient has cancer, you want to pick it up. We need to have a kind of multiplex test where you can test for say10 different entities and have a greater confidence that what you are stating about the tumor is true. Our goal is to develop such a panel and research on sarcosine is a first step toward achieving this."

In his new position at MCG, he's looking to expand the number of metabolites known to be predictive of prostate and other cancers. In prostate cancer, he's beginning with follow up on other metabolites identified in the Michigan study in which researchers identified a total of six metabolites, including sarcosine, linked to increased tumor progression. A total of 89 metabolites were different in metastatic prostate cancer compared to localized disease.

He's excited about what metabolites will one day tell cancer physicians and patients but adds that they are just a piece of what our bodies can tell us about a potential cancer growing inside. Scientists also need to continue to look at genes expressed by tumors and the proteins expressed by those genes to get the bigger picture. "It's basically a systems approach you need to take," he says.

The young scientist has worked with all those pieces in his relatively short career. He started his postdoctoral fellowship at the University of Michigan in1999, when the ability to look at gene expression was new. With his mentor, Dr. Arul M. Chinnaiyan, director of Michigan Center for Translational Pathology, Pathology Research Informatics and Cancer Bioinformatics at Michigan, he helped develop the next step: the ability to look at expression of hundreds of proteins at a time, instead of a handful, an important advance in light of the fact that there are about 1 million proteins. Recently they were among the first to venture into the world of metabolites, which are made by proteins.

"Previous technology was looking at a cell from a narrow perspective and cells never act in isolation, proteins never act in isolation, they always form complexes, act in pathways," Dr. Sreekumar says.

His inspiration to follow those pathways is a fellow Ph.D. student who died too young and quickly of an aggressive leukemia and the fact that cancer is a leading cause of death worldwide.


--------------------------------------------------------------------------------

Journal reference:

Sreekumar et al. Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature, 2009; 457 (7231): 910 DOI 10.1038/nature07762

Drug Shows Activity In Men With Advanced Prostate Cancer

ScienceDaily (Apr. 8, 2009) — 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 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.

"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.

The study was supported in part by the Prostate Cancer Foundation, the National Cancer Institute, and a Prostate Cancer Research Program Clinical Consortium Award.

Mayo Clinic Study Shows Advanced Prostate Cancer Previously Considered Inoperable May Be Operable, Curable

ScienceDaily (Apr. 12, 2005) — ROCHESTER, Minn. -- New findings from Mayo Clinic indicate that cT3 prostate cancer, a disease in which the cancer has spread locally from inside the prostate to immediately outside it, is operable and has 15-year cancer survival rates of almost 80 percent.

"These patients have a better chance if they undergo surgery and are living longer than if they undergo radiation therapy," says Horst Zincke, M.D., Ph.D., Mayo Clinic urologist and senior study investigator.

Treatment of this type of prostate cancer has been controversial, as it is a stage 3 cancer in which the malignancy has spread. Due to its advanced stage, some physicians have considered it inoperable via radical prostatectomy, according to Dr. Zincke. He explains that many patients come to him for a second opinion after being told their cT3 prostate cancers could not be surgically removed.

"It's considered inoperable by some urologists and referred to radiation oncology," says Dr. Zincke. "They think surgery can't be done because the cancer is outside the prostate. Currently, only 15 percent are referred for surgery."

The problem with radiation therapy as the first line of treatment for cT3 prostate cancer, according to the Mayo Clinic researchers, is the cancer survival rate, which is 79 percent at only five years. In contrast, with radical prostatectomy, 79 percent of the patients lived at least 15 years. Says Dr. Zincke, "So, obviously surgery does a better job for these patients."

Dr. Zincke also explains that when malignant prostate tumors are high grade -- more aggressive -- they are not especially responsive to radiation therapy alone.
He believes the current trend away from surgery is a disservice to patients. "Patients are being denied surgical treatment when indeed they could have had surgery," Dr. Zincke says.

The cancer survival rates for cT3 prostate cancer with radical prostatectomy not only approach those of cT2 prostate cancer (cancer confined to the prostate), which is 90 percent at 15 years, but they are even more impressive due to the ages of the patients, says Dr. Zincke. "It's significant because the average patient is only 62 years old," he says. "So, a 15-year survival is a long time."

In addition to a favorable survival rate for the cT3 prostate cancer patients studied, the Mayo Clinic researchers also found urinary incontinence rates and complications were akin to those for cT2 prostate cancer.

Some of the patients studied with cT3 prostate cancer had additional, or adjuvant, therapy after surgery, such as hormone therapy or radiotherapy. Dr. Zincke indicates that adjuvant therapy is necessary for patients whose prostate cancer affects the lymph nodes. Surgery alone may be sufficient treatment for those without lymph node involvement. Approximately 50 percent of the cases of cT3 prostate cancer do not involve the lymph nodes.

The study also found that 25 percent of the patients were overstaged -- told that they had a cT3 prostate cancer, a more advanced form, rather than what they really had a cT2 prostate cancer in which the malignancy is confined inside the prostate.

Dr. Zincke points to following patients over 15 years post-treatment as a strength of the study.

"The highest incidence of prostate cancer death is not reached until 11 years after treatment, so 15-year data is significant," he says. "In contrast, five-year data is less meaningful."

Dr. Zincke recommends that patients with cT3 prostate cancer seek a surgeon who performs at least one prostate surgery per week and has completed at least 300 prostate surgeries. He explains that currently only 3 to 4 percent of urologists are doing more than one prostate cancer surgery per week. As they seek an appropriate surgeon, he encourages patients that "if someone tells you your cT3 prostate cancer is inoperable, don't give up."

With more common use of prostate-specific antigen (PSA) testing in the United States, more prostate cancers are now caught earlier, before the cancer spreads. Thus, the frequency of cT3 prostate cancers seen at Mayo Clinic has declined to 3 percent of all prostate cancers. Canada and Europe have much higher rates of cT3 prostate cancer, as PSA testing is not conducted as frequently and more cancers are discovered later than in the United States, allowing the cancers more opportunity to spread outside the prostate.

This study was conducted as a single-institution, retrospective study of 5,652 men who had radical prostatectomy at Mayo Clinic for confirmed prostate cancer.

The title of the paper is "Radical Prostatectomy for Clinically Advanced (cT3) Prostate Cancer Since the Advent of Prostate-Specific Antigen Testing: 15-Year Outcome." The first author is a former Mayo Clinic urology fellow, John F. Ward, M.D., Division of Urology, Naval Medical Center, Portsmouth, Va. Other Mayo Clinic authors include Jeffrey Slezak, Eric Bergstralh, and Michael Blute, M.D.

Prostate cancer screenings: a second opinion

Doctors are rethinking the value of the tests because the disease is rarely a killer and the treatment can do serious harm. By H. Gilbert Welch - April 1, 2009.

I probably have prostate cancer.

There's no need to feel sorry for me -- so do about half the men my age (I'm in my mid-50s). We doctors have learned this from microscopic examinations of the prostates of men who are autopsied following an accidental death. And the older men get, the more likely it is that they have prostate cancer. Autopsies of men in their 70s have found that about 80% of them had the disease.

I almost certainly won't die from prostate cancer, however. The lifetime risk of prostate cancer death for American males is only about 3%. So, although the prevalence of the cancer may sound alarming, 97% of men will die from something else.

These two observations have forced doctors to rethink what it means to have this cancer. Some have envisioned the problem to be like an iceberg. In the past, we only saw the part of the iceberg above the waterline -- the cancers that caused disease and death. With early detection, we can see below the waterline -- and there are a lot more cancers there. Many of these will never cause problems. They would have been better off undiagnosed.

But doctors can't tell who is better off undiagnosed. We can't reliably distinguish between prostate cancers that will never cause symptoms and those that are deadly. So we tend to treat everyone. The bulk of men who are treated won't benefit from it, because there is nothing to fix. But many of them will be harmed. Treatment causes significant side effects in about 30% of those treated, most commonly a decline in sexual function, leaking urine and/or rectal irritation.

That's why prostate cancer screening is such a challenging issue. Yes, it may save some men's lives, but it will harm many others along the way.

Two weeks ago, we learned more. The results of two large, randomized trials of prostate cancer screening were published. The studies represented an enormous research effort: almost 20 years of work, involving more than a quarter of a million men and many millions of dollars.

Yet there is still some uncertainty whether screening saves any lives. The European study said yes; the U.S. study said no. That in itself tells you something: If there is a benefit, it is undoubtedly small. In contrast, researchers in the 1960s were able to convincingly demonstrate the benefit of treating very high blood pressure by studying about 150 men over a two-year period. Why were they able to do this with so few men so quickly? Because the benefit was huge.

I believe there probably is a benefit to prostate cancer screening. But it is accompanied by a substantial human cost. Let's assume the European study is right. Its data gives us some idea of the magnitude of the trade-off: For every man who avoids a prostate cancer death, about 50 are treated needlessly (some of my colleagues might say the number is closer to 30, others might say it's closer to 100).

Being 50 times more likely to be diagnosed and treated needlessly than being the one man who avoids a prostate cancer death doesn't strike me as a good gamble. To the extent I have control over my cause of death, avoiding a prostate cancer death isn't my top priority (I'm more concerned about a lingering cognitive decline in a long-term care facility.) And death is not the only outcome that matters to me. I place considerable value on not being medicalized and suffering the side effects of treatment any more than I need to.

But it doesn't matter what I think about the trade-off. What matters is what you think.

American men have been engaged in prostate cancer screening for almost two decades with relatively little effort given to communicating the trade-off between the benefit and the potential harm of unnecessary treatment. The time has come to make that trade-off clear. There are a lot of bad arguments out there for screening. They include:

* Doctors who tell you they don't want to go back to the era when all their prostate cancer patients had advanced disease. It is true that the typical prostate cancer patient in the past had advanced disease. But we now know that the primary reason these patients now seem so rare is that they are being diluted by the many new prostate cancer patients who would have never been diagnosed in the past -- the majority of whom had cancers that weren't destined to progress.

* Media messages that highlight the tremendous improvements in survival. It is true that over the last 50 years, the five-year survival for prostate cancer has increased more dramatically than any other cancer (from less than 50% to almost 100%). But we now know that these numbers too are largely an artifact of over-diagnosis -- diagnosing a lot of men with prostate cancer who were never destined to die from the disease.

* Friends, family, acquaintances or celebrities who "owe their life" to screening. There are now a lot of men who appear to be in this group. But once you understand the problem of over-diagnosis, you recognize an alternative explanation: They never needed treatment in the first place. Some have labeled this the popularity paradox of screening: The more over-diagnosis screening causes, the more people who feel they owe it their lives and the more popular screening becomes.

There is no imperative to be screened, or not screened, for prostate cancer. The only imperative is that men be informed about the consequences of either choice.

H. Gilbert Welch is a professor of medicine at the Dartmouth Institute of Health Policy and Clinical Practice. He is the author of "Should I Be Tested for Cancer? Maybe Not and Here's Why."