From Arthur L. Burnett II, M.D. and Norman Morris

 Lots of new research is being targeted at treating advanced prostate cancer. Here’s the latest.  At the University of Texas Southwestern Medical Center in Dallas a team of scientists led by Dr. Ganesh Raj has developed a novel class of drugs to fight the cancer.

As we’ve reported many times, the growth of cancer cells depends on androgen receptor signaling.  Androgen (testosterone) reaches out to the receptor and that in turn leads the tumor to grow.  To thwart tumor growth patients have been given drugs that block the production of androgen…or they block the receptor where the androgen binds.

In this new study, the team found that they could disrupt the androgen receptor signaling  by using a novel class of drugs called peptidomimetics.  They engineered a small protein-like chain that the androgen receptors need to function.

Dr. Raj explains how it works like this. Think of a lock and key. The receptor is the lock and the androgen is the key. In advanced prostate cancer, despite drugs that target the lock or the key, the new drug uncouples the lock and key mechanism, and so the androgen receptor does not receive the required signal to proliferate and the tumor stops growing.

The novel drug in testing has proven to be non-toxic and the response has been highly promising, suggesting that the drug –in a class called peptidomimetcs—may be a viable therapeutic approach with men with advanced prostate cancer.

Further testing is needed, the researchers say, before the drug can move to Phase 1 clinical trials.

Details of this study can be found in the online site Nature Communications.

 Breaking news for patients suffering from advanced prostate cancer that has spread to the bones.  The Food and Drug Administration has just approved a drug called Xofigo produced by Bayer Pharmaceuticals. It is administered by injection and uses radiation to treat the cancer.  Xofigo targets bone tumors even after patients have received medication or surgery to lower testosterone.

FDA approval comes following a study of 809 men with advanced prostate cancer who received either the drug or a placebo.  According to Bayer,  patients who were taking Xofigo typically lived 14 months compared to 11.2 months for those who were taking placebo.  Researchers also reported side effects to be nausea and diarrhea.  News of this new drug was first reported on NBC Nigthly News.

Men diagnosed with minimal prostate cancer are considered to be at low risk when it comes to a life threatening form of the disease. Still, confronted with options of treatment vs surveillance and/or no immediate treatment, many men choose treatment—surgery and radiation– to lower their risks of developing full blown prostate cancer.  This is a subject that has led to a great deal of controversy and speculation among prostate cancer experts. Those who support treatment as “prevention” and those who contend there is and has been excessive and unnecessary treatment.

A new study—although admittedly encompassing a very small sample—probes a different direction that seeks to find a safer course for low risk prostate cancer patients. Researchers at the University of Chicago have completed a “phase 1” trial of a procedure called focal therapy which they say is very much akin to a lumpectomy in breast cancer.  Using a flexible laser fiber placed directly under the tumor with MRI scans to guide the delivery of laser energy to precisely destroy small  prostate tumors.  A 6 month follow up of seven of the nine men in the phase 1 study no longer reportedly showed evidence of cancerous tissue in biopsies of the treated area. The lead scientist, Dr. Aytekin Oto, a radiology professor and chief of abdominal imagining for U of C  Medicine, is quoted in the Chicago Sun Times, “This experimental approach appears to combine the most attractive element of treatment, eradication of the cancer, with the most appealing element of active surveillance, maintaining quality of life.” He expressed the hope that focal treatment will turn out to represent “a middle ground” for men with low risk prostate cancers. But he adds, “We definitely need longer term data.”

Support for these trials comes from Dr. Michael McGuire, chief of urology for North Shore University Health System who called the trial “interesting and exciting.”  But he cautioned that most prostate cancer is not found in just one focal area, which is why he says why at his hospital they don’t do a the equivalent of a lumpectomy.  (At least, so far.) But he added that a certain group of men might benefit.

Caution was expressed by Dr. William J. Catalona, director of the clinical prostate cancer program at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.  He believes focal therapy could make it, in his words, “more difficult or impossible to perform a clean nerve-sparing radical prostatectomy when it finally became apparent that focal therapy was inadequate.”  Dr. Scott Eggener, a U of C Medicine surgeon involved in the focal therapy study disagreed, saying focal therapy would not prevent more aggressive therapy down the road, if needed.

The usual treatment for advanced prostate cancer involves injections of hormones to reduce the levels of testosterone.  The problem is that these injections may have side effects including hot flashes, osteoporosis, bone fractures and diabetes.  The goal here is to reduce testosterone so as to shrink the tumor and/or slow down the growth of cancer cells.

There is encouraging news now from the Cancer Research UK group in Britain that has discovered that estrogen patches, usually used to treat menopause in women, can reduce testosterone in men to a similar extent as the current treatment by injection. And why is that better?  The answer appears to be reduced glucose and cholesterol levels that can lead to heart disease and stroke. The authors of the study—reported in The Lancet Oncology—say the next step is to determine if the patches are as effective at stopping the growth of prostate cancer as the current hormone treatments.  They are now testing over 600 patients and early results are expected to be announced later this year.

For researchers working on battling advanced prostate cancer it’s not unlike scenes in the popular TV program CSI. Using current treatment modes to uncover newer ones.  Or abandoning accepted hypotheses and thinking entirely outside the box.  When a patient has a recurrence of the disease, doctors know survival means stemming the recurrence as quickly as possible is key to survival. Rising levels of  PSA can suggest a man’s cancer is not cured. It’s been said that the PSA is like a puff of smoke signifying an early fire.

The problem is that the rising PSA doesn’t tell the doctor much. It doesn’t tell where the cancer is located. And if it is not found soon enough it is likely to spread and make treatment very difficult.  A new tool called PET has come along to help in the discovery process.  A PET ( positron emission tomography) scan involves the injection of a form of radioactivity containing glucose that can be detected by the scanner.  A lot of normal tissues use glucose rapidly ( the heart, liver, spleen and kidneys ) and cancer cells suck up the glucose in large amounts enabling them to grow and multiply at a higher rate than normal cells.  Those radiated glucose cells are then picked up to help locate the presence of cancer cells. The physician then can decide on treatment options.

That’s the theory. But the problem has been that prostate cancer cells are often slow in ingesting the  radioactive glucose, allowing the cancer to continue spreading elsewhere.  It meant that the principal test for helping to locate advanced cancer would still be a bone scan.  Until now.

Mayo Clinic in Rochester, MN has recently received Food and Drug approval to use a new imaging agent.  It is the only health care provider in the U.S. offering the new scan agent to patients.  Mayo Clinic’s new Cholin C 112 PET imaging agent is being ingested by prostate cancer cells easily, allowing doctors to actually see where the cancer is located.  That represents a remarkable breakthrough.

Urologist Dr. Eugene Kwon at Mayo says,” I’ve seen a single  hot spot in the middle of the breastbone.  I’ve seen a single hot spot behind the eyeball.  So  instead of guessing you absolutely know what you’re dealing with.”

The scanning technique uses choline, a common nutrient that all cells, including cancer cells, need to grow.  Doctors at Mayo believe they have essentially designed a homing beacon to find progressing cancer cells.  Mayo Clinic radiologist Dr. Val Lowe says prostate cancer cells absorb a lot of choline and it makes the compound a good biomarker for detecting tumors.  “If a cancer is growing and producing more cells, then the  hypothesis is that it’s going to need more choline than other cells around it.”

Before the test, Lowe’s team attaches a radioactive isotope to the choline.  When the solution is injected into a patient’s bloodstream it emits a signal that can be seen on a PET scan.

The Mayo Clinic reports it is booking approximately 22,000 prostate cancer visits a year—most of them for men whose cancer has returned.

The FDA approved drug Provenge has been a welcome advance in treating advanced prostate cancer.  It works by training the body’s immune system to find and attack prostate cancer cells.

For the first time researchers at Georgia’s Health Sciences University are conducting clinical trials combining Provenge with two other cancer-fighting drugs to further improve life expectancy.  The two are CT-011 and cyclophosphamide.

Provenge has been found to extend life  by nearly 20% and the lead scientist Dr. Samir Khleif says the latest tests represent the latest attempt to eradicate the disease completely. Both of these drugs used alone have been shown to reverse immune suppression caused by cancer.  But they’ve never been combined before in treating prostate cancer.  Pre clinical trials in Dr. Khlieif’s lab found that the combination of Provenge with these two drugs led to a significant increase in survival and complete tumor regression in more than 50% of the mice.  Based on these results, the makers of Provenge—Dendreon Corporation—and Dr. Khleif are collaborating on this first in human trial.

Patients who undergo prostate cancer surgery and whose penile nerve bundles have been spared, nevertheless, know that natural erections don’t come back right away. Depending on a particular patient, they can return in rare instances in several weeks following the operation, but more likely months later; in a lot of instances it can take a year or more. But why?

The bundles of nerves on either side of the prostate are responsible for erection. If the cancer is not near by the prostate capsule, the careful surgeon can take extreme care to treat the nerves gently. Nevertheless, these nerves don’t have the same kind of protective coating (called myelin sheath) that insulates larger nerves.  This sheath in larger nerves is like an electrical insulation and so the penile nerves are vulnerable to injury from heat and stretching that occurs in the surgical procedure.

Dr. Burnett, co-author of our book, is the neuro-urologist whose scientific work has led to innumerable breakthroughs in the realm of physiology of erection and in developing strategies to give extra protection to these nerves. He explains that these nerves often take a hit when neighboring tissues are removed.  He likens it to” windows shattered throughout a city block after a grenade goes off in a parked car.”  In the winter 2012 issue of Hopkins’ Prostate Cancer Discovery

Dr. Burnett reveals that his laboratory has been working on developing strategies to give extra protection to these penile nerves. His task has been to somehow jump-start or stimulate regeneration. In the latest issue of the Journal of Sexual Medicine Dr. Burnett explains his group is working on developing an external vibration stimulatory device that may be applied under a specified protocol after surgery.  He says, “ Our preliminary results suggest a likely benefit of this treatment. A definitive clinical trial is already under way.”

The breakthrough drug cabazitaxel to treat metastatic and hormonal refractory prostate cancer is now available to patients.  Cabazitaxel, developed by the French pharmaceutical company Sanofi, is designed to prevent prostate cancer cells from dividing and spreading. The drug is administered intravenously and is a prescription anti-cancer medicine used with prednisone.

Cabazitaxel has been approved by the U.S. and Philippines Food and Drug Administration. It’s the first approved drug to demonstrate improved survival in patients with metastatic hormone refractory prostate cancer with progressive disease after docetaxel-based treatment following Sanofi’s Phase 3 trials.

This new drug was shown to reduce the risk of death by 30% the researchers said when used in combination with the anti-inflammatory drug prednisone.  Patients who received cabazitaxel had “significantly prolonged time to tumor progression,” according to the developers.

Hormone therapy us generally the first line of treatment for advanced prostate cancer.  When the patient becomes unresponsive to it, doctors turn to chemotherapy, usually with docetaxel.  Until now, if chemo becomes unresponsive, the next step has been palliative therapy because there were no other options open to patients that could prolong their lives. Now, with cabaztaxel available, there is a second line of defense proven to have survival benefits.

American and British scientists have identified two separate “genetic signatures” for prostate cancer that they hope will predict the severity of the disease. If their hopes bear fruit, doctors will be able to predict with accuracy severe cases and treatment of the disease can be greatly improved.

News of these findings appear in two articles published recently in The Lancet Oncology.  Both articles reveal distinctive patterns of RNA. That’s the genentic material that helps turn DNA into proteins. The patterns are said to tell whether patients have an aggressive prostate cancer or whether they have a milder form of the disease.

The authors of one article ( at The Institute of Cancer Research, London—and The Royal Marsden NHS Foundation Trust, UK) have identified a set of genes that were able to predict whether patients had castration-resistant prostate cancer.  ( Castration-resistant prostate cancer shows wide variation in survival times, though the reason is so far not clear.)

In the second article, researchers at Mount Sinai Medical School in New York identified a different set of genes with predictive properties similar to those in the British study.

Independent researchers say the scarcity of prognostic markers presents a major challenge for the clinical management of castration-resistant prostate cancer. And these latest results suggest that a few selected genes in blood samples from patients with castration-resistant prostate cancer can significantly improve the prediction of outcomes.  More work they say has to be done to better our understanding of the biological mechanisms at work here.

Erectile dysfunction will occur for certain following prostate surgery.  If the fragile nerves surrounding the prostate can be spared (saved), erectile dysfunction will for the most part be only a temporary condition. Men who have had good erections prior to surgery are the ones more likely in time to recover well. During the recovery period, while the fragile nerves are restored to health, patients can still engage in sexual relations using various devices that produce erections. It can take up to a year or more for natural erections to be restored. The time element varies with all individuals. Some fortunate patients are able to have natural erections in a matter of months.

But what of patients who choose radiation as an option to deal with prostate cancer? Will these men develop erectile dysfunction? According to the National Cancer Institute, in the case of men who choose external beam radiation, 65% to 85% are likely to experience erectile dysfunction.  The prevalence of erectile dysfunction following seed therapy (brachytherapy) is between 25% to 50%.  The good news for these radiation patients is that they will in most cases regain their potency with time and treatments.

But doctors would like to know which men may be more likely to develop this side effect of erectile dysfunction following radiation. What are the causes?

In the first study of its kind, a research team led by Albert Einstein College of Medicine (of Yeshiva University) and Mount Sinai School of Medicine—both New York City institutions—discovered 12 genetic markers associated with the development of erectile dysfunction (ED) in prostate cancer patients who were treated with radiation.  Findings are reported online in the International Journal of Radiation Oncology-Biology-Physics.  They are cited as a major step toward helping physicians determine the best course of treatment for prostate cancer patients undergoing radiation.

Patients in the study were divided in three groups or cohorts: those treated with seed therapy; those with seeds plus beam radiation; and those with external beam therapy alone.  The authors were able to identify specific genes that make certain patients susceptible to erectile dysfunction. The researchers concluded that certain genes sensitize some patients to developing ED.  They say further studies will be necessary to nail down which specific genes can offer a predictive test to identify men at highest risk for developing erectile dysfunction following radiotherapy.  The researchers are also evaluating the impact of radiation treatment on urinary complications and inflammation of the rectum known as proctitis.