A new urine test for prostate cancer that measures minute fragments of ribonucleic acid (RNA) is now commercially available nationwide through the University of Michigan MLabs. The new test [Mi-Prostate Score (MiPS)], improves the utility of the PSA blood test, increases physicians’ ability to differentiate high-risk prostate tumors from low-risk tumors in patients, and may help many men avoid unnecessary biopsies. While there are currently no perfect biomarkers that identify only high-risk prostate cancer, the MiPS test incorporates blood PSA levels and two molecular RNA biomarkers specific for prostate cancer in one final score that provides men and their doctors with a more personalized prostate cancer risk assessment. One biomarker is a snippet of RNA made from a gene (PCA3) that is overactive in 95 percent of all prostate cancers. The second biomarker is RNA that is made only when two genes (TMPRSS2 and ERG) abnormally fuse. The presence of this fusion RNA in a man’s urine is very specific for prostate cancer. A commercial urine test (PROGENSA PCA3) for PCA3, developed and marketed by the California-based biotech company Gen-Probe, gained FDA approval in 2012 for use in men who are considering repeat biopsy after an initially negative result. The new urine test offered by MLabs that measures both PCA3 and TMPRSS2:ERG should improve a doctor’s ability to stratify men suspected of having prostate cancer. In a study published in Science Translational Medicine, University of Michigan investigators found a correlation between the highest rates of cancer in men with the highest levels of TMPRSS2:ERG and PCA3 in their urine. The men in the study were divided into three groups based upon the levels of TMPRSS2:ERG and PCA3 in their urine: low, intermediate and high levels. Cancer was diagnosed in each of the groups respectively: 21%, 43%, and 69%. High-grade prostate cancer, defined in the study as a Gleason score greater than 6, also occurred at different frequencies in the three groups with 7%, 20%, and 40% diagnosed in each group respectively. For additional information on this test, see the following link from the December 20th, 2013 Prostate Cancer Foundation Newsletter. Earlier references to these tests can also be found on this website in 2013 posts dated October 8th, and July 16th as well as those dated March 25th, 2012 and September 21st, 2011.
Christmas-New Year 2013 Greeting
First and foremost, as we are nearing the end of 2013, I wish to thank the nearly 200,000 readers of this website. Writing it is a joy for me personally, and it was especially gratifying to receive comments from prostate cancer patients who had been successfully treated at my “alma mater”, Johns Hopkins in Baltimore, Maryland. Hopkins continues to be one of the best sources of information about this disease as evidenced by recent articles on brachytherapy and general therapy options in the Johns Hopkins Health Alerts to which one can subscribe. There is a lot of new medical information which will be posted shortly. At this time however, I would like to wish you all a belated meaningful and gratifying Christmas season and a truly fulfilling and healthy New Year. The significance of these holidays is best expressed by the prophets Isaiah and Jeremiah as follows. “For a child (Jesus) will be born to us, a Son will be given to us, and the government will rest on His shoulders; and His name will be called Wonderful Counselor, Mighty God, Eternal Father, Prince of Peace.” (Isaiah 9:6). “‘For I know the plans I have for you’, declares the Lord, ‘plans for welfare’ (not governmental) ‘and not calamity to give you a future and a hope.'” (Jeremiah 29:11.) Finally, a verse from Matthew 1:23 which is most meaningful, comforting and indeed mind-boggling, which states “a virgin shall be with child and shall bear a Son, and they shall call His name Immanuel, which translated means ‘God with us’.” Imagine the eternal God of a myriad of universes can be so personal through Jesus His Son that He can truly be known individually. May we all experience this in 2014.
Targeted Delivery of Cancer Drugs Such as Docetaxel (Taxotere).
An August 11th, 2013 blog (below) on this website described how a chemotherapeutic drug such as docetaxel (taxotere) used in the treatment of advanced prostate cancer could be administered more effectively and with less side effects. Taxotere is a variant of an anti-cancer drug (taxol) originally isolated from yew plants.
Nanoparticles are chemical species which can serve as a targeted delivery system for drugs, proteins and other therapeutics. The drug to be delivered is contained within the nanoparticle whose surface is then coated with targeting moieties such as antibodies. The overall result is the delivery of a specific drug directly to the cancer cells thereby allowing for higher localized doses and minimized systemic side effects. This type of delivery system for docetaxel (taxotere) is given as an example in a video and accompanying article from the July 31st, 2013 issue of the Prostate Cancer Foundation NewsPulse. Docetaxel is a chemotherapy used in metastatic, hormone-refractory prostate cancer patients. While it is efficacious, it also can produce serious side effects. It is also limited in the amount of drug which can be administered intravenously. Therefore, nanoparticle delivery can be much more efficacious.
Now in the October 31st, 2013 issue of the Prostate Cancer Foundation (PCF) NewsPulse, the nanoparticle delivery system for docetaxel (taxotere) which specifically targets cancer cells is described and illustrated in more detail. This technology allows higher doses to be administered and reach the tumor with fewer side effects for the patient. This targeted taxotere delivery system (called BIND-014) is being developed by BIND Therapeutics and is currently in Phase II clinical trials in men with treatment-resistant, metastatic prostate cancer and non-small cell lung cancer. BIND-014 specifically targets an antigen called prostate-specific membrane antigen (PSMA) found on the membranes of prostate cancer cells as well as on blood vessels within tumors that feed cancer cells. Details of the current Phase II clinical trial of BIND-014 are discussed in the NewsPulse article.
In a Test of my Faith, I Received a Grade of C(-). I Passed but Could Do Better.
During my personal and scientific career, I have been blessed to meet and interact with some extremely interesting and gifted people. One such person, Dr. Raymond Damadian, is the inventor of magnetic resonance (MR) scanning. He and I formerly attended the same church in Long Island, New York. One of Dr. Damadian’s chief scientific passions continues to be the use of MR scanning in the early detection of cancer. His company, Fonar, is focused on the design, manufacture and application of upright multi-position MR scanners. As I have previously written, I have micro-metastatic, PSA-producing prostate cancer cells at some unknown site(s) in my body but I continue to be totally healthy and asymptomatic. During conversations with Dr. Damadian, it was proposed that I undergo upright MR scanning to see if metastatic prostate cancer could be detected in common metastatic sites such as bladder, lymph nodes and pelvis. I underwent the scan in a seated position, optimal for receiving MR signals from areas such as prostate amd bladder. After consultation with his radiologist, Dr. Damadian reported that he could not detect any cancer in the prostate-bladder-lymph node areas which was good news. However, there was a suspicious area in my right pelvis. In 1991, as a result of a severe auto accident, my right hip had been replaced. Subsequently, my right pelvic area (acetabulum), had suffered considerable wear-and-tear over the years, hence a process called arthroplasty was performed in 2007 wherein significant bone grafts were inserted in my right pelvic area. But my original replaced hip remained in place and functioning well. The area surrounding the bone grafts required further review by Dr. Damadian and his radiologist. Upon hearing this preliminary report, I immediately began envisioning the worst logical scenario. Knowing that prostate cancer metastasizes to the pelvis, I left Fonar somewhat with a sense of impending dread fearing that the MR scan had revealed some pockets of tumor cells. That evening, I found myself anxious and somewhat angry with God thinking that He had allowed my cancer to metastasize to the pelvic bone, which I knew eventually would result in considerable pain and possibly death. The next morning I again asked God why He had allowed me to receive this negative result and I voiced my extreme concern. However, upon spending some time reading His Word and in a few moments of fervent prayer, I reluctantly agreed to trust Him for whatever outcome would emerge, even though I was not happy with the entire scenario. I compared my situation with that of the apostle Paul, to whom was given a physical “thorn in the flesh”. Paul had pleaded with God on three occasions to remove this physical malady but God had not done so. I am sure Paul was not overjoyed about having this physical “thorn”. Instead God told him (in 2 Corinthians 12:7-9) that “His grace was sufficient” for Paul’s situation and Paul later concluded that “God’s power was perfected in his (Paul’s) weakness.” So I awaited Dr. Damadian’s further radiological evaluation of my pelvis with some anxiety but a mediocre though significant degree of trust in God’s eventual provision. A very short time later, as I was boarding my return flight to Florida, Dr. Damadian called and proclaimed that he and his radiologist could not detect any cancer during subsequent intensive review of my scans. The presence of the areas of grafted bone were not commonly observed in other more clearly defined pelvic scans. My spirit soared along with the ascending plane in which I was traveling. God had tested me again to see if I would trust Him regardless of the medical outcome. Initially my faith faltered but it recovered somewhat within a 24-hour period. Often God allows us to view ourselves in His divine mirror. Hopefully, we will remember what we observed and learn from seeing our mirror image and grow spiritually in our loving and trusting relationship with the Father and His Son, our Saviour, Jesus Christ.
Neuroendocrine Prostate Cancer; a Lethal Result of Resistance to Hormone Therapy.
Most (90%) of all prostate cancers are initially diagnosed as treatable adenocarcinoma. However, every adenocarcinoma type of cancer contains a sub-type of cells (often 1% or less) called neuroendocrine prostate cancer (NEPC) cells. While adenocarcinoma cells often metastasize to bone, NEPC can metastasize to liver or other abdominal organs. Cancer cells have the ability to evolve to possess different characteristics from the original tumor cells. In doing so, the new altered cells may become resistant to the initial therapy such as hormonal therapy for prostate cancer. NEPC is often a result of treatment with hormone therapy.
One goal of drug development is to find therapies that delay development of drug resistance thereby making prostate cancer a chronic, treatable disease instead of a lethal one. Currently, there are several new therapies available for men whose prostate cancer has become resistant to standard hormonal therapy. These new agents can prolong survival times. They act as anti-androgens, i.e. they inhibit the production or cellular action of testosterone that stimulates prostate cancer growth. In stimulating prostate cancer cell growth, androgens such as testosterone bind to a receptor on the cell (the androgen receptor, AR) and thus stimulate the production of prostate-specific antigen or PSA. The newly-approved drug Zytiga (abiraterone acetate) works by inhibiting androgen (testosterone) production while Xtandi (enzalutamide or MDV3100) works by blocking the cell’s androgen receptor thus inhibiting its action. In some patients however, exposure to these drugs can stimulate the conversion of adenocarcinoma prostate cancer cells into neuroendocrine cells which are no longer dependent on androgen production or binding, thus resulting in resistance to hormonal therapy. For men with NEPC, PSA levels may be low but survival time is often a year or less. Researchers currently are not sure if neuroendocrine cells originally have the stem cell-like renewal quality that makes them so difficult to treat, or if that is part of the conversion process occurring when hormone therapy is given over time. A normal gene called p53 is involved in the control of many cancers and may keep neuroendocrine cells in check. But it is possible that the p53 gene mutates thereby allowing the NEPC to aggressively multiply un-checked. A clinical test for NEPC is being developed by Empire Genomics in collaboration with researchers at Weill-Cornell Medical Center in New York. Such a test would be a valuable tool in the diagnosis of this deadly type of prostate cancer, NEPC.
There is however good news on the horizon. Researchers have found that two normal genes, Aurora kinase A and N-myc are overactive (overexpressed) in NEPC when compared to adenocarcinoma and normal benign prostate cells. Many NEPC cells actually had extra copies of these two genes. Only 5% of adenocarcinoma prostate cancer cells have the extra gene copies and they are absent in normal benign prostate tissue. An oral drug, MLN8237 (alisertib) which inhibits the activity of Aurora kinase A, is currently in clinical trials for the treatment of neuroendocrine prostate cancer (NEPC) as well as other types of cancers such a lymphomas. Specifically, a phase I, II trial is underway examining the effects of alisertib, abiraterone acetate (Zytiga) and prednisone in men with hormone-resistant prostate cancer whose cancers evolved to the NEPC subtype. In mouse models, MLN8237 shrank NEPC tumors between 50-85% while having virtually no effect against adenocarcinoma. “Researchers believe that Aurora kinase A and N-myc work in tandem to transform adenocarcinoma prostate cancer into the NEPC subtype. When Aurora kinase A mutates, becoming an oncogene that goes into overdrive, that in turn dysregulates N-myc, which drives adenocarcinoma cells to morph (evolve) into NEPC cells that have stem-cell like qualities associated with rapid, uncontrolled growth. This domino-like chain of events in the development of NEPC means that inhibiting Aurora kinase A may likely be enough to halt the transformation process, which indirectly inhibits N-myc.” N-myc overexpression is involved in other fast-growing, aggressive cancers such as certain pediatric brain tumors and T-cell lymphomas. Researchers propose that if men with extra copies of the Aurora kinase A and N-myc genes could be identified at the time of their initial prostate cancer diagnosis, then treatment with Aurora kinase A inhibitors at an early stage in the disease process might limit the transformation of their adenocarcinomas into the aggressive NEPC subtype. This scenario could also lessen or avoid hormonal deprivation treatment with anti-androgens. The ultimate goal would be to lengthen the time before the appearance of drug resistance thus increasing survival. For a more complete description of this work, see the July, 2013 issue of the Prostate Cancer Foundation NewsPulse.
Nerve-Sparing Radical Prostatectomy
Surgery (radical prostatectomy) is one option for treating prostate cancer. Personally, since I was in my mid-50’s when prostate cancer was detected, I opted for this route. The two major risks posed by surgery and other treatments are incontinence and impotence. The area surrounding the prostate gland is densely composed of small blood vessels and nerves which control urinary function and erections. The presence of numerous small blood vessels in the area surrounding the prostate make the surgical field a bloody one, hence the chances of severing an essential nerve(s) are increased. In the 1980’s, Dr. Patrick Walsh of Johns Hopkins Hospital in Baltimore, Maryland developed a surgical technique wherein sensitive nerves could be spared to a large degree, hence the term “nerve-sparing” prostatectomy. This technique is described in numerous on-line websites including the September 14th issue of the Johns Hopkins Health Alerts. If you are considering having a radical prostatectomy either robotically or via the traditional surgical route, I highly suggest you seek out an experienced surgeon who has been specifically trained in the nerve-sparing technique and has performed many often thousands of these procedures successfully. One should also inquire about their success rates for maintaining erections and minimizing incontinence. From personal experience, I have found that an individual is “never quite the same” after most forms of treatment. Hence limiting any undesirable side effects is of maximum importance. While surgeons proficient in this technique are not limited to Johns Hopkins physicians, I have found numerous sites of interest by searching the internet using the term “nerve sparing prostatectomy, Johns Hopkins.” or “nerve-sparing technique, prostate cancer.” There are also a series of videos depicting the surgery itself which illustrate the challenges and surgical prowess necessary to preserve urinary and erection-maintaining functions. Seeking the proper surgeon is the key to success. In my own case, upon my diagnosis in 1995, my first impulse was to contact Dr. Patrick Walsh at Johns Hopkins but when I sought God’s advice, He led me to one of Dr. Walsh’s colleagues, Dr. Jacek Mostwin, currently Professor of Urology at John Hopkins Medicine. I can personally recommend him most highly. There are however many other skilled and experienced surgeons at fine hospitals and university centers. The reader is urged to seek them out and ask pertinent questions. God often treats and heals our infirmities through gifted physicians, a fact to which I can testify.
A New Urine Test for Prostate Cancer Combining Genetic Biomarkers.
Considerable academic and commercial research efforts are underway in order to identify and utilize genetic biomarkers to aid in the diagnosis and characterization of prostate cancers, to determine their aggressiveness, to ascertain the need for biopsies, and to monitor therapeutic regimens. These have been reviewed in this website’s blog posts dated March 26th, 2012 and more recently, July 16th, 2013. Two such genetic markers found in urine are PCA3 (developed by Gen-Probe and approved by the FDA as PROGENSA PCA3) and TMPRSS2:ERG (from the University of Michigan). A three-way collaboration is underway between these two entities and the National Cancer Institute (NCI) of the National Institutes of Health (NIH) to combine and maximize the accuracy and utility of these tests. These efforts have been described in detail in an article published on September 30th by the Prostate Cancer Foundation (PCF). I suggest reading the entire article. If you feel that these tests may be applicable to your specific prostate cancer condition, definitely discuss them with your urologist, oncologist or medical provider.
Measuring PSA Activity May Be a Better Predictor of Prostate Cancer Aggressiveness.
Research results recently published online in the August 9th issue of The Prostate (Prostate 2013, DOI:10.1002/pros.22714) suggest that measuring the biological enzymatic activity (or lack thereof) of prostate-specific antigen (PSA) could be used as a predictor of prostate cancer (PCa) aggressiveness. As we know, the level of PSA in serum is often used to determine the necessity of prostate biopsies in the diagnosis of prostate cancer. Much research is on-going to discover tests which can be used to measure the aggressiveness of the cancer while at the same time, minimizing the negative side effects often accompanying prostate biopsies. Such a test could also be useful in determining which cancers could be candidates for active surveillance. In a study of 778 surgically-treated prostate cancer patients, a research team from Ohmx Corporation and Northwestern University have found that higher levels of PSA’s enzymatic activity (aPSA) correspond with less aggressive types of PCa (and vice versa). Stated differently, the activity of PSA (aPSA) is inversely proportional to disease stage. “Patients with the most aggressive PCa have significantly reduced PSA activity compared to those with less aggressive disease.” The researchers note that 22% of the men in their study population, namely the diagnosed patients with non-aggressive prostate cancer, could have averted or delayed radical prostatectomy based on their PSA activity findings. Ohmx Corporation is continuing validation studies and developing a commercial test, which they have trademarked PPA (PSA Peptidase Activity). Biochemically, PSA (a protein) is an androgen (hormone) – regulated serine protease enzyme produced by both prostate epithelial and prostate cancer cells. PSA is the major protein found in semen. It is secreted into the prostatic ducts in an inactive form that is then activated biochemically. PSA that enters the circulation is rapidly “bound” although a fraction is inactivated and circulates as “free PSA”. High PSA levels may be predictive of advanced PCa but a large fraction of organ-confined cancers show much lower PSA values that overlap those levels found in men without PCa. Measurement of free versus total PSA can increase specificity for PCa. PSA is also used widely to monitor responses to therapy and is under investigation as a therapeutic target itself. Remember to always discuss these issues with your physician before taking any actions.
But more importantly, whatever your current situation, if you are concerned about prostate cancer either personally or for someone else, remember that God Himself has a message for you. David writes in Psalm 55:22, “Cast your burden upon the Lord and He will sustain you; He will never allow the righteous to be shaken.” In addition, Psalm 34:19 states “many are the afflictions of the righteous; but the Lord delivers him out of them all.”
Johns Hopkins Urology: A Valuable Resource for Prostate Cancer Information.
The Department of Urology at the Johns Hopkins Hospital in Baltimore, Maryland has consistently been rated best (#1) in the annual survey published in U.S. News and World Report. Hopkins urologists provide an excellent source of prostate information via a number of publications. Recent examples are as follows. The July 28th-Aug. 3rd issue of the Johns Hopkins Health Alerts contained an article describing new therapies for men with metastatic, castrate-resistant (hormone-refractory) prostate cancer. Recently approved drugs, which inhibit testosterone and its biological activity, include abiraterone acetate (Zytiga) and enzalutamide (Xtandi). These agents, in addition to the earlier-approved treatments Provenge and Jevtana, provide new options for men with advanced prostate cancer. The Aug. 4th-Aug. 10th issue featured a discussion on diet and prostate cancer. Regular intake of vegetables, especially cruciferous vegetables such as broccoli (containing the active compound sulforaphane) and cabbage, soy foods and lycopene-rich tomato products, have all been associated with a lower risk of prostate cancer. In addition, pomegranate and its juice may slow prostate cancer progression. The same issue discussed the effect of diabetes and its association with aggressive prostate cancer. The most recent weekly issue of the Johns Hopkins Health Alerts (Aug. 18th-24th) featured an article discussing possible help in reducing hot flashes, an undesirable side effect often experienced by men receiving androgen deprivation (hormonal) therapy. A reader can subscribe to automatically receive these Health Alerts electronically for specific conditions such as prostate cancer. Finally, a comprehensive treatise entitled “Prostate Cancer Outlook 2013” written by the Hopkins physicians describing the latest developments in their own specialties, is available for purchase as an invaluable reference.