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 oftreatment 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.
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.
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.