Neuroendocrine Prostate Cancer; a Lethal Result of Resistance to Hormone Therapy.

Church yard in Middletown, Maryland; BJ Gabrielsen photo.
Church yard in Middletown, Maryland; BJ Gabrielsen photo.

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.

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