Aggressive Prostate Cancers: What’s New in Research and Treatment?

This year, approximately 180,000 men in the United States will be diagnosed with prostate cancer. Prostate cancer comes in many forms and we have a slew of acronyms to help us categorize not just the stage of the prostate cancer, but its various sub-types. These sub-types are based on biological markers and the genetic makeup of the tumor and tell us a lot about how the tumor may behave. We have even found that these tumor cells can change over time to avoid detection, and in the process they can become resistant to treatments.

Aggressive prostate cancer sub-types represent approximately 25% of all prostate cancer cases. A common treatment for aggressive prostate cancer that hasn’t spread (non-metastatic prostate cancer) is “castration” through surgery or other therapies to deplete the androgen and testosterone hormones that feed the tumor.

Castration-resistant prostate adenocarcinoma or CRPC is the medical term for prostate cancer that does not respond to these therapies. Adenocarcinoma is a fancy way of saying a glandular cancer, an umbrella term for cancers that originate in different glands in the body, of which the prostate is one.

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Microscopic images of aggressive prostate cancers. Top: castration-resistant prostate cancer (CRPC) Bottom: Neuroendocrine prostate cancer (NEPC)

New and emerging research has shown that CRPC can evolve and morph into neuroendocrine prostate cancer (NEPC), another aggressive type of prostate cancer. The mechanism by which this happens is not yet completely known, but at Weill Cornell Medicine we’re hard at work to discover the answers.

On a molecular level, neuroendocrine prostate cancers are associated with over-expression and gene amplification of MYCN (the gene that encodes the N-Myc protein). MYCN is a gene that has been proven to drive cancer (a.k.a. an oncogene) in several rare tumor types, but the role it plays in the progression of prostate cancer has not yet been well established.

On Sunday, April 17th at the 2016 American Association for Cancer Research (AACR) Annual Meeting, Dr.
Rickman and colleagues
showed that by integrating a novel genetically-engineered mouse model and human prostate cancer transcriptome data (the product of the genes that were expressed in those patients’ tumors), N-Myc over-expression leads to the development of poorly differentiated, invasive prostate cancer that is similar to human neuroendocrine prostate cancer tumors on molecular and histological levels.

NMYC slide[1] copyThis research also demonstrated that N-Myc over-expression sensitizes cells to specific inhibitors targeting epigenetic modifiers that are linked to neuroendocrine prostate cancers. In plain language, this means that the controllers of the genes (the epigenome) in NEPC may be especially sensitive to certain drugs (such as EZH2 inhibitors that are in the clinic currently). This provides strong rationale for developing additional new therapeutic strategies in order to treat this aggressive subtype of prostate cancer more effectively and prevent it from becoming neuroendocrine prostate cancer.

For more information about our open clinical trial using an EZH2 inhibitor, please contact Amelyn Rodriguez, RN at amr2017@med.cornell.edu or (212) 746-1362.

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