SAN FRANCISCO, CA USA (UroToday.com) - Dr. Andrew Armstrong’s presentation was focused on the evolving mechanisms and pathways which potentially lead to persistent androgenic and androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC).
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He also discussed some novel therapeutic strategies to overcome these mechanisms in a “post-enzalutamide and abiraterone world.” He went on talking about as the disease evolves, selection for cell survival mechanisms that compensate for restricted ligand or inhibited AR become important. These mechanisms are the reverse of androgen and AR-independent prostate cancer (e.g., neuroendocrine prostate cancer), androgenic ligand dependent but hijacked receptor (e.g., glucocorticoid receptor), androgenic ligand-independent but AR-dependent mechanisms (e.g., AR deletion or splice variants), and the common scenario of androgenic ligand and AR-dependent prostate cancer (i.e., wild-type AR, AR mutants, and amplified AR12–14). Being able to therapeutically address these categories of persistent hormonal signaling will require knowledge of the sophisticated relationship between androgen synthesis, oncogenic signaling pathways, epigenetic regulation, AR effectors, AR chaperones and transport to the nucleus, and reciprocal pathways that intersect with the AR transcriptome. And more recently, microRNA species and long noncoding RNAs have become increasingly recognized as important in CRPC development through AR interactions.
Understanding of AR interaction with a large network of co-regulators that may alter AR function and transcriptional targets is the key to the design of novel targets for therapy. Dr. Armstrong discussed that it is likely that planned sequential approaches and use of novel systemic therapies, will be driven by biomarkers that identify the different mechanism(s) of resistance in a given patient. For example, measuring Rb status may predict which men benefit from cell-cycle checkpoint inhibitors combined with androgen pathway inhibitors.
Finally, he acknowledged that clinical trials will be needed to address combination approaches vs sequential designs. It would be beneficial to know if upfront combination approaches are superior to waiting for resistance to develop and sequentially adding or substituting a second agent. Since it is more likely that a single agent sequential therapy may induce resistance more rapidly than combination approaches (e.g., HIV therapy), combination therapy and development of biomarkers are becoming increasingly important to address CRPC which uses cellular processes to thrive in the presence of abiraterone or enzalutamide.
Highlights of a presentation by Andrew J. Armstrong, MD at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA
Duke University School of Medicine, Durham, NC USA