MADRID, SPAIN (UroToday.com) - In this lecture, Dr. Norman Maitland offered his theories as to why all prostate cancers ultimately progress to castration-resistance. He began by emphasizing that the mechanism by which androgens stimulate prostate cancer is not simply a switch that is turned on and off, but instead is via a highly regulated signaling pathway. This pathway may be blocked at multiple different points and the agents to achieve this already exist, however these therapies are associated with a significant number of known resistance mechanisms.
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He addressed the pitfalls of focusing on targeting only the androgen receptor (AR) pathway in metastatic prostate cancer. AR expression is not limited to the prostate and testes, but instead is widespread and can be found in organs like the brain, bone marrow, and spleen. As a result, targeting the AR pathway with new potent anti-androgens has the potential for unknown significant long-term off-target effects. He also discussed that AR pathway blockade alone is insufficient in the treatment of prostate cancer and it ultimately results in the activation of salvage or compensation pathways which bypass the established blockade, allowing for disease progression. Identifying and targeting these salvage pathways using combination therapies may ultimately prove more effective than targeting the AR pathway alone.
Dr. Maitland then focused on resistance mechanisms inherent to tumors. He discussed that stem cells resistant to all current therapies make up a small proportion of tumors and act as a reservoir for tumor progression. He presented data demonstrating that this population of stem cells actually expands in response to chemotherapy and radiation. These stem cells may be heterogenous in genetic composition which also contributes significantly to treatment failure.
Dr. Maitland outlined what he believed was the “life story” of prostate cancer. After a period of pre-tumor progression, the expansion of a single clone results in an initial cancer focus. Within this focus, random mutations and selection in the tumor microenvironment result in the development of multiple different resistant clones. These clones persist after the administration of androgen deprivation therapy which targets only the initial predominant clone. The resistant clones may then mutate further or expand, and ultimately multiple different resistant populations of tumor result in making effective targeting of all stem cell variants very difficult. He believes the solution to this problem ultimately would be the use of aggressive combination therapies early on to address both androgen-sensitive and resistant clones. He applauded the efforts of the CHAARTED trial and emphasized the need for similar further investigation in the future.
Presented by Norman Maitland, PhD at the 30th Annual European Association of Urology (EAU) Congress - March 20 - 24, 2015 - IFEMA - Feria de Madrid - Madrid, Spain
YCR Cancer Research Unit, University of York, UK
Reported by Timothy Ito, MD, medical writer for UroToday.com