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Published on: November 19, 2019
Delineating the Molecular Events Underlying Development of Prostate Cancer Variants with Neuroendocrine/Small Cell
1Department of Urology, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Abstract:
The treatment landscape of prostate cancer has changed dramatically following the advent of novel systemic therapies, most of which target the androgen receptor (AR). Agents such as abiraterone, enzalutamide, apalutamide, darolutamide were designed to further suppress androgen receptor signaling following gonadal suppression achieved by first-line androgen deprivation therapies. These potent AR targeting agents are increasingly used in the earlier stages of the disease spectrum with the goal of delaying disease progression and extending survival. Although these therapies are effective in controlling prostate tumors dependent on or addicted to AR signaling, prostate tumors surviving the onslaught of potent treatments may evolve and develop drug resistance. A substantial proportion of treatment failures can be explained by the development of treatment-induced aggressive prostate cancer variants such as neuroendocrine/small cell carcinoma. These emerging disease entities demand detailed characterization and precise definitions. We postulate that these treatment-induced prostate cancer entities should be defined molecularly to overcome the drawbacks associated with the current clinical and pathological definitions. A precise molecular definition conforms with current knowledge on the molecular evolution of this disease entity and will enable early detection and early intervention.
Insights
Novel therapies for prostate cancer targeting the androgen receptor (AR) are effective but can lead to resistance. Treatment-induced aggressive variants, like neuroendocrine prostate cancer, require precise molecular definitions for early detection and intervention.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The prostate cancer treatment landscape has been revolutionized by novel systemic therapies targeting the androgen receptor (AR).
- Agents like abiraterone and enzalutamide suppress AR signaling, extending survival and delaying progression, especially in earlier disease stages.
- Despite efficacy, prostate tumors can develop resistance to these potent AR-targeting agents.
Purpose of the Study:
- To address the challenge of treatment resistance in prostate cancer.
- To highlight the emergence of aggressive, treatment-induced variants, such as neuroendocrine prostate cancer.
- To advocate for precise molecular definitions for these emerging prostate cancer entities.
Main Methods:
- Review of current prostate cancer treatment strategies and resistance mechanisms.
- Analysis of the evolution of prostate cancer under potent AR-targeted therapies.
- Postulation of molecular definition for treatment-induced prostate cancer variants.
Main Results:
- Novel AR-targeting therapies have significantly altered prostate cancer treatment paradigms.
- Treatment resistance can lead to the development of aggressive variants like neuroendocrine prostate cancer.
- Current clinical and pathological definitions for these variants have limitations.
Conclusions:
- Molecular definitions are crucial for accurately characterizing and defining treatment-induced aggressive prostate cancer variants.
- Precise molecular definitions will facilitate early detection and timely intervention strategies.
- This approach aligns with the understanding of prostate cancer's molecular evolution.
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