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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Adaptive pathways and emerging strategies overcoming treatment resistance in castration resistant prostate cancer
Cameron M Armstrong1, Allen C Gao1,2,3
1Department of Urology, University of California, Davis, Sacramento, CA, USA.
Abstract:
The therapies available for prostate cancer patients whom progress from hormone-sensitive to castration resistant prostate cancer include both systemic drugs, including docetaxel and cabazitaxel, and drugs that inhibit androgen signaling such as enzalutamide and abiraterone. Unfortunately, it is estimated that up to 30% of patients have primary resistance to these treatments and over time even those who initially respond to therapy will eventually develop resistance and their disease will continue to progress regardless of the presence of the drug. Determining the mechanisms involved in the development of resistance to these therapies has been the area of intense study and several adaptive pathways have been uncovered. Androgen receptor (AR) mutations, expression of AR-V7 (or other constitutively active androgen receptor variants), intracrine androgen production and overexpression of androgen synthesis enzymes such as Aldo-Keto Reductase Family 1, Member C3 (AKR1C3) are among the many mechanisms associated with resistance to anti-androgens. In regards to the taxanes, one of the key contributors to drug resistance is increased drug efflux through ATP Binding Cassette Subfamily B Member 1 (ABCB1). Targeting these resistance mechanisms using different strategies has led to various levels of success in overcoming resistance to current therapies. For instance, targeting AR-V7 with niclosamide or AKR1C3 with indomethacin can improve enzalutamide and abiraterone treatment. ABCB1 transport activity can be inhibited by the dietary constituent apigenin and antiandrogens such as bicalutamide which in turn improves response to docetaxel. A more thorough understanding of how drug resistance develops will lead to improved treatment strategies. This review will cover the current knowledge of resistance mechanisms to castration resistant prostate cancer therapies and methods that have been identified which may improve treatment response.
Insights
Resistance to prostate cancer therapies like enzalutamide and docetaxel is common. Understanding mechanisms such as androgen receptor variants and drug efflux is key to developing new treatments for castration-resistant prostate cancer.
Area of Science:
- Oncology
- Pharmacology
- Cancer Biology
Background:
- Prostate cancer patients often develop resistance to standard therapies, including anti-androgens (enzalutamide, abiraterone) and taxanes (docetaxel, cabazitaxel).
- Primary resistance affects up to 30% of patients, with acquired resistance developing over time, leading to disease progression.
- Mechanisms of resistance are diverse, involving adaptive pathways that circumvent therapeutic effects.
Purpose of the Study:
- To review current knowledge on resistance mechanisms in castration-resistant prostate cancer (CRPC).
- To explore strategies targeting these resistance mechanisms to improve treatment response.
- To highlight the importance of understanding resistance for developing advanced therapeutic approaches.
Main Methods:
- Review of existing literature on CRPC therapies and resistance mechanisms.
- Identification of key molecular pathways and genetic alterations contributing to drug resistance.
- Analysis of strategies aimed at overcoming resistance, including drug repurposing and combination therapies.
Main Results:
- Resistance to anti-androgens is linked to androgen receptor (AR) mutations, AR-V7 expression, and intracrine androgen production (e.g., AKR1C3 overexpression).
- Taxane resistance is often associated with increased drug efflux mediated by ATP Binding Cassette Subfamily B Member 1 (ABCB1).
- Targeting resistance mechanisms, such as AR-V7 with niclosamide or ABCB1 with apigenin, shows promise in preclinical and clinical studies.
Conclusions:
- Understanding the molecular basis of CRPC therapy resistance is crucial for clinical success.
- Targeted inhibition of resistance pathways, like AR-V7 or ABCB1, can potentially restore sensitivity to existing treatments.
- Further research into resistance mechanisms will drive the development of more effective treatment strategies for advanced prostate cancer.
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