Limits...
Targeting molecular resistance in castration-resistant prostate cancer.

Chandrasekar T, Yang JC, Gao AC, Evans CP - BMC Med (2015)

Bottom Line: Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone.While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly.Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of California, Davis, USA. tchandrasekar@ucdavis.edu.

ABSTRACT
Multiple mechanisms of resistance contribute to the inevitable progression of hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone. While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly. Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment. Understanding the mechanisms of resistance resulting in progression as well as identifying new targetable pathways remains the focus of current prostate cancer research. We review current knowledge of mechanisms of resistance to the currently approved treatments, development of adjunctive therapies, and identification of new pathways being targeted for therapeutic purposes.

No MeSH data available.


Related in: MedlinePlus

Androgen synthesis pathway. Reproduced with permission from Clinical Cancer Research [68]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4556222&req=5

Fig2: Androgen synthesis pathway. Reproduced with permission from Clinical Cancer Research [68]

Mentions: Progression to CRPC includes utilization of the 5α-dione pathway, which allows prostate cancer cells to bypass testosterone in the steroidogenesis pathway (Fig. 2), leading to DHT production. However, CRPC cells are still dependent on adrenal androgens such as dihydroepiandrosterone and its sulfated form, which are converted to androstenedione in the prostate or adrenal gland by 3βHSD, an enzyme encoded by HSD3B. Androstenedione is then converted to DHT via a two-step process using 5α-androstenedione as an intermediary, with the enzymes 17βHSD3 and AKR1C3 (encoded by HSD17B3 and AKR1C3 respectively) mediating this conversion. By targeting adrenal androgen production, abiraterone prevents formation of adrenal androgen precursors needed for intratumoral androgen production [64].Fig. 2


Targeting molecular resistance in castration-resistant prostate cancer.

Chandrasekar T, Yang JC, Gao AC, Evans CP - BMC Med (2015)

Androgen synthesis pathway. Reproduced with permission from Clinical Cancer Research [68]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4556222&req=5

Fig2: Androgen synthesis pathway. Reproduced with permission from Clinical Cancer Research [68]
Mentions: Progression to CRPC includes utilization of the 5α-dione pathway, which allows prostate cancer cells to bypass testosterone in the steroidogenesis pathway (Fig. 2), leading to DHT production. However, CRPC cells are still dependent on adrenal androgens such as dihydroepiandrosterone and its sulfated form, which are converted to androstenedione in the prostate or adrenal gland by 3βHSD, an enzyme encoded by HSD3B. Androstenedione is then converted to DHT via a two-step process using 5α-androstenedione as an intermediary, with the enzymes 17βHSD3 and AKR1C3 (encoded by HSD17B3 and AKR1C3 respectively) mediating this conversion. By targeting adrenal androgen production, abiraterone prevents formation of adrenal androgen precursors needed for intratumoral androgen production [64].Fig. 2

Bottom Line: Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone.While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly.Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of California, Davis, USA. tchandrasekar@ucdavis.edu.

ABSTRACT
Multiple mechanisms of resistance contribute to the inevitable progression of hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). Currently approved therapies for CRPC include systemic chemotherapy (docetaxel and cabazitaxel) and agents targeting the resistance pathways leading to CRPC, including enzalutamide and abiraterone. While there is significant survival benefit, primary and secondary resistance to these therapies develops rapidly. Up to one-third of patients have primary resistance to enzalutamide and abiraterone; the remaining patients eventually progress on treatment. Understanding the mechanisms of resistance resulting in progression as well as identifying new targetable pathways remains the focus of current prostate cancer research. We review current knowledge of mechanisms of resistance to the currently approved treatments, development of adjunctive therapies, and identification of new pathways being targeted for therapeutic purposes.

No MeSH data available.


Related in: MedlinePlus