Cargando…

Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer

Since the Nobel Prize-winning work of Huggins, androgen ablation has been a mainstay for treatment of recurrent prostate cancer. While initially effective for most patients, prostate cancers inevitably develop the ability to survive, grow, and metastasize further, despite ongoing androgen suppressio...

Descripción completa

Detalles Bibliográficos
Autores principales: Nordeen, Steven K., Su, Lih-Jen, Osborne, Gregory A., Hayman, Perry M., Orlicky, David J., Wessells, Veronica M., van Bokhoven, Adrie, Flaig, Thomas W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465783/
https://www.ncbi.nlm.nih.gov/pubmed/34575033
http://dx.doi.org/10.3390/life11090884
_version_ 1784572964173250560
author Nordeen, Steven K.
Su, Lih-Jen
Osborne, Gregory A.
Hayman, Perry M.
Orlicky, David J.
Wessells, Veronica M.
van Bokhoven, Adrie
Flaig, Thomas W.
author_facet Nordeen, Steven K.
Su, Lih-Jen
Osborne, Gregory A.
Hayman, Perry M.
Orlicky, David J.
Wessells, Veronica M.
van Bokhoven, Adrie
Flaig, Thomas W.
author_sort Nordeen, Steven K.
collection PubMed
description Since the Nobel Prize-winning work of Huggins, androgen ablation has been a mainstay for treatment of recurrent prostate cancer. While initially effective for most patients, prostate cancers inevitably develop the ability to survive, grow, and metastasize further, despite ongoing androgen suppression. Here, we briefly review key preclinical studies over decades and include illustrative examples from our own laboratories that suggest prostate cancer cells titrate androgen signaling to optimize growth. Such laboratory-based studies argue that adaptations that allow growth in a low-androgen environment render prostate cancer sensitive to restoration of androgens, especially at supraphysiologic doses. Based on preclinical data as well as clinical observations, trials employing high-dose testosterone (HDT) therapy have now been conducted. These trials suggest a clinical benefit in cancer response and quality of life in a subset of castration-resistant prostate cancer patients. Laboratory studies also suggest that HDT may yet be optimized further to improve efficacy or durability of response. However, laboratory observations suggest that the cancer will inevitably adapt to HDT, and, as with prior androgen deprivation, disease progression follows. Nonetheless, the adaptations made to render tumors resistant to hormonal manipulations may reveal vulnerabilities that can be exploited to prolong survival and provide other clinical benefits.
format Online
Article
Text
id pubmed-8465783
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-84657832021-09-27 Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer Nordeen, Steven K. Su, Lih-Jen Osborne, Gregory A. Hayman, Perry M. Orlicky, David J. Wessells, Veronica M. van Bokhoven, Adrie Flaig, Thomas W. Life (Basel) Review Since the Nobel Prize-winning work of Huggins, androgen ablation has been a mainstay for treatment of recurrent prostate cancer. While initially effective for most patients, prostate cancers inevitably develop the ability to survive, grow, and metastasize further, despite ongoing androgen suppression. Here, we briefly review key preclinical studies over decades and include illustrative examples from our own laboratories that suggest prostate cancer cells titrate androgen signaling to optimize growth. Such laboratory-based studies argue that adaptations that allow growth in a low-androgen environment render prostate cancer sensitive to restoration of androgens, especially at supraphysiologic doses. Based on preclinical data as well as clinical observations, trials employing high-dose testosterone (HDT) therapy have now been conducted. These trials suggest a clinical benefit in cancer response and quality of life in a subset of castration-resistant prostate cancer patients. Laboratory studies also suggest that HDT may yet be optimized further to improve efficacy or durability of response. However, laboratory observations suggest that the cancer will inevitably adapt to HDT, and, as with prior androgen deprivation, disease progression follows. Nonetheless, the adaptations made to render tumors resistant to hormonal manipulations may reveal vulnerabilities that can be exploited to prolong survival and provide other clinical benefits. MDPI 2021-08-27 /pmc/articles/PMC8465783/ /pubmed/34575033 http://dx.doi.org/10.3390/life11090884 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Nordeen, Steven K.
Su, Lih-Jen
Osborne, Gregory A.
Hayman, Perry M.
Orlicky, David J.
Wessells, Veronica M.
van Bokhoven, Adrie
Flaig, Thomas W.
Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer
title Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer
title_full Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer
title_fullStr Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer
title_full_unstemmed Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer
title_short Titration of Androgen Signaling: How Basic Studies Have Informed Clinical Trials Using High-Dose Testosterone Therapy in Castrate-Resistant Prostate Cancer
title_sort titration of androgen signaling: how basic studies have informed clinical trials using high-dose testosterone therapy in castrate-resistant prostate cancer
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465783/
https://www.ncbi.nlm.nih.gov/pubmed/34575033
http://dx.doi.org/10.3390/life11090884
work_keys_str_mv AT nordeenstevenk titrationofandrogensignalinghowbasicstudieshaveinformedclinicaltrialsusinghighdosetestosteronetherapyincastrateresistantprostatecancer
AT sulihjen titrationofandrogensignalinghowbasicstudieshaveinformedclinicaltrialsusinghighdosetestosteronetherapyincastrateresistantprostatecancer
AT osbornegregorya titrationofandrogensignalinghowbasicstudieshaveinformedclinicaltrialsusinghighdosetestosteronetherapyincastrateresistantprostatecancer
AT haymanperrym titrationofandrogensignalinghowbasicstudieshaveinformedclinicaltrialsusinghighdosetestosteronetherapyincastrateresistantprostatecancer
AT orlickydavidj titrationofandrogensignalinghowbasicstudieshaveinformedclinicaltrialsusinghighdosetestosteronetherapyincastrateresistantprostatecancer
AT wessellsveronicam titrationofandrogensignalinghowbasicstudieshaveinformedclinicaltrialsusinghighdosetestosteronetherapyincastrateresistantprostatecancer
AT vanbokhovenadrie titrationofandrogensignalinghowbasicstudieshaveinformedclinicaltrialsusinghighdosetestosteronetherapyincastrateresistantprostatecancer
AT flaigthomasw titrationofandrogensignalinghowbasicstudieshaveinformedclinicaltrialsusinghighdosetestosteronetherapyincastrateresistantprostatecancer