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Inhibitoren des Androgenrezeptor-N-Terminus’

Zielgerichtete Therapien gegen die Achillesferse verschiedener Androgenrezeptormoleküle im fortgeschrittenen Prostatakarzinom

Inhibitors of the androgen receptor N‑terminal domain

Therapies targeting the Achilles’ heel of various androgen receptor molecules in advanced prostate cancer

Der Urologe volume 57, pages 148–154 (2018)Cite this article

Zusammenfassung

Obwohl das Prostatakarzinom (PCa) anfänglich gut auf primäre Hormontherapien anspricht, kommt es oft innerhalb weniger Jahre zur Tumorprogression mit der Bildung sog. kastrationsresistenter PCa-(CRPC)-Zellen. Leider sprechen aber nicht alle der CRPC-Patienten auf eine Zweitlinienhormontherapie mit Abirateron oder Enzalutamid an. Des Weiteren entwickeln auch viele Patienten, welche initial auf eine sekundäre Hormontherapie ansprechen, in einem relativ kurzen Zeitraum eine Therapieresistenz gegenüber Abirateron und/oder Enzalutamid. Ursache dieser Resistenzmechanismen sind neben einer Erhöhung intrazellulärer Androgenrezeptor-(AR)-Spiegel oftmals AR-Aberrationen (Punktmutationen, Spleißvarianten), welche vornehmlich die Androgen- bzw. Ligandenbindedomäne (LBD) des AR betreffen. Die vorliegende Übersicht skizziert jüngste Fortschritte bei der Entwicklung von AR-Inhibitoren, welche einen von der Androgenbindung unabhängigen Wirkungsmechanismus aufweisen und mögliche AR-Inhibitoren der dritten Generation darstellen.

Abstract

Although prostate cancer responds well to primary endocrine therapies, tumor progression with castration resistant tumor cells almost invariably occurs within a few years. Unfortunately, some CRPC patients do not respond to second-line therapies with abiraterone or enzalutamide. Moreover, patients who initially responded well to second-line hormone therapy develop resistance to abiraterone and/or enzalutamide within a short period of time. Besides an increase of intracellular androgen receptor (AR) levels, the predominant resistance mechanisms include AR aberrations (point mutations, AR splice variants) occurring predominantly at the androgen or ligand binding domain of the AR. The following review delineates recent progress in the development of AR inhibitors that do not depend on androgen binding and represent a putative third generation of AR inhibitors.

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Author information

Affiliations

  1. Klinik für Urologie, Universitätsklinikum Schleswig-Holstein – Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Deutschland

    M. C. Hupe, A. S. Merseburger &  M. V. Cronauer

  2. Pathologie, Universitätsklinikum Schleswig-Holstein - Campus Lübeck, 23538, Lübeck, Deutschland

    A. Offermann & S. Perner

  3. Pathologie, Forschungszentrum Borstel, Leibniz-Zentrum für Medizin und Biowissenschaften, 23845, Borstel, Deutschland

    A. Offermann & S. Perner

  4. ESSA Pharmaceuticals Corp., 77030, Houston, TX, USA

    F. Perabo & C. Chandhasin

Authors
  1. M. C. Hupe
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  2. A. Offermann
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  3. F. Perabo
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  4. C. Chandhasin
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  5. S. Perner
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  6. A. S. Merseburger
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  7. M. V. Cronauer
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Corresponding author

Correspondence to M. V. Cronauer.

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Interessenkonflikt

F. Perabo ist Mitglied der Geschäftsführung von ESSA Pharma Inc., Vancouver, BC V5Z 1K5, Canada. C. Chandhasin ist Angestellte von ESSA Pharmaceuticals Corp, Houston, TX. M.C. Hupe, A. Offermann, S. Perner, A.S. Merseburger und M.V. Cronauer geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

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Hupe, M.C., Offermann, A., Perabo, F. et al. Inhibitoren des Androgenrezeptor-N-Terminus’. Urologe 57, 148–154 (2018). https://doi.org/10.1007/s00120-017-0541-y

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  • DOI: https://doi.org/10.1007/s00120-017-0541-y

Schlüsselwörter

  • Androgenrezeptor-N‑Terminus
  • AR-V7
  • Prostatakarzinom, kastrationsresistentes
  • Resistenzmechanismen
  • Therapie, zielgerichtete

Keywords

  • Androgen receptor N‑terminus
  • AR-V7
  • Castration resistant prostate cancer
  • Resistance mechanisms
  • Targeted therapy