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Pathophysiology of Castration-Resistant Prostate Cancer

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Managing Metastatic Prostate Cancer In Your Urological Oncology Practice

Abstract

Androgen-targeted therapy aimed at abrogating androgen receptor (AR) mediated growth is the mainstay of treatment of advanced prostate cancer. Targeting of microtubules (taxane chemotherapy) and androgen signaling (antiandrogens) have survival benefits in patients with metastatic CRPC (mCRPC), but therapeutic resistance invariably develops yielding lethal disease. Addiction of tumor cells in CRPC to AR signaling and constitutively active AR splice variants is the primary driver of this resistance. Multiple mechanisms, including an innate intratumoral feed-back mechanism resulting in increased de novo production of steroids, account for the higher androgen levels in CRPC, despite castrate levels of circulating androgens. The AR “zip code” localization has been placed into a critical targeting position in CRPC, not only by AR signaling inhibitors, but also by microtubule-targeting taxane chemotherapy. This chapter discusses the current understanding of addiction of CRPC to aberrant AR activity via its interactions with other signaling networks and the effect of targeted therapeutics in overcoming cross-resistance in advanced disease towards increasing patient survival.

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Abbreviations

CRPC:

Castration resistant prostate cancer

PSA:

Prostate specific antigen

ADT:

Androgen deprivation therapy

DHT:

Dihydrotestosterone

AR:

Androgen receptor

DHEA:

Dehydroepiandrosterone

AD:

Androstenedione

HSP:

Heat shock protein

IAP:

Inhibitors of apoptosis proteins

PTEN:

Phosphatase and tensin homolog

BTG1:

B-Cell translocation gene 1

BCL2:

B-Cell CLL/Lymphoma 2

IGF-1:

Insulin like growth factor 1

KGF:

Keratinocyte growth factor

EGF1:

Epidermal growth factor 1

TIF2:

Transcriptional intermediary factor 2

RTK:

Receptor tyrosine kinase

MAPK:

Mitogen activated protein kinase

STAT:

Signal transducer and activator of transcription

AF-1, 2:

Activating function

NTD:

N-terminal domain

DBD:

DNA binding domain

LBD:

Ligand binding domain

NLS:

Nuclear localization signal

ARV:

Androgen receptor variant

ASO:

Antisense oligonucleotide

LHRH:

Lutenizing hormone-releasing hormone

MAB:

Maximum androgen blockade

CVD:

Cardiovascular disease

IAD:

Intermittent androgen deprivation

FDA:

Food and Drug Administration

SWOG:

Southwest Oncology Group

FOXO1:

Forkhead box O1

HSET:

Human kinesin-14

MCAK:

Mitotic centromere associated kinesin

Src:

Proto-oncogene protein tyrosine kinase Src

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  1. Department of Urology, University of Kentucky, 800 Rose Street, Lexington, KY, 40536, USA

    Justin C. Penticuff & Natasha Kyprianou

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  1. Justin C. Penticuff
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  1. School of Medicine, Wake Forest University, Winston Salem, North Carolina, USA

    K.C Balaji

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Penticuff, J.C., Kyprianou, N. (2016). Pathophysiology of Castration-Resistant Prostate Cancer. In: Balaji, K. (eds) Managing Metastatic Prostate Cancer In Your Urological Oncology Practice. Springer, Cham. https://doi.org/10.1007/978-3-319-31341-2_2

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