title: Evolving therapeutic concepts in prostate cancer based on genome-wide analyses (review).
abstract: Treatment of castration resistant prostate cancer (CRPC) continues to represent a major urooncological challenge due to tumor heterogeneity and the inevitable development of therapy resistance. Although androgen deprivation therapy retains an important role in the management of CRPC, recent evidence suggests that a broader spectrum of therapeutic targets may improve patient response and delay development of advanced disease. Genome-wide analyses have identified four major signaling nodes that are most frequently altered in prostate cancer: i) the androgen receptor (AR); ii) the PI3K pathway; iii) the Ras/Raf/MEK/ERK pathway; and iv) the retinoblastoma protein (pRB) signaling pathway. Extensive crosstalk and redundancy exists between these signaling pathways, which underscores the need for combination therapies. There are several novel AR pathway inhibitors currently in clinical use. Clinical trials are being performed on single-agent PI3K inhibitors with some success in tumors with genetically altered PI3K components. MEK/ERK inhibitors are also in clinical trials and the importance of pRB inactivation in prostate cancer is becoming more widely recognized. A greater understanding of the effects of single agent therapy on compensatory signaling pathway activation that can potentially thwart antitumoral responses is urgently needed and will provide additional insight into the mechanism of therapy resistance and how to further delay the progression to lethal disease.
authors: Department of Urology, University of Heidelberg School of Medicine, D-69120 Heidelberg, Germany.
authors: Björn
authors: B
authors: Georgi
authors: Section of Molecular Urooncology, Department of Urology, University of Heidelberg School of Medicine, D-69120 Heidelberg, Germany.
authors: Nina
authors: N
authors: Korzeniewski
authors: Department of Urology, University of Heidelberg School of Medicine, D-69120 Heidelberg, Germany.
authors: Boris
authors: B
authors: Hadaschik
authors: National Center for Tumor Diseases, Department of Medical Oncology, University of Heidelberg School of Medicine, D-69120 Heidelberg, Germany.
authors: Carsten
authors: C
authors: Grüllich
authors: Department of Pathology, University of Heidelberg School of Medicine, D-69120 Heidelberg, Germany.
authors: Wilfried
authors: W
authors: Roth
authors: Division for Cancer Genome Research, National Center for Tumor Diseases and German Cancer Research Center, D-69120 Heidelberg, Germany.
authors: Holger
authors: H
authors: Sültmann
authors: Department of Urology, University of Heidelberg School of Medicine, D-69120 Heidelberg, Germany.
authors: Sascha
authors: S
authors: Pahernik
authors: Department of Urology, University of Heidelberg School of Medicine, D-69120 Heidelberg, Germany.
authors: Markus
authors: M
authors: Hohenfellner
authors: Department of Urology, University of Heidelberg School of Medicine, D-69120 Heidelberg, Germany.
authors: Stefan
authors: S
authors: Duensing
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016159:Tumor Suppressor Protein p53