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An Orthotopic Murine Model of Human Prostate Cancer Metastasis
06:48

An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Published on: September 18, 2013

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Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling

Eric G Bluemn1, Ilsa M Coleman2, Jared M Lucas2

  • 1Department of Medicine, University of Washington, Seattle, WA, USA; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Mailstop D4-100, 1100 Fairview Avenue N, Seattle, WA 98109-1024, USA.

Cancer Cell
|October 11, 2017
PubMed

Insights

Metastatic prostate cancer (mPC) is evolving. Researchers identified a new AR-null, NE-null phenotype in mPC, driven by FGF and MAPK pathways. Targeting these pathways shows promise for treating this aggressive cancer subtype.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Androgen receptor (AR) signaling is crucial in prostate cancer (PC) and a primary target for metastatic PC (mPC) treatment.
  • AR antagonism can lead to tumors bypassing AR dependence, often via neuroendocrine (NE) transdifferentiation.

Purpose of the Study:

  • To investigate the molecular evolution of mPC over two decades.
  • To identify emerging phenotypes and their underlying molecular drivers in mPC.
  • To evaluate potential therapeutic strategies against novel mPC subtypes.

Main Methods:

  • Longitudinal molecular assessment of mPC samples over 20 years.
  • Phenotypic and pathway analysis of emerging mPC subtypes.
  • In vitro and in vivo evaluation of pharmacological inhibitors (MAPK, FGFR).

Main Results:

  • A significant phenotypic shift in mPC was observed, with the emergence of an AR-null, NE-null phenotype.
  • These 'double-negative' PCs exhibit elevated Fibroblast Growth Factor (FGF) and Mitogen-Activated Protein Kinase (MAPK) pathway activity.
  • Pharmacological inhibition of MAPK or FGF receptor (FGFR) pathways suppressed the growth of double-negative PCs in vitro and in vivo.

Conclusions:

  • The emergence of AR-null, NE-null mPC represents a critical evolutionary step in the disease.
  • Elevated FGF/MAPK pathway activity is a key driver in these AR-independent tumors.
  • FGF/MAPK pathway blockade presents a promising therapeutic avenue for AR-null mPC.
Keywords:
FGFID1androgen-pathway independencecastration-resistant prostate cancerneuroendocrine

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