Androgen Receptor Signaling in Castration-Resistant Prostate Cancer Alters Hyperpolarized Pyruvate to Lactate Conversion and Lactate Levels In Vivo

Niki Zacharias, Jaehyuk Lee, Sumankalai Ramachandran, Sriram Shanmugavelandy, James McHenry, Prasanta Dutta, Steven Millward, Seth Gammon, Eleni Efstathiou, Patricia Troncoso, Daniel E. Frigo, David Piwnica-Worms, Christopher J. Logothetis, Sankar N. Maity, Mark A. Titus, Pratip Bhattacharya

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Purpose: Androgen receptor (AR) signaling affects prostate cancer (PCa) growth, metabolism, and progression. Often, PCa progresses from androgen-sensitive to castration-resistant prostate cancer (CRPC) following androgen-deprivation therapy. Clinicopathologic and genomic characterizations of CRPC tumors lead to subdividing CRPC into two subtypes: (1) AR-dependent CRPC containing dysregulation of AR signaling alterations in AR such as amplification, point mutations, and/or generation of splice variants in the AR gene; and (2) an aggressive variant PCa (AVPC) subtype that is phenotypically similar to small cell prostate cancer and is defined by chemotherapy sensitivity, gain of neuroendocrine or pro-neural marker expression, loss of AR expression, and combined alterations of PTEN, TP53, and RB1 tumor suppressors. Previously, we reported patient-derived xenograft (PDX) animal models that contain characteristics of these CRPC subtypes. In this study, we have employed the PDX models to test metabolic alterations in the CRPC subtypes. Procedures: Mass spectrometry and nuclear magnetic resonance analysis along with in vivo hyperpolarized 1-[ 13 C]pyruvate spectroscopy experiments were performed on prostate PDX animal models. Results: Using hyperpolarized 1-[ 13 C]pyruvate conversion to 1-[ 13 C]lactate in vivo as well as lactate measurements ex vivo, we have found increased lactate production in AR-dependent CRPC PDX models even under low-hormone levels (castrated mouse) compared to AR-negative AVPC PDX models. Conclusions: Our analysis underscores the potential of hyperpolarized metabolic imaging in determining the underlying biology and in vivo phenotyping of CRPC.

Original languageEnglish (US)
Pages (from-to)86-94
Number of pages9
JournalMolecular Imaging and Biology
Volume21
Issue number1
DOIs
StatePublished - Feb 15 2019

Keywords

  • 13C MR
  • Hyperpolarized pyruvate
  • NMR spectroscopy

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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