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10.05.2018 | Research Article

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

verfasst von: 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

Erschienen in: Molecular Imaging and Biology | Ausgabe 1/2019

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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-[¹³C]pyruvate spectroscopy experiments were performed on prostate PDX animal models.

Results

Using hyperpolarized 1-[¹³C]pyruvate conversion to 1-[¹³C]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.

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Titel: Androgen Receptor Signaling in Castration-Resistant Prostate Cancer Alters Hyperpolarized Pyruvate to Lactate Conversion and Lactate Levels In Vivo
verfasst von: 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
Publikationsdatum: 10.05.2018
Verlag: Springer International Publishing
Erschienen in: Molecular Imaging and Biology / Ausgabe 1/2019
Print ISSN: 1536-1632
Elektronische ISSN: 1860-2002
DOI: https://doi.org/10.1007/s11307-018-1199-6

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

Abstract

Purpose

Procedures

Results

Conclusions

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Springer Medizin

Abstract

Purpose

Procedures

Results

Conclusions

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