The metabolic repression effect of carbon-ion radiotherapy in synchronous hormone-sensitive oligometastatic prostate cancer

Zhenshan Zhang; Yulei Pei; Wei Hu; Yushan Xue; Renli Ning; Xiaomao Guo; Yun Sun; Qing Zhang

doi:10.3389/fendo.2023.1291653

The metabolic repression effect of carbon-ion radiotherapy in synchronous hormone-sensitive oligometastatic prostate cancer

Front Endocrinol (Lausanne). 2023 Nov 13:14:1291653. doi: 10.3389/fendo.2023.1291653. eCollection 2023.

Authors

Zhenshan Zhang^{1

2

3}, Yulei Pei^{1

2

3}, Wei Hu^{1

2

3}, Yushan Xue^{1

2

3}, Renli Ning^{2

3

4}, Xiaomao Guo^{1

2

3}, Yun Sun^{2

3

4}, Qing Zhang^{1

2

3}

Affiliations

¹ Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China.
² Shanghai Key Laboratory of Radiation Oncology, Shanghai, China.
³ Shanghai Engineering Research Center of Proton and Heavy Ion Radiation Therapy, Shanghai, China.
⁴ Department of Research and Development, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, China.

Abstract

Background: Metastatic prostate cancer (PCa) poses a significant public health concern. While radiation therapy (RT) is commonly utilized in the treatment of synchronous oligometastatic hormone sensitive prostate cancer (OM-HSPC), the occurrence of biochemical recurrence still remains. To deepen our understanding and optimize the outcome of OM-HSPC, we conducted this study to investigate the characteristics of PCa progression and explore potential synergistic mechanisms involving carbon-ion radiotherapy (CIRT) and neoadjuvant androgen deprivation treatment (naADT) in OM-HSPC.

Methods: Metabolomic analysis was conducted with 72 urinary samples (at different timepoints) from 33 Patients (T2-3N0M0-1b) and 18 healthy volunteers by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). MetaboAnalyst website and R software were employed for metabolomic analysis and visualization (using the criteria of p value < 0.05 and |FC|>1.5). The impact of CIRT on metabolism were further verified and explored through in vitro and in vivo experiments.

Results: We found that most metabolites (223 out of 233) were upregulated in treatment-naïve PCa samples compared to healthy samples. After naADT, 60 core risk metabolites were still significantly related to PCa's progression, and the glutamine level which was significantly higher in OM-HSPC compared to other groups. Remarkably, after CIRT treatment, the glutamine levels in OM-HSPC were significantly reduced to the level of healthy samples. Experiments further confirmed CIRT's ability to suppress glutamine levels in PCa tumors and its potential enhancement with glutamine deprivation intervention.

Conclusion: CIRT with naADT might synergistically inhibit HS-OMPC development, progression and even the ADT resistance through glutamine metabolism repression, moreover, the glutamine metabolism might be a novel target to further improved the efficacy of CIRT.

Keywords: carbon ion radiotherapy; glutamine; hormone treatment; metabolomics; metastatic prostate cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Androgen Antagonists
Carbon
Chromatography, Liquid
Glutamine
Hormones
Humans
Male
Prostatic Neoplasms* / pathology
Prostatic Neoplasms* / radiotherapy
Tandem Mass Spectrometry

Substances

Androgen Antagonists
Glutamine
Hormones
Carbon

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by the Science and Technology Development Fund of the Shanghai Pudong New Area (Grant number PKJ2020-Y52) and the Natural Science Foundation of Shanghai (21ZR1481800). Financial support was provided by the Shanghai Pudong New Area Health Committee (Item No. PW2020A-64).