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Rapid Eradication of Extensive Spinal Metastases in a Prostate-Cancer Patient Taking Androgen-deprivation Therapy, Chemotherapy, and Oral Recombinant Methioninase on a Low-Methionine Diet

YOHEI ASANO, QINGHONG HAN, SHUKUAN LI, TOSHIHIKO SATO, CHIHIRO HOZUMI, BYUNG MO KANG, JIN SOO KIM, YUTA MIYASHI, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, KENTARO IGARASHI, TAKASHI HIGUCHI, SEI MORINAGA, HIROYUKI TSUCHIYA, SATORU DEMURA and ROBERT M. HOFFMAN
Anticancer Research December 2025, 45 (12) 5799-5805; DOI: https://doi.org/10.21873/anticanres.17912

Abstract

Background/Aim: Bone metastasis of prostate cancer is a recalcitrant disease treated by androgen-deprivation therapy (ADT), chemotherapy, and radiation. We have previously shown that methionine restriction with oral recombinant methioninase (o-rMETase) alone or in combination with chemotherapeutic agents was apparently effective for prostate-cancer patients, including a patient with extensive bone metastases. In the present study, we described a patient with spinal metastases of prostate cancer treated with ADT, chemotherapy with docetaxel, and methionine restriction with o-rMETase and a low-methionine diet.

Case Report: The present report is on a 62-year-old male prostate-cancer patient with a history of prostatectomy who was subsequently diagnosed by prostate specific membrane antigen (PSMA)-PET imaging to have extensive spinal metastases. The patient then received combination therapy with ADT (relugolix and darolutamide), docetaxel chemotherapy, o-rMETase (twice a day 250 units, 5 mg), and a low-methionine diet. Six months later, a second PSMA-PET demonstrated marked regression of metastases, with only residual uptake in the cervical spine. At nine months, [11C]methionine-PET confirmed complete disappearance of the residual lesion, and no distant metastases were detected. The present findings suggest remission of spinal metastases from prostate cancer.

Conclusion: The patient achieved an apparent complete response of prostate-cancer spinal metastases after treatment with ADT, chemotherapy, and methionine restriction. Further studies, including controlled clinical trials are necessary to validate this new paradigm of treatment for prostate-cancer bone metastases.

Keywords:

Introduction

Prostate cancer is one of the most-frequent malignancies among men worldwide, alongside lung cancer (1). Since many prostate-cancer patients remain asymptomatic in the early stages, some of them present with distant metastases at the time of initial diagnosis (2). In patients with advanced prostate cancer, bone is the most common site of metastasis, with the spine being the most-frequently affected region (3). Spinal metastases can lead to skeletal-related events (SREs), including severe bone pain and neurological deficits caused by spinal-cord compression (4, 5). These events significantly impair activities of daily living and ultimately worsen prognosis (4-7). Therefore, optimal treatment of bone metastases is crucial to improving quality of life and overall survival in patients with metastatic prostate cancer.

Methionine addiction is a fundamental and general hallmark of cancer termed the Hoffman effect (8-17). Methionine restriction of cancer cells results in a late-S/G2 phase cell-cycle arrest which potentiates responses to chemotherapy drugs when attack cells in this phase of the cell cycle (18, 19). Previous studies have demonstrated that methionine restriction has efficacy on all major cancer types, including prostate-cancer pre-clinically, and in the clinic (20, 22-24).

The present study describes combination therapy of a prostate-cancer patient with spinal metastases taking androgen-deprivation therapy (ADT), standard chemotherapy, oral recombinant methioninase (o-rMETase), and a low-methionine diet.

Materials and Methods

Production of recombinant methioninase (rMETase). rMETase was produced by fermentation of recombinant E. coli transformed with the methioninase gene from Pseudomonas putida. Methioninase was purified using a heat step at 60 degrees, polyethylene glycol precipitation, and column chromatography with diethylaminoethyl (DEAE)-Sepharose FF, with high yield (25).

[11C] methionine-PET imaging (MET-PET). MET-PET was performed at the Utsunomiya Central Clinic, Japan, as previously described (26, 27). The patient was pre-treated with o-rMETase (5 mg, 250 units in 1 ml normal saline 4 times per day for 2 days prior to MET-PET.

Case Report

A 62-year-old male prostate-cancer patient with a history of radical prostatectomy with pelvic lymph-node dissection and seminal vesicle removal in March 2021 was found on follow-up in September 2024 with prostate-specific membrane antigen (PSMA)-positron emission tomography (PET) imaging, to have extensive spinal metastases involving the cervical, thoracic, and lumbar vertebrae (Figure 1A). The patient was treated with ADT using relugolix and darolutamide, docetaxel chemotherapy, oral rMETase (o-rMETase) (250 units, 5 mg, twice daily), and a low-methionine diet.

Figure 1.
Figure 1.

(A) PSMA-PET scan before initiation of combined treatment with androgen-deprivation therapy, chemotherapy, and methionine restriction with oral methioninase and a low-methionine diet, showing extensive spinal metastases (white arrows). (B) Six months after treatment initiation, PSMA-PET demonstrated marked regression of spinal metastases, with only residual abnormal uptake in a portion of the cervical spine. (C) Nine months after treatment, [11C] methionine-PET showed disappearance of the cervical uptake, and no distant metastases, including in the spine, were detected. PSMA: Prostate-specific membrane antigen; PET: positron emission tomography.

Six months after the initiation of treatment, the patient underwent a second PSMA-PET scan, which demonstrated apparent eradication of spinal metastases, with only residual abnormal uptake in a portion of the cervical spine (Figure 1B). At nine months after initiation of treatment, the patient underwent further evaluation with [11C]methionine (MET)-PET (26, 27), which showed that the residual abnormal uptake observed on PSMA-PET in the cervical spine had disappeared, and no distant metastases, including in the spine, were detected (Figure 1C). Before undergoing MET-PET the patient was treated with o-rMETase as above, but 4 times per day in the previous two days before MET-PET.

The present PET findings confirmed the remission of spinal metastases from prostate cancer, and the patient is currently under regular follow-up.

Discussion

The present study showed that a patient with spinal metastasis from prostate cancer treated with ADT, chemotherapy, and methionine restriction, using o-rMETase and a low-methionine diet, demonstrated an apparent complete response by PSMA-PET and MET-PET.

Methionine addiction is a general and fundamental hallmark of cancer (8-17). Methionine restriction has demonstrated efficacy against numerous types of cancer, including prostate cancer, both pre-clinically and clinically, (20-23). Furthermore, o-rMETase, which targets methionine addiction, has synergistic efficacy when combined with numerous chemotherapeutic agents (24). In the present case, one possible reason for the remission of extensive spinal metastases is that o-rMETase may have potentiated the patient response to ADT (relugolix, darolutamide) and the chemotherapeutic agent (docetaxel).

MET-PET is based on cancer methionine addiction, which is termed the Hoffman effect, resulting from the excessive utilization of methionine due to increased transmethylation reactions universally observed in cancer (32, 33). MET PET has been most frequently used for brain tumors (34). We have demonstrated a high detection rate by MET-PET for lesions in the trunk (26). Previous studies comparing MET-PET with standard [18F]fluorodeoxyglucose (FDG)-PET of cancer patients, including a prostate cancer patient, have shown that the Hoffman effect of methionine addiction is stronger than the Warburg effect of glucose addiction of cancer (27). This may be a partial explanation for the unusually extensive and rapid response of the prostate cancer patient to methionine restriction in combination with ADT and chemotherapy in the present study. Accurate differentiation between metastatic lesions and reactive changes on FDG-PET is critically important, as it directly influences subsequent therapeutic strategies. In such situations, MET-PET, along with PSMA-PET, may offer higher diagnostic accuracy and thus its significance in future cancer treatment is expected to increase.

In the present case, the efficacy of combination therapy with ADT, chemotherapy, o-rMETase, and a low methionine diet against bone metastases from prostate cancer represents a novel finding. The apparent synergistic efficacy of methionine restriction with o-rMETase and a low methionine diet in combination with ADT and chemotherapy holds the potential to provide a novel therapeutic strategy for prostate cancer with bone metastases. Future clinical trials are necessary.

Conclusion

In a patient with prostate cancer, extensive spinal metastases rapidly achieved an apparent complete response following treatment with ADT, chemotherapy, and methionine restriction using o-rMETase and a low-methionine diet. Combination therapy including o-rMETase holds promise as a novel treatment option for prostate cancer with bone metastases, warranting further investigation to validate these findings.

rMETase is effective because it targets the fundamental hallmark of cancer, methionine addiction (8-19, 32, 33, 35-58). rMETase has previously shown preliminary clinical promise in prostate cancer (20, 22, 23).

Acknowledgements

This paper is dedicated to the memory of A.R. Moossa, MD; Sun Lee, MD; Professor Philip Miles; Richard W. Erbe, MD; Professor Milton Plesur; Professor Gordon H. Sato; Professor Li Jiaxi; Masaki Kitajima, MD; Shigeo Yagi, Ph.D.; Jack Geller, MD; Joseph R. Bertino; MD, J.A.R. Mead Ph.D.; Eugene P. Frenkel, MD; Professor I. J. Fidler; John Mendelsohn, MD; Professor Lev Bergelson; Professor Sheldon Penman; Professor John R. Raper and Joseph Leighton, MD.

Footnotes

  • Authors’ Contributions

    YA was a major contributor to writing the manuscript and RMH revised the paper. QH and SL produced methioninase. TS, CH, BMK, JSK, YM, NY, KH, ShM, KI, TH, SeM, HT and SD critically read and approved the final paper.

  • Conflicts of Interest

    The Authors declare no competing interests regarding this work.

  • Funding

    The Robert M. Hoffman Foundation for Cancer Research provided funds for the present study.

  • Artificial Intelligence (AI) Disclosure

    No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.

  • Received September 12, 2025.
  • Revision received September 26, 2025.
  • Accepted October 7, 2025.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Rapid Eradication of Extensive Spinal Metastases in a Prostate-Cancer Patient Taking Androgen-deprivation Therapy, Chemotherapy, and Oral Recombinant Methioninase on a Low-Methionine Diet
YOHEI ASANO, QINGHONG HAN, SHUKUAN LI, TOSHIHIKO SATO, CHIHIRO HOZUMI, BYUNG MO KANG, JIN SOO KIM, YUTA MIYASHI, NORIO YAMAMOTO, KATSUHIRO HAYASHI, HIROAKI KIMURA, SHINJI MIWA, KENTARO IGARASHI, TAKASHI HIGUCHI, SEI MORINAGA, HIROYUKI TSUCHIYA, SATORU DEMURA, ROBERT M. HOFFMAN
Anticancer Research Dec 2025, 45 (12) 5799-5805; DOI: 10.21873/anticanres.17912
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