Research ArticleClinical Studies
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First-line Chemotherapy in Combination With Oral Recombinant Methioninase and a Low-methionine Diet for a Stage IV Inoperable Pancreatic-Cancer Patient Resulted in 40% Tumor Reduction and an 86% CA19-9 Biomarker Decrease

MOTOKAZU SATO, QINGHONG HAN, CHIHIRO HOZUMI, HIDEO KUJIRAOKA, KOHEI MIZUTA, SEI MORINAGA, BYUNG MO KANG, NORITOSHI KOBAYASHI, YASUSHI ICHIKAWA, ATSUSHI NAKAJIMA and ROBERT M. HOFFMAN
Anticancer Research September 2024, 44 (9) 3885-3889; DOI: https://doi.org/10.21873/anticanres.17215

Abstract

Background/Aim: Pancreatic cancer has a very poor prognosis with a 5-year survival rate of less than 5% among patients with distant metastasis, a figure that has not improved over many decades. Only 10 to 20% patients are candidates for curative surgery at presentation due to the aggressive nature and asymptomatic progression of pancreatic cancer. Although first-line chemotherapy, such as FOLFIRINOX and gemcitabine + nab paclitaxel, improved the median survival from 8.5 to 11.1 months, more effective treatments are immediately needed. The aim of the present study was to evaluate the efficacy of methionine restriction with oral rMETase (o-rMETase) and a low-methionine diet combined with first-line chemotherapy on a patient with stage IV metastatic pancreatic cancer. Case Report: A 63-year-old female was diagnosed with metastatic pancreatic cancer in October 2023. The patient started FOLFIRINOX as first-line chemotherapy in combination with methionine restriction, which comprised o-rMETase 250 units twice a day and a low-methionine diet. The patient was monitored using computed tomography and CA19-9 blood tests. After five months from the start of combination therapy, the size of the primary tumor decreased by 40% along with liver-metastasis regression. The CA19-9 blood marker decreased by 86%. The patient sustains a high performance status and continues the combination therapy without severe side effects. Conclusion: Methionine restriction consisting of o-rMETase and a low-methionine diet, in combination with first-line chemotherapy, was highly effective in a patient with inoperable stage IV pancreatic cancer.

Key Words:

The prognosis of pancreatic cancer is poor with a 5-year survival rate of approximately 12% (1) although many novel therapies have been introduced over five decades. Pancreatic cancer frequently progresses asymptomatically, and only 10 to 20% of patients are eligible for surgery due to tumor invasion of adjacent organs or distant metastases at the time of presentation (1-3). Therefore, chemotherapy plays a significant role in pancreatic cancer treatment. Currently, FOLFIRINOX (5-fluorouracil/leucovorin, irinotecan, and oxaliplatin) and gemcitabine (GEM) + nab-paclitaxel (nab-PTX) are first-line chemotherapies for advanced pancreatic cancer. However, the median survival increased marginally from 8.5 to 11.1 months with these regimens (4, 5). More effective treatments are urgently needed.

Methionine addiction is a fundamental and general hallmark of cancer, termed as the Hoffman effect (6-9). Methionine addiction is at least partly due to excess transmethylation in cancer cells, leading to a significantly greater demand for methionine from external sources compared to normal cells, regardless of high-endogenous synthesis of methionine from homocysteine (6, 10-14). As a result, cancer cells are dependent on exogenous methionine for survival, despite their high production of methionine (6, 12-14).

Our laboratory has developed recombinant methioninase (rMETase) to target methionine addiction (15). When administered orally, this enzyme breaks down methionine in the gut, resulting in a reduction in methionine levels in the blood and in tumors (16, 17). rMETase has shown efficacy in inhibiting pancreatic cancer in patient-derived orthotopic xenograft (PDOX) models (18).

Methionine restriction, including oral rMETase (o-rMETase) selectively arrests the cell cycle of cancer cells in the late-S/G2 phase (19, 20). Since S-phase is the main target of cytotoxic chemotherapy, it is synergistic with methionine restriction. There have been numerous reports that o-rMETase has synergistic efficacy with many chemotherapy drugs without side effects (21).

We previously showed that the biomarker level and tumor size of a stage IV inoperable pancreatic cancer patient treated with FOLFIRINOX in combination with o-rMETase and a low-methionine diet remained stable for 19 months with a high performance status (22).

In the present case report, a 63-year-old female with inoperable pancreatic cancer treated with first-line chemotherapy, combined with o-rMETase and a low-methionine diet, demonstrated a 40% tumor reduction, liver-metastasis regression, and an 86% of decrease in the pancreatic-cancer biomarker CA19-9 over five months.

Materials and Methods

Production and formulation of rMETase. rMETase was produced by fermenting recombinant Escherichia coli transformed with the methioninase gene from Pseudomonas putida. The purification of methioninase involved a high-yield method that had a heat step at 60 degrees Celsius, polyethylene glycol precipitation, and ion-exchange column chromatography using diethylaminoethyl (DEAE)-Sepharose FF (23,24).

Methionine restriction and rMETase administration. The patient went on a methionine-restricted diet, following the Nutritional Oncology Research Institute (NORI) protocol (25). This procedure recommends less than 2 mg/kg methionine intake per day. rMETase was administered orally twice a day approximately 30 min after each meal at a dose of 250 units as a supplement.

Case Report

A 63-year-old female was diagnosed with liver-metastatic pancreatic cancer in October 2023. The computed tomography (CT) images of October 2023 revealed that the patient had pancreatic cancer with the primary tumor highly invasive to adjacent organs and vasculature, and massive liver metastasis. The patient started FOLFIRINOX as first-line chemotherapy along with methionine restriction consisting of o-rMETase and a low-methionine diet. After the start of the combination therapy, the size of the primary tumor decreased by 40% and the liver metastasis shrunk over five months (Figure 1 and Figure 2). CA19-9, which is an important pancreatic cancer biomarker, also decreased by 86% (Figure 3). The patient experienced a repetitive neutropenia due to the side effects of FOLFIRINOX. Therefore, the regimen of chemotherapy was changed to GEM plus nab-PTX. The patient maintains a high-performance status and continues chemotherapy.

Figure 1.
Figure 1.

Computed tomography images of pancreatic cancer before (10/20/23) and after (1/20/24 and 3/20/24) o-rMETase and a low-methionine diet were started in combination with first-line chemotherapy. Red circles denote the tumor circumference.

Figure 2.
Figure 2.

Ratio of tumor size with respect to size at the start of treatment of a pancreatic cancer patient with o-rMETase and a low-methionine diet along with first-line chemotherapy. A 40% reduction of the primary tumor was observed.

Figure 3.
Figure 3.

CA19-9, biomarker of pancreatic cancer patient. CA19-9 decreased by 86% after the start of o-rMETase and a low-methionine diet along with first-line chemotherapy.

Discussion

A 40% decrease in the tumor size of a stage IV pancreatic cancer patient treated with standard chemotherapy is rare (5). Pancreatic cancer, especially cases with distant metastasis, have a poor prognosis, with reported 1-year survival rates of less than 10% (26), although the overall response rate is approximately 30% (5, 26). In the present case the patient achieved a 40% decrease in the primary tumor, a significant partial response (PR). The present patient has continued first-line treatment with GEM plus nab-PTX after FOLFIRINOX for seven months. Further observation is needed.

We first found that methionine restriction is synergistic with chemotherapy, termed the Hoffman protocol, almost 40 years ago (21, 27). There is synergy between methionine restriction, with rMETase and/or a low-methionine diet, and all types of chemotherapy (21). Cancer cells selectively arrest in the late-S/G2 phase of the cell cycle in response to methionine depletion (19, 20). Hence, chemotherapy drugs targeting S-phase exhibit enhanced efficacy when combined with methionine restriction. o-rMETase is showing promise in the clinic for pancreatic cancer as shown in the present and previous study (22), and for others major cancers (28-36). Further clinical studies are necessary to test a combination of methionine restriction and first-line chemotherapy for stage IV pancreatic cancer.

Methionine addiction is a promising target for cancer therapy since it is tightly linked to malignancy (37-43) and is a universal hallmark of cancer (44-46).

Acknowledgements

This paper is dedicated to the memory of A. R. Moossa, MD, Sun Lee, MD, Professor Gordon H. Sato, Professor Li Jiaxi, Masaki Kitajima, MD, Shigeo Yagi, PhD, Jack Geller, MD, Joseph R Bertino, MD, J.A.R. Mead, PhD, Eugene P. Frenkel, MD, Professor Sheldon Penman, Professor Lev Bergelson, Professor John R. Raper and Joseph Leighton, MD.

Footnotes

  • Authors’ Contributions

    MS and RMH wrote the article. QH provided methioninase. CH and HK provided methioninase to the patient. MS, QH, KM, SM, BMK, NK, YI, AN, and RMH critically reviewed the article.

  • Conflicts of Interest

    The Authors declare no competing interests regarding this work.

  • Funding

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

  • Received June 9, 2024.
  • Revision received June 24, 2024.
  • Accepted June 26, 2024.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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First-line Chemotherapy in Combination With Oral Recombinant Methioninase and a Low-methionine Diet for a Stage IV Inoperable Pancreatic-Cancer Patient Resulted in 40% Tumor Reduction and an 86% CA19-9 Biomarker Decrease
MOTOKAZU SATO, QINGHONG HAN, CHIHIRO HOZUMI, HIDEO KUJIRAOKA, KOHEI MIZUTA, SEI MORINAGA, BYUNG MO KANG, NORITOSHI KOBAYASHI, YASUSHI ICHIKAWA, ATSUSHI NAKAJIMA, ROBERT M. HOFFMAN
Anticancer Research Sep 2024, 44 (9) 3885-3889; DOI: 10.21873/anticanres.17215
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