Chronic Treatment of an Advanced Prostate-cancer Patient With Oral Methioninase Resulted in Long-term Stabilization of Rapidly Rising PSA Levels

Han, Qinghong; Hoffman, Robert M.

doi:10.21873/invivo.12488

Cited by 21 publications

(19 citation statements)

References 8 publications

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“…rMETase alone or at combination with chemotherapy has been shown to be active clinically with major cancer types (20)(21)(22)(23)(24). Synergy of methionine restriction and chemotherapy was discovered by our team (25) and is called the Hoffman protocol, which targets methionine addiction which is the fundamental chracteristic of cancer (13,(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

Oral-recombinant Methioninase in Combination With Rapamycin Eradicates Osteosarcoma of the Breast in a Patient-derived Orthotopic Xenograft Mouse Model

Masaki¹,

Han²,

Samonte³

et al. 2022

Anticancer Res

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Section: Discussionmentioning

confidence: 99%

Oral-recombinant Methioninase in Combination With Rapamycin Eradicates Osteosarcoma of the Breast in a Patient-derived Orthotopic Xenograft Mouse Model

Masaki¹,

Han²,

Samonte³

et al. 2022

Anticancer Res

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“…Previously we have shown that o-rMETase has potential clinical efficacy in prostate and pancreatic cancer patients (30)(31)(32)(33).…”

Section: Discussionmentioning

confidence: 99%

Long-term Stable Disease in a Rectal-cancer Patient Treated by Methionine Restriction With Oral Recombinant Methioninase and a Low-methionine Diet

et al. 2022

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Background/Aim: Rectal cancer is a recalcitrant disease with limited treatment options. Pre-clinical studies have shown the efficacy of methionine restriction with a lowmethionine diet and oral recombinant methioninase (o-rMETase) for colorectal cancer. There are also clinical studies on methionine restriction with o-rMETase for other recalcitrant cancer types. The goal of the present study was to determine the efficacy of a low-methionine diet and o-rMETase on a rectal cancer patient. Patient and Methods: A 55-year-old man diagnosed with recurrent locally-advanced rectal-cancer was treated with o-rMETase and a low-methionine diet, during which time, he did not receive standard chemotherapy. Disease stability was monitored by carcinoembryonic antigen (CEA) levels, sigmoidoscopy, and computed tomography (CT). Results: The patient was diagnosed with stage II rectal cancer (adenocarcinoma) in 2018. After neoadjuvant chemoradiotherapy, the patient received total mesorectal excision (TME) in 2018. Local recurrence was found by sigmoidoscopy one year later. The patient was given chemotherapy, the recurrent lesion shrunk, and was then removed endoscopically in December 2019, with positive margins. The tumor did not become apparent for about a year after that. An endoscopic examination performed in December 2020, revealed a local recurrence. Since that time, the patient had an elevated CEA. The patient went on o-rMETase and a low-methionine diet from January 2021. Since then, the patient's CEA level has remained stable for the next year and a half. He received sigmoidoscopy and CT regularly, and the tumor size has not changed. Conclusion: This patient's clinical course indicates that o-rMETase and a low-methionine diet may be effective for rectal cancer, for long-term disease stabilization. Further case studies and clinical trials are needed to determine the generality of the present result.Colorectal cancer is the fourth-most common cancer and the second leading cause of cancer death in the United States (1). Rectal cancer accounts for about one-third of these cases. Regarding locally-advanced disease (T3-4, N0), neoadjuvant chemoradiotherapy and adjuvant chemotherapy are the standard-of-care for rectal cancer. Although the 3-year diseasefree survival rate has increased from 62.9 % to 75.9 % for locally-advanced disease, it is still not sufficient (2-4). It is also important for patients with rectal cancer to preserve anal function. Most patients with rectal cancer, especially those whose tumor is located close to the anal verge, have undergone total mesorectal excision with a colostomy.Methionine addiction is a fundamental and general hallmark of cancer (5-7) and is termed the Hoffman effect (8). Since cancer cells require a greater amount of methionine than normal cells, which is due to the excess transmethylation reactions in cancer cells, they cannot survive under the condition of methionine restriction (9-11). We have developed recombinant methioninase (rMETase) (12), which catabolizes methionine, and have shown th...

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“…o-rMETase has shown clinical promise as therapy for advanced prostate cancer, stage IV pancreatic cancer and rectal cancer (25)(26)(27)(28)(29). Future studies will determine efficacy of rMETase in clinical breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Oral-recombinant Methioninase Lowers the Effective Dose and Eliminates Toxicity of Cisplatinum for Primary Osteosarcoma of the Mammary Gland in a Patient-derived Orthotopic Xenograft Mouse Model

Masaki

Han

et al. 2022

In Vivo

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Background/Aim: Primary osteosarcoma of the mammary gland is a very rare disease, accounting for under 1% of all mammary gland malignancies. There is no established first-line treatment, and prognosis is poor compared to conventional breast cancer. We previously demonstrated the efficacy of cisplatinum and eribulin in a patient-derived orthotopic xenograft (PDOX) mouse model of primary breast osteosarcoma. However, these drugs show significant clinical toxicity. All cancers are addicted to methionine (Hoffman effect). In the present study, we determined whether methionine restriction with oral recombinant methioninase (o-rMETase) would lower the effective dose of cisplatinum in a PDOX model of primary osteosarcoma of the mammary gland, thereby reducing its toxicity. Materials and Methods: Mouse PDOX models of primary osteosarcoma of the breast were randomized into the following groups: control; cisplatinum (weekly at 3 or 6 mg/kg); twice-daily o-rMETase; or o-rMETase combined with 3 mg/kg cisplatinum, with treatment for 2 weeks. Results: Cisplatinum at 6 mg/kg significantly inhibited breast osteosarcoma growth compared with the untreated control and mice treated with 3 mg/kg cisplatinum (p=0.01 and 0.009, respectively). There was no significant difference in tumor growth between mice treated with cisplatinum at 3 mg/kg and the control (p=0.16). Combination therapy with cisplatinum at 3 mg/kg and twice daily o-rMETase regressed the osteosarcoma of the mammary gland (p=0.009), similar to the inhibition by cisplatinum at 6 mg/kg alone. Cisplatinum at 6 mg/kg caused a significant loss of mouse body weight, compared to the control (p=0.02). There was no significant body-weight loss with the combination therapy of o-rMETase and cisplatinum at 3 mg/kg, compared to the untreated control. Conclusion: o-rMETase halved the effective dose of cisplatinum, thereby eliminating cisplatinum toxicity, demonstrating a future clinical strategy for therapy of osteosarcoma of the breast.

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Chronic Treatment of an Advanced Prostate-cancer Patient With Oral Methioninase Resulted in Long-term Stabilization of Rapidly Rising PSA Levels

Cited by 21 publications

References 8 publications

Oral-recombinant Methioninase in Combination With Rapamycin Eradicates Osteosarcoma of the Breast in a Patient-derived Orthotopic Xenograft Mouse Model

Oral-recombinant Methioninase in Combination With Rapamycin Eradicates Osteosarcoma of the Breast in a Patient-derived Orthotopic Xenograft Mouse Model

Long-term Stable Disease in a Rectal-cancer Patient Treated by Methionine Restriction With Oral Recombinant Methioninase and a Low-methionine Diet

Oral-recombinant Methioninase Lowers the Effective Dose and Eliminates Toxicity of Cisplatinum for Primary Osteosarcoma of the Mammary Gland in a Patient-derived Orthotopic Xenograft Mouse Model

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