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Gastric cancer is highly malignant and recalcitrant to first line chemotherapies that include 5-fluorouracil (5-FU). Cancer cells are addicted to methionine for their proliferation and survival. Methionine addiction of cancer is known as the Hoffman effect. Methionine restriction with recombinant methioninase (rMETase) has been shown to selectively starve cancer cells and has shown synergy with cytotoxic chemotherapy including 5-FU. The present study aimed to investigate the efficacy of rMETase alone and the combination with 5-FU on poorly differentiated human gastric cancer cell lines (MKN45, NUGC3, and NUGC4) in vitro and vivo. rMETase suppressed the tumor growth of 3 kinds of poorly differentiated gastric cancer cells in vitro. The fluorescence ubiquitination-based cell cycle indicator (FUCCI) demonstrated cancer cells treated with rMETase were selectively trapped in the S/G 2 phase of the cell cycle. In the present study, subcutaneous MKN45 gastric cancer models were randomized into four groups when the tumor volume reached 100 mm3: G1: untreated control; G2: 5-FU (i.p., 50 mg/kg, weekly, three weeks); G3: oral-rMETase (o-rMETase) (p.o., 100 units/body, daily, three weeks); G4: 5-FU with o-rMETase (5-FU; i.p., 50 mg/kg, weekly, three weeks o-rMETase; p.o., 100 units/body, daily, three weeks). All mice were sacrificed on day 22. Body weight and estimated tumor volume were measured twice a week. 5-FU and o-rMETase suppressed tumor growth as monotherapies on day 18 (p = 0.044 and p = 0.044). However, 5-FU combined with o-rMETase was significantly superior to each monotherapy (p < 0.001 and p < 0.001, respectively) and induced extensive necrosis compared to other groups. The combination of 5-FU and o-rMETase shows promise for transformative therapy for poorly differentiated gastric cancer in the clinic. • Methionine addiction is a fundamental and general hallmark of cancer. • Methionine restriction arrests the cell cycle of cancer cells in the S/G2 phase. • Oral recombinant methioninase shows synergy with 5-fluorouracil on poorly differentiated gastric cancer cells. • Oral recombinant methioninase has clinical potential for treating gastric cancer. [ABSTRACT FROM AUTHOR]

Glioma is a highly recalcitrant disease with a 5-year survival of 6.8 %. Temozolomide (TMZ), first-line therapy for glioma, is more effective in O6-methylguanine-DNA methyltransferase (MGMT)-negative gliomas than in MGMT-positive gliomas as MGMT confers resistance to TMZ. Methionine restriction is effective for many cancers in mouse models including glioma. The concern is that methionine restriction could induce MGMT by decreasing DNA methylation and confer resistance to TMZ. In the present study, we investigated the efficacy of combining methionine restriction with TMZ for the treatment of MGMT-negative glioma, and whether methionine restriction induced MGMT. Human MGMT-negative U87 glioma cells were used to determine the efficacy of TMZ combined with methionine restriction. Recombinant methioninase (rMETase) inhibited U87 glioma growth without induction of MGMT in vitro. The combination of rMETase and TMZ inhibited U87 cell proliferation more than either agent alone in vitro. In the orthotopic nude-mouse model, the combination of TMZ and a methionine-deficient diet was much more effective than TMZ alone: two mice out of five were cured of glioma by the combination. No mice died during the treatment period. Methionine restriction enhanced the efficacy of TMZ in MGMT-negative glioma without inducing MGMT, demonstrating potential clinical promise for improved outcome of a currently incurable disease. • Glioma is a clinically-incurable cancer. • Temozolomide (TMZ) is first-line therapy to glioma. • TMZ efficacy is decreased by MGMT. • TMZ in combination with methionine restriction (MR) did not reactivate MGMT. • The combination of TMZ and MR was much more effective than TMZ alone. [ABSTRACT FROM AUTHOR]

Methionine addiction is a fundamental and general hallmark of cancer. Methionine addiction prevents cancer cells, but not normal cells from proliferation under methionine restriction (MR). Previous studies reported that MR altered the histone methylation levels in methionine-addicted cancer cells. However, no study has yet compared the status of histone methylation status, under MR, between cancer cells and normal cells. In the present study, we compared the histone methylation status between cancer cells and normal fibroblasts of H3K4me3 and H3K9me3, using recombinant methioninase (rMETase) to effect MR. Human lung and colon cancer cell lines and human normal foreskin fibroblasts were cultured in control medium or medium with rMETase. The viability of foreskin fibroblasts was approximately 10 times more resistant to rMETase than the cancer cells in vitro. Proliferation only of the cancer cells ceased under MR. The histone methylation status of H3K4me3 and H3K9me3 under MR was evaluated by immunoblotting. The levels of the H3K4me3 and H3K9me3 were strongly decreased by MR in the cancer cells. In contrast, the levels of H3K4me3 and H3K9me3 were not altered by MR in normal fibroblasts. The present results suggest that histone methylation status of H3K4me3 and H3K9me3 under MR was unstable in cancer cells but stable in normal cells and the instability of histone methylation status under MR may determine the high methionine dependency of cancer cells to survive and proliferate. • Methionine addiction is a fundamental and general hallmark of cancer. • H3K4me3 and H3K9me3 are unstable in cancer but not normal cells under methionine restriction (MR). • These results help explain why cancer cells and not normal cells cease proliferation under MR. • MR is efficiently effected by recombinant methioninase. [ABSTRACT FROM AUTHOR]

Cancer cells are methionine (MET) and methylation addicted and are highly sensitive to MET restriction. The present study determined the efficacy of oral-recombinant methioninase (o-rMETase) and the DNA methylation inhibitor, decitabine (DAC) on restricting MET in an undifferentiated-soft tissue sarcoma (USTS) patient-derived orthotopic xenograft (PDOX) nude-mouse model. The USTS PDOX models were randomized into five treatment groups of six mice: Control; doxorubicin (DOX) alone; DAC alone; o-rMETase alone; and o-rMETase-DAC combination. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was arrested only in the o-rMETase-DAC condition. Tumors treated with the o-rMETase-DAC combination exhibited tumor necrosis with degenerative changes. This study demonstrates that the o-rMETase-DAC combination could arrest the USTS PDOX tumor suggesting clinical promise. • Cancer cells are methionine (MET) and methylation addicted. • Oral rMETase (o-rMETase) is efficacious in cancers grown in patient-derived orthotopic xenograft (PDOX) models. • Combination of o-rMETase and DAC arrests undifferentiated-soft tissue sarcoma (USTS) USTS-PDOX. • Tumor treated with o-rMETase-DAC combination show tumor necrosis with degenerative changes. • Efficacy of o-rMETase-DAC combination on USTS PDOX tumor show clinical promise. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the efficacy of oral recombinant methioninase (o -rMETase) on a colon cancer primary tumor using a patient-derived orthotopic xenograft (PDOX) nude mouse model. Forty colon cancer primary tumor PDOX mouse models were divided into 4 groups of 10 mice each (total 40 mice) by measuring the tumor size. The groups were as follows: untreated control; 5-fluorouracil (5-FU) (50 mg/kg, once a week for two weeks, N = 10 mice) and oxaliplatinum (OXA) (6 mg/kg, once a week for two weeks, N = 10 mice); o -rMETase (100 units/day, oral 14 consecutive days, N = 10 mice); combination of 5-FU + OXA and o -rMETase (N = 10 mice). All treatments inhibited tumor growth compared to the untreated control. The combination of 5-FU + OXA and o -rMETase was significantly more efficacious than other treatments. The present study demonstrates the efficacy of o -rMETase combination therapy on a PDOX colon cancer primary tumor, suggesting potential clinical development of o -rMETase in recalcitrant cancer. • Colorectal cancer is the third most common cancer. • Demonstrated the efficacy of o -rMETase in a PDOX primary colon cancer model. • 5-FU + OXA and o -rMETase combination was more efficacious. • Potential clinical development of o -rMETase in recalcitrant cancer. [ABSTRACT FROM AUTHOR]

Recurrent osteosarcoma is a chemotherapy-resistant disease. Individualized precision therapy is needed for this disease. Toward this goal, we have developed the patient-derived othotopic xenograft (PDOX) mouse model of all major cancer types including osteosarcoma. Synergistic efficacy of trabectedin (TRAB) and irinotecan (IRT) has been reported in Ewing's sarcoma, soft-tissue sarcoma, and ovarian cancer. However, the efficacy of this combination on osteosarcoma is not known. The goal of present study was to determine the efficacy of the TRAB and IRT combination on cisplatinum (CDDP)-resistant osteosarcoma PDOX. The osteosarcoma PDOX models were randomized into five treatment groups of six mice: Untreated control; CDDP alone; TRAB alone; IRT alone; and TRAB and the IRT combination. Tumor size and body weight were measured during the 14 days of treatment. Tumor growth was regressed only by the TRAB-IRT combination. Tumors treated with the TRAB-IRT combination had the most tumor necrosis with degenerative change. The present study demonstrates the power of the PDOX model to identify a novel effective treatment strategy of the TRAB and IRT combination for chemotherapy-resistant osteosarcoma. • Osteosarcoma is the most common primary malignant bone tumor. • Osteosarcoma shows resistance to mainly available drugs. • Trabectedin (TRAB) and irinotecan (IRT) combination can regress osteosarcoma PDOX. • First study shows TRAB-IRT combination is active in osteosarcoma. [ABSTRACT FROM AUTHOR]

Abstract There are no effective treatments for leiomyosarcoma (LMS) spreading intraabdominally. The aim of this study was to develop precision chemotherapy for recurrent peritoneal LMS metastases in a patient-derived orthotopic xenograft (PDOX) model. The LMS PDOX models were established orthotopically on the dome of the bladder of nude mice. The LMS PDOX models were randomized into 6 groups when the tumor volume reached 80 mm3: G1: untreated control; G2: doxorubicin (DOX) (DOX: i.p., 3 mg/kg, weekly, 3 weeks); G3: DOX combined with olaratumab (OLA) (DOX: i.p., 3 mg/kg, weekly, 3 weeks; OLA: i.p., 40 mg/kg, 3 times/week, 3 weeks); G4: gemcitabine (GEM) combined with docetaxel (DOC) (GEM: i.p., 100 mg/kg, weekly, 3 weeks; DOC: i.p., 20 mg/kg, weekly, 3 weeks); G5: pazopanib (PAZ) (PAZ: p.o., 100 mg/kg, daily, 3 weeks); G6: palbociclib (PAL) (PAL: p.o., 100 mg/kg, daily, 3 weeks). All mice were sacrificed on day 22. Body weight was assessed twice a week. Tumor volume was measured on day 0 and day 22. Although all regimens had a significant efficacy compared to the untreated group (P < 0.001), only GEM combined with DOC regressed the tumor significantly (P < 0.001), suggesting GEM combined with DOC has clinical potential for this LMS patient. Highlights • Leiomyosarcoma (LMS) is a recalcitrant and rare disease. • LMS has a high risk of metastases and local recurrence. • GEM + DOC regressed the LMS patient-derived orthotopic xenograft (PDOX) model. • PDOX models have a great potential for precision individualized therapy. [ABSTRACT FROM AUTHOR]

Abstract Myxofibrosarcoma (MFS) is the most common sarcomas in elderly patients and is either chemo-resistant or recurs with metastasis after chemotherapy. This recalcitrant cancer in need of improved treatment. We have established a patient-derived orthotopic xenograft (PDOX) of MFS. The MFS PDOX model was established in the biceps femoris of nude mice and randomized into 7 groups of 7 mice each: control; doxorubicin (DOX); pazopanib (PAZ); temozolomide (TEM); Irinotecan (IRN); IRN combined with TEM; IRN combined with cisplatinum (CDDP) and Salmonella typhimurium A1-R (S. typhimurium A1-R). Treatment was evaluated by relative tumor volume and relative body weight. The MFS PDOX models were DOX, PAZ, and TEM resistant. IRN combined with TEM and IRN combined with CDDP were most effective on the MFS PDOX. S. typhimurium A1-R arrested the MFS PDOX tumor. There was no significant body weight loss in any group. The present study suggests that the combination of IRN with either TEM or CDDP, and S. typhimurium have clinical potential for MFS. Highlights • Myxofibrosarcoma (MFS) is the most common sarcomas in elderly patients. • Established patient-derived orthotopic xenograft (PDOX) of Myxofibrosarcoma. • The MFS PDOX models were DOX, PAZ, and TEM resistant. • Combination of IRN with either TEM or CDDP, and S. typhimurium have clinical potential for myxofibrosarcoma. [ABSTRACT FROM AUTHOR]

Undifferentiated soft tissue sarcoma (USTS) is a recalcitrant and heterogeneous subgroup of soft tissue sarcoma with high risk of metastasis and recurrence. Due to heterogeneity of USTS, there is no reliably effective first-line therapy. We have generated tumor-targeting Salmonella typhimurium A1-R ( S. typhimurium A1-R), which previously showed strong efficacy on single patient-derived orthotopic xenograft (PDOX) models of Ewing's sarcoma and follicular dendritic cell sarcoma. In the present study, tumor resected from 4 patients with a biopsy-proven USTS (2 undifferentiated pleomorphic sarcoma [UPS], 1 undifferentiated sarcoma not otherwise specified [NOS] and 1 undifferentiated spindle cell sarcoma [USS]) were grown orthotopically in the biceps femoris muscle of mice to establish PDOX models. One USS model and one UPS model were doxorubicin (DOX) resistant. One UPS and the NOS model were partially sensitive to DOX. DOX is first-line therapy for these diseases. S. typhimurium A1-R arrested tumor growth all 4 models. In addition to arresting tumor growth in each case, S. typhimurium A1-R was significantly more efficacious than DOX in each case, thereby surpassing first-line therapy. These results suggest that S. typhimurium A1-R can be a general therapeutic for USTS and possibly sarcoma in general. [ABSTRACT FROM AUTHOR]

Abstract: Parathyroid hormone-related protein (PTHrP) is an oncoprotein that is expressed in many malignancies as well as normal tissues. At essentially every site of expression, PTHrP regulates cell growth and proliferation. We and other investigators have previously reported that PTHrP is widely expressed by prostate cancer. For this tumor, there are substantial in vitro and correlative data that PTHrP expression regulates the progression of the tumor, especially in bone, but little direct data. We studied the effects of PTHrP expression on prostate cancer behavior directly in a mouse model of human prostate cancer cells that were transfected to express different forms of the polypeptide and then injected intraskeletally. Skeletal progression of the prostate cancer cells was evaluated radiologically and by measurement of serum tumor markers. PTHrP transfection converted a non-invasive cell line into one that progressed in the skeleton: Injection of the PTHrP transfected cells resulted in greater tumor progression in bone when compared to non-transfected cells, and this effect was also influenced by non-amino terminal peptides of PTHrP. Serum measurements of PTHrP, IL-6, IL-8, and calcium reflected tumor burden. Our experiments provide direct in vivo evidence that PTHrP expression results in the skeletal progression of prostate cancer cells. [Copyright &y& Elsevier]