Colon-cancer liver metastasis is effectively targeted by recombinant methioninase (rMETase) in an orthotopic mouse model.

BACKGROUND: Colorectal cancer liver metastasis (CCLM) is the most frequent cause of death of colorectal cancer. Development of novel new effective therapy is needed for CCLM patients to improve outcome. The aim of the present study was to investigate the efficacy of recombinant methioninase (rMETase) on a CCLM orthotopic mouse model of liver metastasis established using the human colon cancer cell line HT29 expressing red fluorescent protein (RFP). MATERIALS AND METHODS: Orthotopic CCLM nude mouse models were randomized into two groups: control group (n = 6, PBS 200 µl, i.p., daily); rMETase group (n = 6, 100 units/200 µl, i.p., daily). Tumor volume was measured on day 0 and day 15. Body weight was measured twice a week. All mice were sacrificed on day 15. RESULTS: rMETase significantly inhibited the increase of the liver metastasis as determined by RFP fluorescence area and intensity (p = 0.016 and 0.015, respectively). There was no significant difference of body weight between either group on any day. CONCLUSIONS: The present study suggests that rMETase has future potential therapy for CCLM in the clinic.

Synergy of oral recombinant methioninase (rMETase) and 5-fluorouracil on poorly differentiated gastric cancer.

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/G2 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.

[A Case of HER2-Positive Advanced Gastric Cancer with Liver Metastasis Treated by Laparoscopic Surgery after Chemotherapy and Achieved Pathological Complete Response].

A 77-year-old man presented to our hospital with diarrhea and weight loss. Upper gastrointestinal endoscopy revealed advanced Type 3 gastric cancer measuring 40 mm in the lower greater curvature of the stomach. Biopsy from a gastric tumor revealed moderately differentiated tubular adenocarcinoma overexpressing HER2. Abdominal contrast-enhanced computed tomography(CT)showed multiple liver metastases in S3 and S5. We diagnosed HER2-positive gastric cancer with liver metastasis. Systemic chemotherapy was administrated, with a total of 13 courses of combination therapy with S-1, oxaliplatin and trastuzumab. After chemotherapy, the primary tumor was significantly reduced and liver metastases were almost undetectable. Laparoscopic distal gastrectomy and partial hepatectomy were performed as conversion surgery. The patient was discharged on the 9th day without any postoperative complications. Postoperative pathological findings showed no residual tumor in either gastric and hepatic specimens, and the therapeutic effect of chemotherapy was diagnosed as pathological complete response. We report a case of HER2-positive advanced gastric cancer with multiple liver metastases that achieved a pathologically complete response to chemotherapy followed by conversion surgery. Laparoscopic surgery would be one of an effective option for conversion surgery.

[Indications and Outcomes of Laparoscopic Endoscopic Cooperative Surgery(LECS)for Gastric Gastrointestinal Stromal Tumor].

Laparoscopic and endoscopic cooperative surgery(LECS)for gastric gastrointestinal stromal tumor(GIST)has become a popular surgery with both curability and functional preservation. In this study, we examined the outcomes of 14 patients who underwent classical LECS or CLEAN-NET in our hospital. Until March 2022, classical LECS was performed in patients with intraluminal growth tumors or tumors close to the gastroesophageal junction. After April 2022, classical LECS was performed in patients with intraluminal growth tumors without ulceration, and CLEAN-NET was performed in patients with ulceration or intramural growth tumors. There were 10 males and 4 females with a median age of 80.5 years. Intraluminal growth tumor were 8 patients, close to the gastroesophageal junction tumor were 3, and intramural growth tumor were 4, respectively. Five of these patients had tumors with ulceration. Classical LECS was performed in 10 patients and CLEAN-NET in 4 patients, and the median operative time was 165.5 minutes. All patients underwent R0 resection, and no postoperative complications or recurrences were observed. LECS was performed safely, and it is important to select the surgical procedure according to the tumor site and growth type.

[A Case of Local Recurrence of Esophageal Cancer after Chemoradiation Therapy Successfully Treated with Nivolumab].

We report a case of a patient with locally recurrent esophageal cancer after chemoradiation therapy(CRT)who responded to nivolumab. The patient was an 86-year-old man with advanced esophageal cancer. Upper gastrointestinal endoscopy (EGD)revealed a type 2 lesion in the middle thoracic esophagus, and biopsy revealed squamous cell carcinoma(SCC). Contrast- enhanced CT showed invasion of the left main bronchi. The patient was diagnosed as Stage Ⅳa advanced esophageal cancer, and was treated with 5-FU plus cisplatin chemotherapy, and 60 Gy of radiation therapy. The tumor disappeared by CT and EGD, and the patient was followed up for observation. The patient experienced a feeling of tightness again, and EGD revealed an ulcerative lesion in the middle thoracic esophagus, and a biopsy detected SCC. Because of the early recurrence after CRT, the patient was judged to be resistant to 5-FU plus cisplatin chemotherapy, and 8 courses of nivolumab were administered as second-line treatment. Follow-up EGD confirmed disappearance of ulcerative lesions, and no tumors have been observed to date.

A novel patient-derived orthotopic xenograft (PDOX) mouse model of highly-aggressive liver metastasis for identification of candidate effective drug-combinations.

Liver metastasis is a recalcitrant disease that usually leads to death of the patient. The present study established a unique patient-derived orthotopic xenograft (PDOX) nude mouse model of a highly aggressive liver metastasis of colon cancer. The aim of the present study was to demonstrate proof-of-concept that candidate drug combinations could significantly inhibit growth and re-metastasis of this recalcitrant tumor. The patient's liver metastasis was initially established subcutaneously in nude mice and the subcutaneous tumor tissue was then orthotopically implanted in the liver of nude mice to establish a PDOX model. Two studies were performed to test different drugs or drug combination, indicating that 5-fluorouracil (5-FU) + irinotecan (IRI) + bevacizumab (BEV) and regorafenib (REG) + selumetinib (SEL) had significantly inhibited liver metastasis growth (p = 0.013 and p = 0.035, respectively), and prevented liver satellite metastasis. This study is proof of concept that a PDOX model of highly aggressive colon-cancer metastasis can identify effective drug combinations and that the model has future clinical potential.

Exquisite Tumor Targeting by Salmonella A1-R in Combination with Caffeine and Valproic Acid Regresses an Adult Pleomorphic Rhabdomyosarcoma Patient-Derived Orthotopic Xenograft Mouse Model.

Adult pleomorphic rhabdomyosarcoma (RMS) is a rare and malignant mesenchymal tumor. Recently, we developed a patient-derived orthotopic xenograft (PDOX) model of adult pleomorphic RMS. In the present study, we evaluated the efficacy of tumor-targeting Salmonella typhimurium (S. typhimurium) A1-R combined with caffeine (CAF) and valproic acid (VPA) on the adult RMS PDOX. An adult pleomorphic RMS cell line was established from the PDOX model. Cell survival after exposure to CAF and VPA was assessed, and the IC50 value was calculated for each drug. The RMS PDOX models were randomized into five groups: untreated control; tumor treated with cyclophosphamide (CPA); tumor treated with CAF + VPA; tumor treated with S. typhimurium A1-R; and tumor treated with S. typhimurium A1-R + CAF + VPA. Tumor size and body weight was measured twice a week. VPA caused a concentration-dependent cytocidal effect. A synergistic effect of combination treatment with CAF was observed against the RMS cell line. For the in vivo study, all treatments significantly inhibited tumor growth compared with the untreated control. S. typhimurium A1-R combined with VPA and CAF was significantly more effective than CPA, VPA combined with CAF, or S. typhimurium A1-R alone and significantly regressed the tumor volume compared with day 0. These results suggest that S. typhimurium A1-R together with VPA and CAF could regresses an adult pleomorphic RMS in a PDOX model and therefore has important future clinical potential.

Patient-derived orthotopic xenograft models of sarcoma.

Sarcoma is a rare and recalcitrant malignancy. Although immune and novel targeted therapies have been tested on many cancer types, few sarcoma patients have had durable responses with such therapy. Doxorubicin and cisplatinum are still first-line chemotherapy after four decades. Our laboratory has established the patient-derived orthotopic xenograft (PDOX) model using surgical orthotopic implantation (SOI). Many promising results have been obtained using the sarcoma PDOX model for identifying effective approved drugs and experimental therapeutics, as well as combinations of them for individual patients. In this review, we present our laboratory's experience with PDOX models of sarcoma, and the ability of the PDOX models to identify effective approved agents, as well as experimental therapeutics.

Pazopanib regresses a doxorubicin-resistant synovial sarcoma in a patient-derived orthotopic xenograft mouse model.

Synovial sarcoma (SS) is an aggressive subgroup of soft tissue sarcoma (STS) with high grade and high risk of metastasis. However, there are no systemic therapies available that target SS. Therefore, transformative therapy is needed for SS. To establish a patient-derived orthotopic xenograft (PDOX) model, a patient tumor with high grade SS from a lower extremity was grown orthotopically in the right biceps femoris muscle of mice. To test the efficacy of drugs, the PDOX models were randomized into five groups: Group 1 (G1), control-without treatment; Group 2 (G2), doxorubicin (DOX); Group 3 (G3), temozolomide (TEM); Group 4 (G4), gemcitabine (GEM) combined with docetaxel (DOC); and Group 5 (G5), pazopanib (PAZ). Tumor size and body weight were measured twice a week for each treatment group. A significant growth inhibition was found on day 14 in each treatment group compared to the untreated control, except for DOX. However, PAZ was significantly more effective than both TEM and GEM + DOC. In addition, PAZ significantly regressed the tumor volume on day 14 compared to day 0. No change was found in body weight on day 14 compared to day 0 in any treatment group. The present study demonstrated the precision of the SS PDOX models for individualizing SS therapy.

Temozolomide targets and arrests a doxorubicin-resistant follicular dendritic-cell sarcoma patient-derived orthotopic xenograft mouse model.

Follicular dendritic cell sarcoma (FDCS) is a very rare and highly recalcitrant disease. A patient's doxorubicin-resistant FDCS was previously established orthotopically on the right high thigh into the biceps femoris of mice to establish a patient-derived orthotopic xenograft (PDOX) model. The aim of the present manuscript was to identify an effective drug for this recalcitrant tumor. Here, we evaluated the efficacy of temozolomide (TMZ), trabectedin (TRAB) and pazopanib (PAZ) on the FDCS PDOX model. PDOX mouse models were randomized into five groups of eight to nine mice, respectively. Group 1, untreated control with PBS, i.p.; Group 2, treated with doxorubicin (DOX), 2.4 mg/kg, i.p., weekly for 3 weeks; Group 3, treated with PAZ, 50 mg/kg, oral gavage, daily for 3 weeks; Group 4, treated with TMZ, 25 mg/kg, oral gavage, daily for 3 weeks; Group 5, treated with TRAB, 0.15 mg/kg, i.v., weekly for 3 weeks. Body weight and tumor volume were assessed 2 times per week. TMZ arrested the FDCS PDOX model compared to the control group (p < 0.05). PAZ and TRAB did not have significant efficacy compared to the control group (p = 0.99, p = 0.69 respectively). The PDOX tumor was resistant to DOX (p= 0.99). as was the patient. The present study demonstrates that TMZ is effective for a PDOX model of FDCS established from a patient who failed DOX treatment, further demonstrating the power of PDOX to identify effective therapy including for tumors that failed first line therapy.

Tumor-targeting Salmonella typhimurium A1-R overcomes nab-paclitaxel resistance in a cervical cancer PDOX mouse model.

PURPOSE: Cervical cancer is a recalcitrant disease. To help overcome this problem, we previously established a patient-derived orthotopic xenograft (PDOX) model of cervical cancer. In the previous study, we found the tumor to be resistant to nab-paclitaxal (nab-PTX). We also previously developed the tumor-targeting bacteria Salmonella typhimurium A1-R (S. typhimurium A1-R). The aim of the present study was to investigate the efficacy of S. typhimurium A1-R to overcome nab-PTX resistance in the cervical cancer PDOX model. METHODS: Cervical-cancer tumor fragments were implanted orthotopically into the neck of the uterus of nude mice. The cervical-cancer PDOX models were randomized into the following four groups after the tumor volume reached 60 mm3: G1: untreated group; G2: nab-PTX (i.v., 10 mg/kg, biweekly, 3 weeks); G3: Salmonella typhimurium A1-R (i.v., 5 × 107 CFU/body, weekly, 3 weeks); G4: nab-PTX combined with Salmonella typhimurium A1-R (nab-PTX, 10 mg/kg, i.v., biweekly, 3 weeks; S. typhimurium A1-R, 5 × 107 CFU/body, i.v., weekly, 3 weeks). Each group comprised eight mice. All mice were sacrificed on day 22. Tumor volume was measured on day 0 and day 22. Body weight was measured twice a week. RESULTS: Nab-PTX and Salmonella typhimurium A1-R did not show significant efficacy as monotherapy compared to the control group (P = 0.564 and P = 0.120, respectively). In contrast, nab-PTX combined with Salmonella typhimurium A1-R significantly suppressed tumor growth compared to the untreated control group and nab-PTX group (P < 0.001 and P = 0.026, respectively). CONCLUSIONS: Salmonella typhimurium A1-R has potential future clinical application to overcome drug resistance in cervical cancer.

Esophageal metastasis of breast cancer during endocrine therapy for pleural dissemination 21 years after breast surgery: a case report.

BACKGROUND: The esophageal metastasis of breast cancer is rare. Moreover, it is extremely unusual for patients to experience the symptoms of esophageal metastasis during their lifetimes. We present a case of dysphagia caused by esophageal metastasis after a long interval following a primary mastectomy. CASE PRESENTATION: A 77-year-old woman with a history of heterochronous bilateral breast cancer and under treatment for pleural dissemination recurrence originating from right breast cancer complained of dysphagia. At the age of 56, she had undergone a right radical mastectomy for right breast cancer. The histopathological findings revealed invasive ductal carcinoma, pT3N1M0, which was estrogen receptor (ER)- and progesterone receptor (PgR)-positive. At the age of 73, she underwent a second operation, a left modified radical mastectomy. The histopathological examination revealed invasive ductal carcinoma, pT1N0M0, which was negative for ER, PgR, and human epidermal growth factor receptor 2 (HER2). Four years after completion of adjuvant therapy for the left breast cancer, pleural effusion on her left side was observed and histopathological examination of a sample revealed pleural dissemination resulting from the right breast cancer. After initiation of therapy for recurrence, she developed dysphagia and, therefore, underwent an upper gastrointestinal tract endoscopic examination. The examination revealed whole circumferential stenosis and a band unstained by Lugol's solution located 30 cm from her incisors. Examination of a biopsy specimen revealed a subepithelial luminal structure and dysplastic cells. Immunostaining was positive for CK7 and negative for CK20; furthermore, the sample was ER and PgR-positive. Considering the pathological findings, the patient was diagnosed with esophageal metastasis of her right breast cancer. CONCLUSIONS: Metastatic lesions in the esophagus are often located in the submucosa; therefore, they may not be definitively diagnosed by histopathological examination of mucosal biopsy specimens. Esophageal metastasis originating from breast cancer often occurs as a part of multiple organ metastases; however, esophageal metastasis is usually not considered a prognostic factor for patients. Therefore, treatment should be determined according to the severity of the other metastatic sites and the degree of esophageal stenosis.

Gemcitabine combined with docetaxel precisely regressed a recurrent leiomyosarcoma peritoneal metastasis in a patient-derived orthotopic xenograft (PDOX) model.

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.

Patterns of sensitivity to a panel of drugs are highly individualised for undifferentiated/unclassified soft tissue sarcoma (USTS) in patient-derived orthotopic xenograft (PDOX) nude-mouse models.

Undifferentiated/unclassified soft tissue sarcoma (USTS) is a recalcitrant disease; therefore, precise individualised therapy is needed. Toward this goal, we previously established patient-derived orthotopic xenograft (PDOX) models of USTS in nude mice. Here, we determined the extent of uniqueness of drug response in a panel on USTS PDOX models from 5 different patients. We previously showed that 3 of the 5 patients were resistant to doxorubicin (DOX) despite DOX being first-line therapy. Two weeks after orthotopic tumour implantation, PDOX mouse models were randomised into five groups: untreated control, DOX, gem-citabine/docetaxel (GEM/DOC), pazopanib (PAZ), temozolomide (TEM). Three PDOX cases were completely resistant to DOX. TEM had high efficacy for 4 USTS PDOX models, including DOX-resistant cases. GEM/DOC and PAZ were effective in three USTS PDOX. One case was completely resistant to TEM. Two cases were completely resistant to PAZ. The results showed the drug sensitivity pattern for each USTS PDOX was highly individualised and that at least one effective drug could be found for each. The PDOX model could be effective in precise individualised drug sensitivity testing which is especially important for heterogeneous cancers such as USTS, and can give the patient a greater chance to be treated with an effective drug.

Detection of Metastasis in a Patient-derived Orthotopic Xenograft (PDOX) Model of Undifferentiated Pleomorphic Sarcoma with Red Fluorescent Protein.

BACKGROUND/AIM: Undifferentiated pleomorphic sarcoma (UPS) is a common soft tissue sarcoma and highly recalcitrant. We have previously developed patient-derived orthotopic xenograft (PDOX) mouse models of UPS and other major sarcoma types. Unlike PDOX models of other cancer types, it has been difficult to demonstrate metastasis in the sarcoma PDOX models. MATERIALS AND METHODS: To visualize metastasis at high resolution in the UPS PDOX model, established tumor fragments were implanted in transgenic nude mice expressing red fluorescent protein (RFP) for one passage. The tumors acquired RFP-expressing stroma from transgenic host. UPS tumor with RFP stromal cells were harvested and implanted orthotopically in non-transgenic nude mice. After six weeks of UPS tumor growth in the PDOX model, the primary tumor was imaged non-invasively and lung, liver, and spleen were resected and imaged ex-vivo in order to visualize the presence of RFP, with a FluorVivo® imaging system and FV1000® confocal laser microscope, respectively. RESULTS: The primary tumor was imaged non-invasively. Confocal microscopy visualized the presence of RFP in the lung and liver indicating metastases in these organs. This is the first report of metastasis in a sarcoma PDOX model. CONCLUSION: This study should prove very useful to screen for anti-metastatic drugs for the PDOX donor patients and to understand the metastatic process in sarcoma.

A combination of irinotecan/cisplatinum and irinotecan/temozolomide or tumor-targeting Salmonella typhimurium A1-R arrest doxorubicin- and temozolomide-resistant myxofibrosarcoma in a PDOX mouse model.

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.

Tumor-targeting Salmonella typhimurium A1-R overcomes partial carboplatinum-resistance of a cancer of unknown primary (CUP).

Cancer of unknown primary (CUP) is metastatic disease without a known primary and therefore very difficult to identify effective therapy. Previously, we demonstrated partial efficacy of Salmonella typhimurium A1-R (S. typhimurium A1-R) alone and carboplatinum alone (CAR) on a CUP patient tumor in the patient-derived xenograft (PDOX) model. The aim of the present study was to investigate the efficacy of S. typhimurium A1-R combined with CAR on the CUP PDOX model. The CUP tumors were implanted orthotopically into the left supraclavicular fossa of nude mice to match the site from which they were resected from the patient. CUP PDOX models were divided randomly into the following 4 groups after the tumor volume reached 100 mm3: G1: untreated group; G2: CAR (30 mg/kg, i.p., weekly, 2 weeks); G3: S. typhimurium A1-R (5x107 CFU/body, i.v., weekly, 2 weeks).; G4: S. typhimurium A1-R combined with CAR (S. typhimurium A1-R; 5x107 CFU/body, i.v., weekly, 2 weeks; CAR, 30 mg/kg, i.p., weekly, 2 weeks). Each group comprised 7 mice. All mice were sacrificed on day 15. Tumor volume and body weight were measured twice a week. S. typhimurium A1-R and CAR moderately inhibited tumor growth compared to the untreated group on day 15 (P < 0.001 and P < 0.001, respectively). S. typhimurium A1-R combined with CAR inhibited the tumor growth significantly more compared to S. typhimurium A1-R monotherapy or CAR monotherapy on day 15 (P = 0.004 and P = 0.001, respectively). The present report demonstrates that S. typhimurium A1-R can increase the efficacy of a standard drug used for CUP in a PDOX model.

Combination therapy of tumor-targeting Salmonella typhimurium A1-R and oral recombinant methioninase regresses a BRAF-V600E-negative melanoma.

Melanoma is a recalcitrant cancer. To improve and individualize treatment for this disease, we previously developed a patient-derived orthotopic xenograft (PDOX) model for melanoma. We previously reported the individual efficacy of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and recombinant methioninase (rMETase) for melanoma in the PDOX models of this disease. In the present study, we evaluated the efficacy of the combination of S. typhimurium A1-R with orally-administered rMETase (o-rMETase) for BRAF-V600E-negative melanoma in a PDOX model. Three weeks after implantation, 60 PDOX mouse models were randomized into six groups of 10 mice each: untreated control, temozolomide (TEM); o-rMETase; S. typhimurium A1-R; TEM + rMETase, S. typhimurium A1-R + rMETase. All treatments inhibited tumor growth compared to untreated control (TEM: p < 0.0001, rMETase: p < 0.0001, S. typhimurium A1-R: p < 0.0001, TEM + rMETase: p < 0.0001, S. typhimurium A1-R + rMETase: p < 0.0001). The most effective was the combination of S. typhimurium A1-R + o-rMETase which regressed this melanoma PDOX, thereby indicating a new paradigm for treatment of metastatic melanoma.

Trabectedin arrests a doxorubicin-resistant PDGFRA-activated liposarcoma patient-derived orthotopic xenograft (PDOX) nude mouse model.

BACKGROUND: Pleomorphic liposarcoma (PLPS) is a rare, heterogeneous and an aggressive variant of liposarcoma. Therefore, individualized therapy is urgently needed. Our recent reports suggest that trabectedin (TRAB) is effective against several patient-derived orthotopic xenograft (PDOX) mouse models. Here, we compared the efficacy of first-line therapy, doxorubicin (DOX), and TRAB in a platelet-derived growth factor receptor-α (PDGFRA)-amplified PLPS. METHODS: We used a fresh sample of PLPS tumor derived from a 68-year-old male patient diagnosed with a recurrent PLPS. Subcutaneous implantation of tumor tissue was performed in a nude mouse. After three weeks of implantation, tumor tissues were isolated and cut into small pieces. To match the patient a PDGFRA-amplified PLPS PDOX was created in the biceps femoris of nude mice. Mice were randomized into three groups: Group 1 (G1), control (untreated); Group 2 (G2), DOX-treated; Group 3 (G3), TRAB-treated. Measurement was done twice a week for tumor width, length, and mouse body weight. RESULTS: The PLPS PDOX showed resistance towards DOX. However, TRAB could arrest the PLPS (p < 0.05 compared to control; p < 0.05 compared to DOX) without any significant changes in body-weight. CONCLUSIONS: The data presented here suggest that for the individual patient the PLPS PDOX model could specifically distinguish both effective and ineffective drugs. This is especially crucial for PLPS because effective first-line therapy is harder to establish if it is not individualized.

Doxorubicin-resistant pleomorphic liposarcoma with PDGFRA gene amplification is targeted and regressed by pazopanib in a patient-derived orthotopic xenograft mouse model.

Pleomorphic liposarcoma (PLPS) is a heterogeneous resistant group of tumors. Complete surgical resection is the only known way to treat PLPS. PLPS is reristant to both radiation and chemotherapy. Therefore, precise individualized therapy is needed to improve outcome of advanced PLPS patients. In this study, a patient-derived orthotopic xenograft (PDOX) model of a PDGFRA-amplified PLPS was established in the biceps femoris of nude mice by surgical orthotopic implantation (SOI) in order to match the patient. The PLPS PDOX was treated with pazopanib (PAZ) which targets PDGFRA, as well as with temozolomide (TEM) and first-line therapy doxorubicin (DOX). The PLPS PDOX was resistant to DOX and responded very well to PAZ as well as TEM. The tumor volume on treatment day-14 relative to day-1 was as follows: DOX (4.50 ±â€¯2.6, p = 0.8087); PAZ (1.29 ±â€¯0.9, p = 0.0008 compared to the control, p = 0.0167 compared to DOX); TEM (1.07 ±â€¯0.8, p = 0.0079 compared to the control, p = 0.0079 compared to DOX). There was no significant difference in body weight between any treated group or control. The PAZ- and TEM-treated tumors showed extensive necrosis compared to the DOX-treated and untreated PDOX tumors. The present study showed that PDGFRA amplification could be effectively targeted by PAZ. The PLPS PDOX model also identified the efficacy of TEM which does not target PDGFRA, indicating that the PDOX model can identify effective targeted therapy as well as standard therapy and at the same time, identify ineffective drugs, even if they are first-line.