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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.

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

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.

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

Recombinant methioninase (rMETase) was previously administered as an injectable drug to target methionine dependence of cancer. Recently, we observed that rMETase could be administered orally (o-rMETase) in a patient-derived orthotopic xenograft (PDOX) mouse model of melanoma. Here, we determined the efficacy of o-rMETase on a pancreatic cancer PDOX model. Forty pancreatic cancer PDOX mouse models were randomized into four groups of 10 mice each. o-rMETase was significantly more effective than i.p.-rMETase, but the combination of both was significantly more effective than either alone. Acquired gemcitabine resistance is a major factor in the recalcitrance of pancreatic cancer. We tested a human pancreatic cancer cell line, which has acquired >100-fold GEM-resistance (PK-9R) than its parental cell line PK-9. In contrast to GEM, both cell lines were very sensitive to rMETase. In orthotopic nude mouse models of PK-9 and PK-9R, GEM inhibited tumor growth in PK-9 but not PK-9R. In contrast, o-rMETase could inhibit both tumors. The combination of GEM + o-rMETase could regress the PK-9 tumor and inhibit PK-9R tumor growth. The present study shows that o-rMETase is effective and overcomes acquired GEM resistance in pancreatic cancer and demonstrates the clinical potential of this strategy.

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.

We have previously established a patient-derived orthotopic xenograft (PDOX) model of undifferentiated spindle cell sarcoma (USCS). Recombinant methioninase (rMETase) has previously demonstrated efficacy in PDOX mouse models of human cancers. In the present study, we determined if rMETase in combination with doxorubicin (DOX) can overcome first-line DOX resistance in a PDOX models of USCS. The USCS PDOX mouse models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks); G3, rMETase (100 units/mouse, i.p., daily, for 2 weeks); G4, DOX (3 mg/kg, i.p., weekly, for 2 weeks) combined with rMETase (100 units/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured twice a week. On day 14 after initiation, the USCS PDOX tumor sizes were (G1): 360 ± 85 mm3; DOX (G2): 355 ± 111 mm3, p = .927; rMETase (G3): 182 ± 57 mm3, p = .0003; DOX + rMETase (G4): 134 ± 29 mm3, p = .00001. These results indicate that rMETase can overcome USCS resistance to DOX, which is first line therapy for this disease. The body weight of treated mice was not significantly different in any group. The present results demonstrate the power of the PDOX model to identify effective therapy for recalcitrant cancer and the potential of rMETase to overcome DOX resistance.