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

Abstract

BackgroundPleomorphic 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.MethodsWe 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.ResultsThe 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.ConclusionsThe 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.

Combination of Trabectedin With Irinotecan, Leucovorin and 5-Fluorouracil Arrests Primary Colorectal Cancer in an Imageable Patient-derived Orthotopic Xenograft Mouse Model

“…In sarcoma (41)(42)(43)(44), recurrent ovarian cancer (45), metastatic breast cancer (46), juvenile myelomonocytic leukemia, and chronic myelomonocytic leukemia (47), trabectedin has also been shown as efficacious. Trabectedin was effective in PDOX mouse models of sarcoma and pancreatic cancer (23)(24)(25)(26)(27)(28) and colon cancer (22).…”

Tumor‐targeting Salmonella typhimurium A1‐R arrests a doxorubicin‐resistant PDGFRA‐amplified patient‐derived orthotopic xenograft mouse model of pleomorphic liposarcoma

“…A PDOX model of the PLPS was initially established subcutaneously in nude mice from the patient’s resected PLPS as previously described . The subcutaneously grown tumors were then harvested and cut into 3 mm 3 fragments.…”

“…After the mice were anesthetized with the ketamine solution described above, a 7‐mm skin incision was made on the right upper thigh into the biceps femoris, which was split to make space for the tumor fragment. A single tumor fragment was implanted orthotopically into the space to establish the PDOX model, as previously described . The wound was closed with a 6‐0 nylon suture (Ethilon; Ethicon Inc, Somerville, NJ).…”

“…A PDOX model of a PDGFRA‐amplified PLPS was previously established in the biceps femoris of nude mice by SOI to match the patient . The PLPS PDOX was resistant to first‐line therapy doxorubicin (DOX).…”

“…These results suggested that the PLPS PDOX model can precisely identify both effective as well as ineffective drugs for the individual patient. This is of particular importance for a heterogeneous group such as PLPS where standard first‐line therapy remains very difficult to determine without individualization …”