Precision medicine for recalcitrant cancers with the patient-derived orthotopic xenograft (PDOX) mouse models for identification of effective therapy.

Abstract

e23164 Background: Our laboratory has developed the patient-derived orthotopic xenograft (PDOX) mouse model of all major cancer types. Methods: Sarcomas from patients were transplanted into the right bicep femoris muscle of nude mice or at a site corresponding to their metastasis. Melanomas were transplanted in nude mice at the orthotopic site corresponding to their metastasis in the patient. An HER-2-expressing cervical cancer was transplanted to the uterine cervix of nude mice. Results: A Ewing’s sarcoma with a FUS-ERG fusion and a CDKN2A-deletion was resistant to doxorubicin as was the patient and sensitive to palbociclib and linsitinib. A spindle-cell sarcoma PDOX was resistant to doxorubicin, but sensitive to pazopanib. A pleomorphic rhabdomyosarcoma PDOX was found resistant to cyclophosphamide, but sensitive to the combination of temozolomide and irinotecan. A melanoma with a BRAF-V600E mutation PDOX was resistant to vemurafenib even thought it targets the BRAF-V600E mutation and was sensitive to trametinib, but resistant to cobimetinib, although both are MEK inhibitors. The primary tumor in a cervical cancer PDOX was resistant to endostatin, but the metastasis in this model was sensitive. Conclusions: The PDOX models have distinguished differential sensitivity of primary and metastatic tumors to the same drug. PDOX models can also distinguish effective drugs when they are sensitive to first-line therapy. Most importantly, the PDOX models can find potential effective therapeutics for recalcitrant disease. Drug evaluation with the PDOX models demonstrate that mutational analysis of the patient tumor may not be sufficient to direct therapy by itself and together with PDOX testing, can result potentially in precision treatment.