A Patient-Derived Xenograft Model of Parameningeal Embryonal Rhabdomyosarcoma for Preclinical Studies

Abstract

Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study.

Figure 1

Radiographic imaging and comparative histology of human and PDX tumors: (a) 1 cm × 2 cm enhancing right-sided skull based mass that was invading the hypoglossal nerve canal. (b) H&E slide, 400x of brain biopsy showing sheets of elongated spindled cells with eosinophilic cytoplasm and a myxoid background, consistent with embryonal rhabdomyosarcoma. An H&E slide, 400x from the frontal lobe at autopsy (c), and a section of mouse xenograft, 200x (d), show highly similar morphologic features.

Figure 2

Preclinical testing of lestaurtinib in a parameningeal PDX. (a, b) Kaplan-Meier analysis of PDX mice from two different treatment cohorts.