Molecular guided therapy leading to exceptional response in relapsed osteosarcoma

Osteosarcoma is the most common type of primary malignant bone tumor in children, adolescents and young adults and remains a significant clinical challenge, especially in the context of metastatic disease. Here we report the case of a 9-year-old female with refractory metastatic osteoblastic osteosarcoma with disease progression in the lungs following neoadjuvant chemotherapy, local control surgery with limb salvage and further aggressive chemotherapy. She was then enrolled on a Molecularly Guided Therapy Clinical Trial (NMTRC009) utilizing genomic analysis to identify novel treatment options. Whole exome sequencing (WES) and RNA-Seq were performed on each patient's tumor to identify genomic aberrations when referenced to normal tissue. WES of the tumor identified no targetable mutations. RNA transcriptome sequencing of the subject's tumor showed overexpression of SLC29A11 (Z-score = 3.3) indicating sensitivity to gemcitabine as well as activation of the biological pathways mTOR, CSF1R, EPHA2, SLC29A1, suggesting possible beneficial treatment with a combination of everolimus, gemcitabine, doxycycline and dasatinib. Cell viability assays on the subject derived cell line SL00339 showed minimal effects of single agent treatments but a significant decrease in cell viability with combination therapies. Western blot analysis of cells treated with drugs alone and in combination showed an increase in apoptosis and decrease in pmTOR and pAKT. The subject responded to the novel drug combination, continuing medications for 5 years with some modifications, and remained on everolimus alone for an additional 4 years with a complete response, no serious adverse events, and excellent quality of life. In conclusion, Molecular Guided Therapy with tumor board recommendations resulted in a novel therapeutic approach leading to long term survival which correlated to response <i>in vitro</i>.