TARGETED INHIBITION OF PI3K, MTOR, AND IGF1R FOR THE TREATMENT OF UNDIFFERENTIATED PLEOMORPHIC SARCOMA

Undifferentiated pleomorphic sarcoma (UPS) is an aggressive mesenchymal malignancy largely devoid of indicators for its originating tissue. Surgery remains the standard of care, as radiation therapy and systemic chemotherapy have limited efficacy in UPS patients with localized and metastatic disease, respectively. Therefore, it is imperative to identify and evaluate novel therapeutic targets in UPS in order to provide more efficacious treatment options for patients. Previous studies have revealed that members of the phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathway can be used to predict patient outcome in cohorts containing patients with various subtypes of soft tissue sarcoma. Furthermore, we have previously shown that high levels of phosphorylated AKT correlate to poorer disease-specific survival in UPS patients, indicating that PI3K/mTOR activity may contribute to the aggressiveness of disease. In this dissertation, we demonstrate that the PI3K/mTOR pathway is active in UPS patient-derived tumor samples and cell strains/lines. Pharmacologic blockade of this pathway using second-generation dual PI3K/mTOR small molecule inhibitors as single agents attenuates UPS cell proliferation, migration, and invasion in vitro. In addition, daily or twice daily drug administration reduces tumor volume and weight in a mouse model harboring a UPS tumor implant. However, single agent therapy was insufficient to eliminate tumor growth, and immunohistochemical analysis revealed that PI3K/mTOR inhibition activates insulin-like growth factor 1 receptor (IGF1R), potentially as a mechanism of adaptive resistance. Combined inhibition of PI3K, mTOR, and IGF1R via small molecule inhibitors resulted in a drastically reduced tumor volume in vivo, despite the lack of substantial antiproliferative effects in vitro. Furthermore, the drug combination significantly decreased UPS cell migration and invasion, due in part to the re-localization of the cyclin-dependent kinase inhibitor p27KIP1 to the nucleus. Taken together, our data indicate that targeted inhibition of key nodes in the PI3K/mTOR pathway in combination with IGF1R reduces UPS tumorigenicity and should be further explored as a novel therapeutic avenue for UPS patients