pazopanib and ridaforolimus

Synovial sarcoma is part of soft tissue sarcomas, an uncommon group of malignant tumors of mesenchymal origin. Unfortunately, a very limited number of useful drugs are active for most advanced synovial sarcoma. These tumors showed VEGF expression, and elevated serum VEGF levels correlate with higher histologic tumor grade. Inhibition of VEGFR was associated with tumor activity in preclinical models of synovial sarcoma and drugs such as sorafenib, pazopanib and bevacizumab have been employed in synovial sarcoma in monotherapy and in combination with chemotherapy. Other targets such as EGFR, HER2, IGFR-1R and mTOR have been exploited, but their inhibition by drugs such as gefitinib, trastuzumab, figitumumab, and temsirolimus, has not resulted in meaningful activity. Newer approaches include CXCR4 inhibition, immune-based therapies (NY-ESO-1), targeting epigenetic misregulation with HDAC inhibitors and targeting developmental pathways such Notch and Hedgehog. This review will summarize achievements and pitfalls of drugs against emerging therapeutic targets for synovial sarcoma.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Bevacizumab; Everolimus; Humans; Indazoles; Indoles; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Sarcoma; Sarcoma, Synovial; Sirolimus; Sorafenib; Sulfonamides; Sunitinib; TOR Serine-Threonine Kinases

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Dacarbazine; Deoxycytidine; Disease-Free Survival; Dose-Response Relationship, Drug; Gemcitabine; Humans; Hyperthermia, Induced; Indazoles; Multimodal Imaging; Neoadjuvant Therapy; Positron-Emission Tomography; Pyrimidines; Randomized Controlled Trials as Topic; Sarcoma; Sirolimus; Soft Tissue Neoplasms; Sulfonamides; Tomography, X-Ray Computed; Treatment Outcome

Soft-tissue sarcomas (STS) comprise a heterogeneous group of rare malignancies from mesenchymal tissues. Although outcome varies by histology, adults with disseminated metastatic STS have a poor prognosis despite current treatment options. The authors reviewed commonly used clinical end points for STS and discussed which end points may be appropriate for evaluating the clinical benefit of novel targeted therapies. In sarcoma, surrogates for both overall survival, the gold standard end point, and the objective response rate, measured by Response Evaluation Criteria in Solid Tumors, are commonly used. More appropriate end points for evaluating newly targeted agents include progression-free survival and clinical benefit rate. Results from recently completed Phase III trials of two targeted therapies in advanced STS, the mTOR inhibitor ridaforolimus and the multikinase inhibitor pazopanib, should shed light on whether progression-free survival and clinical benefit rate are appropriate end points in advanced STS.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Disease-Free Survival; Drug Substitution; Drugs, Investigational; Endpoint Determination; Humans; Indazoles; Molecular Targeted Therapy; Neoplasm Metastasis; Outcome and Process Assessment, Health Care; Prognosis; Pyrimidines; Sarcoma; Sirolimus; Sulfonamides; Survival Rate; TOR Serine-Threonine Kinases; Treatment Outcome