(P 256) EFFICACY AND TOXICITY OF VERTEPORFIN IN COMBINATION WITH PAZOPANIB TESTED IN A PATIENT-DERIVED SYNOVIAL SARCOMA XENOGRAFT

Objective: Synovial sarcoma (SySa) is one of the more common soft-tissue sarcoma subtypes and is characterized by the presence of a pathognomonic translocation between chromosome X and 18, resulting in the formation of an SS18-SSX fusion oncogene. Patients with metastatic SySa have limited treatment options and a very poor prognosis. There is a high unmet medical need to develop more effective treatment options.

Yes associated protein 1 (YAP1) is known to be overexpressed in the majority of SySa and is considered a potential therapeutic target in this disease. We performed preliminary in vitro experiments with the SySa celline (SYO-1) that expresses high levels of YAP1 and noticed that short hairpin antisense (shRNA) knockdown of YAP1 increased sensitivity to the angiogenesis inhibitor pazopanib, a drug with proven clinical activity in SySa. This led to an in vivo experiment, in which the YAP1 inhibitor verteporfin was combined with pazopanib in a patient-derived SySa xenograft (UZLX-STS7).

Methods: A 7-day exploratory toxicological study was performed in non-tumor bearing NMRI nu/nu mice to evaluate potential drug-drug interactions and acute toxicity when combining pazopanib and verteporfin. Bodyweight and general well-being of mice was followed during the treatment period. Livers were collected for histopathological evaluation.

For the efficacy study, NMRI nu/nu mice (n=29, 7-8 mice/group) were bilaterally transplanted with the xenograft model UZLX-STS7. Mice were treated for 23 days with either control, pazopanib (100 mg/kg once daily by oral gavaging), verteporfin (75 mg/kg every 2 days by intraperitoneal injection) or a combination of pazopanib and verteporfin (dose and schedule as for single agents). Efficacy assessment was based on the evaluation of the tumor volume, histopathology and immunohistochemistry.

Results: During the toxicological study, no acute toxicity was observed and no hepatotoxicity was seen on histopathological evaluation. The efficacy study showed that the combination of verteporfin and pazopanib led to tumor growth stabilization (tumor volume of 136% on the last day of treatment versus baseline) compared to any of the monotherapies (average relative tumor volume of 208% for verteporfin and 224% for pazopanib) or control (average relative tumor volume of 438%). However, the combination was poorly tolerated if mice were treated for a longer period, one mouse was found dead and one mouse needed to be sacrificed because of weight loss. Compared to tumors treated with control and verteporfin monotherapy, the combination treatment of verteporfin and pazopanib led to a relative decrease in mitotic and increase in apoptotic activity (similar as in tumors treated with pazopanib in monotherapy).

Conclusion: SySa is a tumor which may benefit from YAP1 inhibition. Combining the YAP1 inhibitor verteporfin with pazopanib led to stabilization of tumors in our in vivo experiment, but was poorly tolerated. Further investigations in this and other models are needed to evaluate whether dose adjustments or other YAP1 inhibitors might be less toxic and/or more effective.