Background: Alveolar Soft Part Sarcoma (ASPS) is a rare soft tissue sarcoma subtype occurring mainly in children and young adults. Malignant tumors develop in the connective tissues, typically in the lower extremities of the legs and thighs, but can also be found in the head and neck regions. ASPS is slow growing, highly angiogenic, and may have unique metabolic properties. ASPS is characterized by an unbalanced translocation between the ASPSCR1 gene (whose product tethers GLUT4 transporters) and the TFE3 gene (encoding a transcription factor). The resulting ASPSCR1-TFE3 fusion gene is responsible for an aberrant transcription factor that is thought to be involved in the pathogenesis of the disease. Methods to assess a number of different agents in combination are needed for practical use in clinical trials.
Methods: Here, we seek to examine the therapeutic activity of single agent and combinations of epigenetic, anti-angiogenic and a diverse mix of other mechanisms of action agents using high-throughput screening platforms and well-established cell line models for ASPS (ASPS-1 and ASPS-KY). We designed stringent screening conditions that assess the compounds at clinically-relevant concentrations and time of exposures that mimic the in vivo pharmacokinetics in an effort to maximize the translational potential of these results to the clinical setting. 54 agents were screened across the 2 cell lines with attention to existing clinical data and angiogenesis inhibitors. The cell titer glo assay was used to determine cell viability at three clinically achievable concentrations for all agents. The most promising 8 agents were then studied in all two-drug combinations to evaluate for synergy.
Results: The results of our screening showed that several agents significantly reduced cell viability at clinically relevant concentrations and exposure times with belinostat (an HDAC inhibitor) and dinaciclib (a CDK 1, 2, 5 and 9 inhibitor) in particular having good activity. Several combinations with doxorubicin showed good efficacy and synergy. Belinostat and doxorubicin affected both ASPS-KY and ASPS-1 cell lines similarly, with an average fraction affected (FA) of 0.87. The combination index (CI) indicated strong synergy in the ASPS-KY (CI = 0.09) and some synergy in ASPS-1 (CI = 0.74). Similarly, dinaciclib and doxorubicin produced a FA of 0.85 with good synergy (CI of 0.51-0.66). In addition, the combination of belinostat and tivantinib showed additive effects in both cell lines (CI of 0.88-1.2) with a FA of ∼0.8. These findings suggest potentially promising opportunities for developing combinational approach to treating childhood soft tissue sarcomas.
Citation Format: Justine Clark, Elliot Kahen, Diana X. Yu, Christopher L. Cubitt, Daniel M. Sullivan, Damon R. Reed. Assessing combinations of chemotherapy in alveolar soft part sarcoma cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 274.