Targeting the Pentose Phosphate Pathway for the Treatment of Synovial Sarcoma
Synovial Sarcoma (SS) is a translocation dependent subtype of soft tissue sarcoma that arises from the fusion of SYT and SSX. The hybrid transcript factor SYT:SSX modulates SWI/SNF chromatin remodeling and gene expression. As no targeted therapy has been developed for SS, we have applied a metabolomics approach to understanding SS and identified a unique glucose metabolism linked to the fusion. We have found that SS cell lines die exceedingly fast within two hours of glucose withdrawal by a mechanism not involving apoptosis or necrosis. In addition, we have identified that glucose-6-phosphate dehydrogenase (G6PD), a glucose metabolizing enzyme at the entrance to the pentose phosphate pathway (PPP), is the key regulatory enzyme needed for the survival of SS after glucose withdrawal. When SS cell lines were treated with an allosteric inhibitor of G6PD, dehydroepiandrosterone (DHEA), cell death occurred. DHEA is a derivative of cholesterol that is involved in the production of testosterone available from compounding pharmacies for human use. When the SYO xenografts are treated in vivo with DHEA, tumor volume decreased dramatically over a time course of seven days and did not recur. Finally, we are the first to identify that malic enzyme 1 (ME1) is not expressed in SS cell lines, clinical samples, or tumors from the SS spontaneous transgenic mouse. ME1, along with G6PD and 6-phosphogluconate dehydrogenase (6PGD) are the main sources of cellular NADPH, which is used for the recycling of glutathione to scavenge free radicals. As ME1 is not expressed in SS, and G6PD can be inhibited by DHEA, a novel therapeutic strategy for the treatment of SS can be developed using DHEA. Prior to testing this is in a clinical trial, a better understanding of SS glucose addiction is needed. Hence, we hypothesize that: understanding glucose and energy metabolism of Synovial Sarcoma and the mechanism of glucose withdrawal cell death, we will develop a therapy for SS based on PPP-based metabolic targets. To test this we propose three specific AIMS. Aim 1 is to characterize the mechanism of cell death caused by glucose withdrawal. This will allow us to better target SS therapeutically. Aim 2 is to determine if the transcriptional down regulation of ME1 in Synovial Sarcoma is directly or indirectly caused by the SYT-SSX translocation. By understanding the mechanism of ME1 silencing, we can try to apply our findings to other types of sarcoma. Aim 3 is to determine the metabolic consequences of DHEA treatment in vivo in a spontaneous model of Synovial Sarcoma. This will allow us to validate our observation in a spontaneous model, and to use metabolomics to determine if there are additional targets for duel metabolic therapy in addition to G6PD inhibition. Taken together, this proposal lays the foundation for a novel therapeutic strategy for SS. If our findings are validated, SFA will provide the needed data to allow DHEA to be tested in SS patients.