Program Director/Principal Investigator: (Van Tine, Brian) Project Summary We recently demonstrated that argininosuccinate synthetase 1 (ASS1) expression is silenced in 88% of all sarcomas (n=708), and this loss is associated with reduced overall survival. In the absence of ASS1, arginine becomes an essential amino acid that tumor cells must obtain from blood. We demonstrated that PEGylated arginine deiminase (ADI-PEG20, an extracellular arginine-depleting enzyme) induces prosurvival metabolic reprogramming in ASS1-deficient sarcomas that redirects glucose into the serine/folate pathway, thereby funneling carbons from glucose into pyrimidine biosynthesis. Metabolomics analyses suggested that this should sensitize cells to death by the pyrimidine antimetabolite gemcitabine. In addition, ADI-PEG20 and docetaxel dramatically increase the expression of SLC29A1, the nucleotide/gemcitabine transporter. The combination of gemcitabine and docetaxel has been demonstrated to be superior to gemcitabine alone in sarcoma. Therefore, we will perform a Phase II clinical trial combining ADI-PEG20 with gemcitabine and docetaxel, which are standard second-line therapeutic agents for soft tissue sarcoma, to model the metabolic consequences of ASS1 deficiency in the presence and absence of arginine starvation. Progression-free survival and overall survival are the primary and secondary endpoints, respectively. Paired biopsies before treatment and 21 days after ADI-PEG20 will be obtained for correlative studies. For preclinical testing, we generated the first conditional murine knockout model of ASS1 that develops sarcomas in the context of p53 loss, a common alteration in sarcomas. We also developed sarcoma patient?derived xenografts (PDXs) to model arginine deprivation by ADI-PEG20. We will determine the effect of ASS1 silencing on tumorigenesis in transgenic mice, and model the adaptive metabolic reprograming response to gemcitabine and docetaxel to determine patterns of sensitivity and resistance to therapy. We anticipate that the proposed studies will lead to the development biomarker-driven therapy for arginine deprivation in ASS1-deficient sarcomas.
(Van Tine, Brian) Project Narrative The goal of this proposal is to test a multi-agent biomarker-driven metabolic therapy based on the loss of argininosuccinate synthetase 1 (ASS1) expression in a clinical trial of sarcoma therapy. The approach of exploiting sarcoma tumor metabolism to induce conditional metabolic reprogramming that exposes several vulnerabilities, and then directly targeting those vulnerabilities, is a new concept for the treatment of sarcoma.
