Abstract
Targeted therapies have yet to have significant impact on the survival of patients with bladder cancer. In this study, we focused on the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) as a therapeutic target in bladder cancer, based on our discovery of the prognostic and functional import of ASS1 in this setting. ASS1 expression status in bladder tumors from 183 Caucasian and 295 Asian patients was analyzed, along with its hypothesized prognostic impact and association with clinicopathologic features, including tumor size and invasion. Furthermore, the genetics, biology, and therapeutic implications of ASS1 loss were investigated in urothelial cancer cells. We detected ASS1 negativity in 40% of bladder cancers, in which multivariate analysis indicated worse disease-specific and metastasis-free survival. ASS1 loss secondary to epigenetic silencing was accompanied by increased tumor cell proliferation and invasion, consistent with a tumor-suppressor role for ASS1. In developing a treatment approach, we identified a novel targeted antimetabolite strategy to exploit arginine deprivation with pegylated arginine deiminase (ADI-PEG20) as a therapeutic. ADI-PEG20 was synthetically lethal in ASS1-methylated bladder cells and its exposure was associated with a marked reduction in intracellular levels of thymidine, due to suppression of both uptake and de novo synthesis. We found that thymidine uptake correlated with thymidine kinase-1 protein levels and that thymidine levels were imageable with [(18)F]-fluoro-L-thymidine (FLT)-positron emission tomography (PET). In contrast, inhibition of de novo synthesis was linked to decreased expression of thymidylate synthase and dihydrofolate reductase. Notably, inhibition of de novo synthesis was associated with potentiation of ADI-PEG20 activity by the antifolate drug pemetrexed. Taken together, our findings argue that arginine deprivation combined with antifolates warrants clinical investigation in ASS1-negative urothelial and related cancers, using FLT-PET as an early surrogate marker of response.
Highlights
Urothelial carcinoma is the fourth most common malignancy diagnosed in men, and the seventh commonest cause of solid cancer-related death in the United States, accounting for15,000 deaths per annum [1]
argininosuccinate synthetase 1 (ASS1) promoter methylation was greatest in UMUC-3 and 253J compared with the T24 cell line by pyrosequencing of six CpG islands within the ASS1 promoter
Progress in the targeted therapy of advanced urothelial carcinoma has lagged behind other urological malignancies, especially prostate and renal cancer
Summary
Urothelial carcinoma is the fourth most common malignancy diagnosed in men, and the seventh commonest cause of solid cancer-related death in the United States, accounting for15,000 deaths per annum [1]. Urothelial carcinoma is the fourth most common malignancy diagnosed in men, and the seventh commonest cause of solid cancer-related death in the United States, accounting for. 40% to 60% for muscle invasive bladder cancer has plateaued over the past three decades, in part, due to the frequent comorbidities in this patient group [2]. Despite $4.0 billion spent each year on bladder cancer treatment in the United States alone—one of the highest expenditures in. Luong contributed as joint first authors and C.-F. Li and P.W. Szlosarek as joint last authors
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