Novel Approach to Bladder Cancer Chemotherapy Based on Arginine Depletion

Studies conducted on arginine-dependent bladder cancer cell cultures and mouse xenografts revealed that this cancer is highly susceptible to treatment with a drug compound comprising the enzyme arginine deiminase (ADI) conjugated to polyethylene glycol (PEG).

Loss of argininosuccinate synthetase 1 (ASS1), a key enzyme for arginine synthesis, which occurs more than 90% of all bladder cancers, makes the cancer cells dependent on extracellular arginine. One approach towards treating ASS1-deficient cancer is to remove its source of external arginine. One way of doing this in vivo is by treating the animal with the arginine-degrading enzyme pegylated arginine deiminase (ADI-PEG 20).

ADI-PEG 20 was designed by Polaris Pharmaceuticals, Inc. (San Diego, CA, USA) to deplete the external supply of arginine, causing arginine-dependent cancer cells to die while leaving the patient’s normal cells unharmed. It is a novel protein therapeutic that has demonstrated anti-tumor activity and safety in clinical trials of patients with various cancers. ADI was conjugated with polyethylene glycol (PEG) of 20,000 dalton molecular weight to increase the circulating half-life and decrease antigenicity of ADI. Similar PEGylation technology has been used with microbially derived therapeutic proteins for systemic delivery of other anticancer drugs. Conjugating ADI with PEG also allowed for the drug to be administered by intramuscular injection, which avoided possible complications known to be associated with multiple intravenous administrations.

Investigators at the University of California, San Diego (USA) evaluated ASS1 expression and effects of ASS1 loss in bladder cancer, which despite affecting more than 70,000 people in the United States annually, has limited therapeutic options.

The authors reported in the December 12, 2016, online edition of The American Journal of Pathology that they detected ASS1 loss in conventional and micropapillary urothelial carcinoma, small cell, and squamous cell carcinoma subtypes of invasive bladder cancer, as well as in T24, J82, and UM-UC-3 but not in 5637, RT112, and RT4 cell lines. ASS1-deficient cells showed preferential sensitivity to ADI-PEG 20, evidenced by decreased colony formation, reduced cell viability, and increased sub-G1 fractions.

ADI-PEG 20 treatment of mice bearing contralateral flank UM-UC-3 (ASS1 deficient) and RT112 (normal ASS1) xenografts selectively arrested tumor growth in the UM-UC-3 xenografts.

"There is a major unmet need to identify additional therapies for bladder cancer patients that includes agents that can target both conventional urothelial carcinoma and less common subtypes of bladder cancer. Our findings suggest that arginine dependency in bladder cancer may be a useful mechanism to selectively target a subset of these cancers using ADI-PEG 20, although further investigation into the mediators of this effect and the role of combination therapy, including chemotherapy, to enhance efficacy is required," said senior author Dr. Donna Hansel, professor of pathology at the University of California, San Diego. "Our results suggest that arginine deprivation may be a useful strategy for treating bladder cancer and show that ADI-PEG 20 functions through a novel signaling mechanism that includes the pathway mediated by the general control nonderepressible II kinase that controls autophagy and apoptosis."

Related Links:
Polaris Pharmaceuticals
University of California, San Diego