A variety of malignancies, including acute lymphoblastic leukemia and ovarian carcinomas, is auxotrophic for L-Asparagine (L-Asn). Under conditions of L-Asn starvation the auxotrophic cancer cells undergo cell cycle arrest and apoptosis, whereas non-malignant cells are unaffected. Systemic depletion of L-Asn via the administration of L-Asparaginase (ASpase) is a potent chemotherapeutic approach for the treatment of L-Asn-auxotrophic cancers; however, the therapeutic Aspases currently in use consist of bacterial enzymes eliciting adverse immune responses that limit their use. Human proteins are less immunogenic than their heterologous counterparts as natural tolerance prevents recognition by the immune system. We reported the bacterial expression and enzymatic characterization of the human asparaginase-like protein 1 (hASRGL1), a mammalian enzyme exhibiting beta-aspartyl peptidase activity as well as ASpase activity. We have been using combinatorial mutagenesis approaches that, coupled to a high throughput screening, aim at optimizing the catalytic and pharmacological properties of hASRGL1 for chemotherapy by L-Asn depletion.

Engineering of a human Asparagine-degrading enzyme for cancer treatment by systemic depletion

245th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.