Bacterial L-asparaginases are nowadays used as a cornerstone drug in the treatment of pediatric acute lymphoblastic leukemia patients. Evidence is accumulating that L-asparaginases may also have clinical potential for the treatment of aggressive solid cancer subtypes with low/no asparagine synthetase (ASNS) expression, including a subgroup of 15-25% of ovarian cancer patients. However, specifically in adult patients, asparaginase administration is associated with immunological side-effects and non-immune related toxicities. Because of these tolerability issues, the clinical potential of asparaginase for the treatment of ovarian cancer has not been fully pursued. We hypothesize that the development of safer asparaginase formulations could expand its therapeutic use, to improve the outcome of ASNS-low ovarian cancer patients. With this in mind, we have generated an alternative mammalian-derived L-asparaginase variant, which has a significantly improved safety and toxicity profile compared to the standard-of-care bacterial L-asparaginases. In this project, we will use a variety of preclinical patient-derived models to evaluate the efficacy of this alternative variant. Our hypothesis is that our less toxic and less immunogenic L-asparaginase variant in combination with first-line therapy could drastically improve the outcome of ASNS-low ovarian cancer patients.