9A. Amino acid depletion therapies for T cell Acute Lymphoblastic Leukemia

Targeting amino acid availability has proven to be effective in the treatment of cancer, although it is not yet broadly applied. The most notable exception is the asparagine depleting enzyme asparaginase, a key component of contemporary ALL treatment protocols. At present, other amino acid depletion therapies targeting glutamine, arginine or methionine are in phase I/II clinical trials. With this proposal we aim to establish the clinical utility of amino acid depletion in the treatment of relapsed or refractory T-ALL, a disease for which very few therapeutic options are available.

We will not only study combinations of amino acid depletion and contemporary ALL therapies but also explore potential synergies between amino acid depletion and novel targeted agents that are currently on trial for the treatment of ALL. In addition, we will use CRISPR-CAS9 based screening methods to identify (metabolic) targets that can further enhance the effects of amino acid depletion. Finally, available metabolic drug libraries will be interrogated using our high throughput drug screening facility, to identify compounds that synergize with amino acid depletion. Priority will be given to compounds that are FDA approved or under clinical investigation. For pre-clinical validation, a large panel patient derived xenograft (PDX) models is available representing paired T-All samples obtained at diagnosis and relapse. The effects of these drug combinations will be tested ex-vivo using flow cytometry-based apoptosis assays that we recently developed. In addition, in vivo drug interactions will be studied in vivo, by transplanting these PDX models in immune compromised mice. We expect that this strategy will lead to the identification of efficient, less toxic, therapies for relapsed T-ALL.