Xenotransplantation in Immunodeficient Mice to Evaluate New Therapeutic Strategies for Refractory Childhood Acute Lymphoblastic Leukemia

New approaches are required to triage among new candidate approaches for the treatment of drug-resistant childhood acute lymphoblastic leukemia. We therefore developed a preclinical research platform by xenotransplantation of primary ALL cells to constitute a bank of highly selected samples from de novo resistant, relapsed and refractory cases on the ALL-BFM-2000 and on the ALL-REZ-BFM-2002 trials. The power of this model resides in the possibility to test new agents on a large number of samples from patients that are eligible for phase I/II studies.

Because modulation of cell death regulators represents an attractive strategy for subverting drug resistance, we first focused on a new class of compounds that can interfere functionally with members of the BCL-2 family. Combination therapy with subcytotoxic concentrations of the putative BH3-mimetic obatoclax achieved complete resensitization of multi-resistant leukemia to several cytotoxic agents. Unexpectedly, reversal of glucocorticoid resistance occurred through rapid activation of autophagy-dependent necroptosis that bypasses the apoptotic blockade. In contrast, a very effective chemosensitization by obatoclax to nucleotide analogs and anthracyclins was associated with induction of mitochondrial apoptosis. The combination of obatoclax with dexamethasone had a marked antileukemic effect in vivo using the xenotransplantation model, providing additional support for a translation of this pharmacological approach into a clinical trial. I will provide new insights into the mechanisms involved with activation of necroptosis by the combination of obatoclax and dexamethasone and discuss the proposal for a multicentric phase I trial to evaluate this pharmacological approach in patients with relapsed and refractory ALL.