Abstract 4251: Evaluating novel targeted therapeutic agents in T-cell acute lymphoblastic leukemia using a zebrafish xenotransplantation model

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy accounting for 25% of adult and 10-15% of pediatric ALL cases. The disease is characterized by infiltration of the bone marrow and peripheral blood with immature lymphoblasts bearing T-lineage markers. Although current multi-agent chemotherapy regimens have dramatically improved cancer outcomes, a significant proportion of T-ALL do not respond to therapy or relapse post therapy. Novel molecular-based treatment strategies are desperately needed to improve outcome and limit toxicity. Mutations that activate the NOTCH and PTEN/PI3K pathways are common in human T-ALL and may drive T-ALL cell proliferation. Gamma secretase inhibiting compounds that block NOTCH signaling have been effective against subtypes of T-ALL with NOTCH mutations but have had limited success in clinical trials due to severe gastrointestinal toxicity, and problems with drug resistance. Recently, inhibition of the PI3K pathway (including the downstream kinase AKT) have shown efficacy in vitro and in pre-clinical animal models. We have recently developed a novel human cancer xenotransplantation (XT) animal model using the zebrafish, which can be used for high throughput pre-clinical testing of human tumour-drug interactions for both leukemia and solid tumours (Corkery et al., 2011 Brit. J. Haemat.). Using the zebrafish XT model we are studying a number of compounds that specifically target the PI3K/AKT kinase pathway for ability to inhibit T-ALL cell proliferation in vivo. Preliminary proof-of-principal studies have shown that we can successfully engraft the PTEN-deficient T-ALL leukemia Jurkat cell line in zebrafish embryos. In agreement with published data, we have shown that treating Jurkat transplanted embryos with the mTOR inhibitor rapamycin inhibits in vivo proliferation of the human leukemia cells line by 60%, while, by contrast, the AKT inhibitor triciribine does not significantly inhibit proliferation. We have also successfully transplanted primary bone marrow from pediatric T-ALL patients which go on to engraft in the zebrafish embryos. The ability to screen novel compounds against a panel of primary patient samples could provide a more accurate means of predicting the efficacy of said compounds across heterogeneous patient populations. We are now employing the zebrafish XT model to study the effects of novel PI3K/AKT kinase inhibition on the proliferation of a panel of human T-ALL cell lines and primary patient samples as a means of rapidly selecting new drug candidates to move forward into the rodent model and Phase I clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4251. doi:1538-7445.AM2012-4251

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