NOVARTIS-SUPPORTED IN-KIND PROJECT - 2012

Michael Cleary (Pathology)

A cell-based phenotypic high-throughput chemical screen was conducted to discover compounds with selective anti-leukemic properties.  This identified a novel class of anti-neoplastic compounds that inhibit the growth of human B-cell acute lymphoblastic leukemia (ALL) cell lines with genetic aberrations of the MLL oncogene.  Out of 130,000 compounds screened, 60 were identified to meet the selection criteria of inhibiting leukemia cell lines harboring high-risk MLL genetic aberrations, but with minimal effect on a cell line with a low-risk genetic aberration (TEL-AML1). Compounds that reduced viability of all cell lines, such as the anthracycline idarubicin, were excluded from further analysis.  Secondary screens revealed 3 structurally related compounds that displayed similar specificity. The lead compound, selected due to its potency, displays cytotoxicity in the low nanomolar range (IC₅₀ 2-15 nM) for ALL cell lines and primary patient samples. 

The lead compound is a structurally novel, cytotoxic agent that induces leukemia cell death, but the biological mechanism is unknown.  An understanding of the mechanism of action will inform identification of patient populations most likely to benefit from treatment and aid understanding of potential side effects.   Therefore, we are requesting assistance in identifying the relevant molecular pathway and/or target.

Efficacy of the lead compound was studied in an orthologous xenograft model of ALL.  In this model, immuno-compromised mice (NSG) invariably succumb to ALL within 35-37 days following intravenous transplantation of a human leukemia cell line programmed to express a luciferase reporter gene, which allows for non-invasive bioluminescence imaging to quantitatively monitor the progression of leukemia in viable mice.  Despite pharmacokinetic constraints on compound exposure in plasma and solubility, mice treated with the lead compound twice daily for 10 days via subcutaneous injection responded with a delay in tumor progression and statistically significant increase in survival.  Efficacy in this model provides a rationale for further advancement to lead optimization and clinical testing.  We are also requesting assistance with evaluation of pharmacokinetics, absorption, distribution, metabolism and elimination.