The TOR Kinase Inhibitor INK128 Is Effective in Pre-B Acute Lymphoblastic Leukemia Models

Abstract

Abstract 2585Pre-B Acute Lymphoblastic Leukemia (B-ALL) remains a significant cause of morbidity and mortality in both adults and children. Targeting signaling pathways that sustain B-ALL cell survival is a promising strategy to improve treatment outcomes. The target of rapamycin (TOR) is a serine/threonine kinase that integrates signals from oncoproteins and the microenvironment to support ALL cell proliferation and survival. A single TOR enzyme in cells forms two multiprotein complexes, TORC1 and TORC2, with distinct regulation and substrates. The classical TOR inhibitor rapamycin inhibits only some functions of TORC1 and does not acutely inhibit TORC2. A new generation of TOR inhibitors has been developed that inhibit all outputs of both TORC1 and TORC2. These ATP-competitive, TOR kinase inhibitors (TOR-KIs) have improved anti-cancer activity in models of both solid tumors and hematological malignancies. Previously we reported that the TOR-KI compound PP242 is effective in mouse models of Philadelphia Chromosome-positive (Ph+) B-ALL, with minimal toxicity to normal hematopoietic cells or immune function (MR Janes et al., Nat. Med. 2010; 16:205). Here we present promising results on the efficacy of a second generation TOR-KI, INK128, in both Ph+ and non-Ph B-ALL. INK128 is an orally active, highly selective TOR-KI that is currently in phase I clinical trials for solid tumors, multiple myeloma and Waldenstrom's Macroglobulinemia. We find that INK128 has similar biological effects as PP242 on Ph+ B-ALL cells, but these effects are apparent at 5-fold lower concentrations in vitro and 80-fold lower doses in mice. In methylcellulose assays using Ph+ and non-Ph B-ALL specimens, INK128 greatly reduces colony numbers and enhances the efficacy of standard-of-care drugs. Both adult and pediatric non-Ph B-ALL specimens are sensitive to growth suppression by INK128. INK128 also causes apoptosis in B-ALL cells cultured on stromal cells. Importantly, INK128 suppresses human Ph+ B-ALL xenograft expansion in mice at doses that do not impair normal hematopoietic cell proliferation. INK128 is also less immunosuppressive than rapamycin. Together these results provide rationale for testing INK128 and other TOR-KIs in clinical trials of B-ALL therapy. Disclosures:Fruman:Intellikine: Membership on an entity's Board of Directors or advisory committees, Research Funding. Janes:Intellikine: Employment. Martin:Intellikine: Employment. Ren:Intellikine: Employment. Liu:Intellikine: Employment. Rommel:Intellikine: Employment.