Abstract 2524: SB1518, a novel oral JAK2-FLT3 inhibitor, is efficacious in models of acute myeloid leukemia and primary leukemic cells from patients
Authors: Hart Stefan , Goh Kee Chuan , Tan Yong Cheng , Amalini Chithra , Wood Jeanette M. 
Published: February 2011

Introduction

FLT3 and JAK2 are tyrosine kinases with crucial roles in hematopoietic progenitor cell survival and proliferation. Over-expression and/or mutation of FLT3 is frequently detected in acute myeloid leukemias (AML) and are strongly associated with a poor prognosis. JAK2 mutations are linked to the pathogenesis of myeloproliferative neoplasms. SB1518 is a novel inhibitor of both FLT3 (IC50 = 22 nM) and its drug-resistant mutant D835Y (IC50 = 6 nM) as well as JAK2 (IC50 = 22 nM) and its JAK2V617F mutant (IC50 = 19 nM). It inhibits the proliferation of cells dependent on FLT3 or JAK2 signaling. SB1518 is currently being evaluated in clinical trials for advanced hematologic malignancies. We report here the promising activity of SB1518 in models of AML generated with a human AML cell line, as well as on primary AML cells obtained from patients.

Methods

MV4-11 cell line, derived from a FLT3-ITD AML patient, was tested for the anti-proliferative effects of SB1518 and used to establish subcutaneous tumors in nude mice. The xenografted animals were dosed orally once daily (25, 50 and 100 mg/kg) for 21 days with SB1518 and monitored for clinical response. For progenitor expansion, PBMCs of AML patients (AllCells Inc) were cultured using a medium containing IL-3, IL-6, SCF and FLT3L (StemCell Technologies TB 28440). The expanded progenitors were treated with SB1518 to determine effects on cell viability, apoptosis, cell cycle and pathway inhibition.

Results

SB1518 potently inhibited the proliferation of the MV4-11 cell line (IC50 = 32 nM) and demonstrated significant antitumor activity in the MV4-11 tumor model in mice. SB1518 was extremely well tolerated with no body weight loss and induced tumor growth inhibition of 26%, 98%, and 116% at doses of 25, 50, and 100 mg/kg respectively. Complete regression was observed at the highest dose level. Flow cytometric analysis confirmed a significant enrichment of CD123+ progenitors in the expanded population of primary cells from AML patients. Cells from the individual patients showed markedly different sensitivity to inhibition of proliferation in response to ex vivo treatment with SB1518 (IC50 values from 180-1330 nM). Sensitivity of the cells was not related to FLT3-ITD mutation status. SB1518 inhibited phospho-STAT3/5 in these cells and induced activation of caspase-3/7.

Conclusions

SB1518, a novel JAK2-FLT3 inhibitor, has demonstrated promising activities in an AML cell line as well as primary cells from AML patients and is highly efficacious in a mouse model of human myeloid malignancy. It is currently undergoing evaluation in Phase 1/2 trials and has shown signs of activity in a limited number of AML patients. Understanding the molecular basis of differential sensitivity to the anti-proliferative efficacy of SB1518 in individual AML patients may provide a basis for future patient selection in this indication.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2524.