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ASLAN003 for differentiation of AML
together, the therapeutic effects of ASLAN003 were multi- ple: prolonged survival, and prevention of tumor dissemi- nation and leukemic infiltration into organs.
Next, we tested the in vivo effect of ASLAN003 on leukemic burden (human CD45+ cells) and differentiation (CD11b+ or CD14+ cells). The numbers of human CD45+ cells in BM, peripheral blood, spleen and liver were all sig- nificantly reduced in ASLAN003-treated mice compared to those in control mice in both models (Figure 6B). In
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agreement with in vitro observations, FACS analysis showed significantly increased numbers of CD11b+ and CD14+ cells in BM of treated mice in both models (Figure 6B). Taken together, these experiments confirmed that ASLAN003 could induce differentiation and reduce leukemic burden in vivo.
We also evaluated the therapeutic efficacy of ASLAN003 in patient-derived AML xenografts. For AML- 14, an indolent line, at the end of experiments all mice
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CDE
Figure 6. The in vivo efficacy of ASLAN003 in xenograft models. (A) Kaplan-Meier survival curves of mice treated with either ASLAN003 or vehicle control for the MOLM-14 and THP-1 xenograft models. Mice were administered either ASLAN003 50 mg/kg or the same volume of the vehicle by daily oral gavage. Treatment was started 3 days after inoculation of leukemic cells. The number of mice in each group and log-rank P values are indicated. (B) The leukemic burdens in mouse bone marrow (BM), peripheral blood (PB), spleen and liver were compared for the ASLAN003-treated and vehicle-treated groups for MOLM-14 xenograft models (n=3) and THP-1 models (n=4). The number of human CD45+ cells was determined by FACS analysis as a surrogate marker for leukemic burden. FACS analysis was per- formed to assess the percentage of human specific CD11b+, CD14+ leukemic cells in BM and PB samples harvested from these mice. *P<0.05; **P<0.01. (C) FACS analysis of human CD45+ cells in BM samples harvested from mice with AML-14 patient-derived xenotransplants (PDX) treated with ASLAN003 or vehicle control (n=4, *P=0.039). (D) Kaplan-Meier survival curves of animals with AML-23 PDX receiving ASLAN003 or control treatment. (E) FACS analysis was performed to assess the percentage of human specific CD45+ in BM, PB, spleen and liver, as well as CD11b+, CD14+ leukemic cells in BM samples harvested from mice with AML- 23 PDX (n=3). *P<0.05; **P<0.01.
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