Abstract:FLT3 has been identified as a valid target for the treatment of acute myeloid leukemia (AML), and some FLT3 inhibitors have shown very good efficacy in treating AML in clinical trials. Nevertheless, recent studies indicated that relapse and drug resistance are still difficult to avoid, and leukemia stem cells (LSCs) are considered one of the most important contributors. Here, we report the characterization of SKLB-677, a new FLT3 inhibitor developed by us recently. SKLB-677 exhibits low nanomolar potency in bi… Show more
“…While the median survival after the start of treatment in control treated mice are similar between these studies, the overall median survival from the MV4;11 injection are farther apart, with the original study reporting a median time of 35 days and this replication attempt reporting 59 days due to the added time from injection to beginning of treatment. Comparatively, other published studies using this model have reported a range of median survival times, such as 41 days (O'Farrell et al, 2003), 51 days (Dorn et al, 2009; Lopes de Menezes et al, 2005; Ma et al, 2015), and 60 days (Hardwicke et al, 2009) after intravenous injection of MV4;11 cells into NOD-SCID mice. To summarize, for this experiment we found the survival results were not in the same direction as the original study and not statistically significant where predicted.10.7554/eLife.25306.008Figure 4.Efficacy study of I-BET151 in xenograft mouse model of MLL-fusion leukaemia.Female NOD-SCID mice were xenotransplanted with 1 × 10 7 MV4;11 cells after conditioning with Busulfan.…”
In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Fung et al., 2015), that described how we intended to replicate selected experiments from the paper "Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia" (Dawson et al., 2011). Here, we report the results of those experiments. We found treatment of MLL-fusion leukaemia cells (MV4;11 cell line) with the BET bromodomain inhibitor I-BET151 resulted in selective growth inhibition, whereas treatment of leukaemia cells harboring a different oncogenic driver (K-562 cell line) did not result in selective growth inhibition; this is similar to the findings reported in the original study (Figure 2A and Supplementary Figure 11A,B; Dawson et al., 2011). Further, I-BET151 resulted in a statistically significant decrease in BCL2 expression in MV4;11 cells, but not in K-562 cells; again this is similar to the findings reported in the original study (Figure 3D; Dawson et al., 2011). We did not find a statistically significant difference in survival when testing I-BET151 efficacy in a disseminated xenograft MLL mouse model, whereas the original study reported increased survival in I-BET151 treated mice compared to vehicle control (Figure 4B,D; Dawson et al., 2011). Differences between the original study and this replication attempt, such as different conditioning regimens and I-BET151 doses, are factors that might have influenced the outcome. We also found I-BET151 treatment resulted in a lower median disease burden compared to vehicle control in all tissues analyzed, similar to the example reported in the original study (Supplementary Figure 16A; Dawson et al., 2011). Finally, we report meta-analyses for each result.DOI:
http://dx.doi.org/10.7554/eLife.25306.001
“…While the median survival after the start of treatment in control treated mice are similar between these studies, the overall median survival from the MV4;11 injection are farther apart, with the original study reporting a median time of 35 days and this replication attempt reporting 59 days due to the added time from injection to beginning of treatment. Comparatively, other published studies using this model have reported a range of median survival times, such as 41 days (O'Farrell et al, 2003), 51 days (Dorn et al, 2009; Lopes de Menezes et al, 2005; Ma et al, 2015), and 60 days (Hardwicke et al, 2009) after intravenous injection of MV4;11 cells into NOD-SCID mice. To summarize, for this experiment we found the survival results were not in the same direction as the original study and not statistically significant where predicted.10.7554/eLife.25306.008Figure 4.Efficacy study of I-BET151 in xenograft mouse model of MLL-fusion leukaemia.Female NOD-SCID mice were xenotransplanted with 1 × 10 7 MV4;11 cells after conditioning with Busulfan.…”
In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Fung et al., 2015), that described how we intended to replicate selected experiments from the paper "Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia" (Dawson et al., 2011). Here, we report the results of those experiments. We found treatment of MLL-fusion leukaemia cells (MV4;11 cell line) with the BET bromodomain inhibitor I-BET151 resulted in selective growth inhibition, whereas treatment of leukaemia cells harboring a different oncogenic driver (K-562 cell line) did not result in selective growth inhibition; this is similar to the findings reported in the original study (Figure 2A and Supplementary Figure 11A,B; Dawson et al., 2011). Further, I-BET151 resulted in a statistically significant decrease in BCL2 expression in MV4;11 cells, but not in K-562 cells; again this is similar to the findings reported in the original study (Figure 3D; Dawson et al., 2011). We did not find a statistically significant difference in survival when testing I-BET151 efficacy in a disseminated xenograft MLL mouse model, whereas the original study reported increased survival in I-BET151 treated mice compared to vehicle control (Figure 4B,D; Dawson et al., 2011). Differences between the original study and this replication attempt, such as different conditioning regimens and I-BET151 doses, are factors that might have influenced the outcome. We also found I-BET151 treatment resulted in a lower median disease burden compared to vehicle control in all tissues analyzed, similar to the example reported in the original study (Supplementary Figure 16A; Dawson et al., 2011). Finally, we report meta-analyses for each result.DOI:
http://dx.doi.org/10.7554/eLife.25306.001
“…Cell proliferation assays were carried out as previously reported. 36 A variety of human pancreatic cancer cell lines were seeded at an appropriate density in 96-well plates (1000-5000 cells per well) overnight. Then they were treated with indicated concentrations of LY-1816 or other agents.…”
Despite tremendous efforts, the clinical prognosis of pancreatic ductal adenocarcinoma (
PDAC
) remains disappointing. There is an urgent need to develop more effective treatment strategies to improve the prognosis of patients with
PDAC
. In this study, we evaluate the anti‐
PDAC
effects of
LY
‐1816, a new multikinase inhibitor developed by us. In in vitro assays,
LY
‐1816 showed significant inhibitory effects on the proliferation, migration, and invasion of human
PDAC
cells, and induced
PDAC
cell apoptosis. Western blot analysis revealed that
LY
‐1816 markedly suppressed the Src signaling, and downregulated the expression of
FOSL
1;
FOSL
1
is an oncogene vulnerability in
KRAS
‐driven pancreatic cancer. In in vivo models of
PDAC
xenografts (Aspc‐1 and Bxpc‐3),
LY
‐1816 showed more potent antitumor activity than dasatinib and gemcitabine. Moreover, mice treated with
LY
‐1816 showed a much more significant survival advantage in a metastatic model of
PDAC
compared with those treated with vehicle, dasatinib, or gemcitabine. These results provide effective support for the subsequent clinical evaluation of
LY
‐1816 in the treatment of
PDAC
.
“…8 Aberrant Wnt/β-catenin pathway activity has been demonstrated to be essential for AML initiation and progression and is required for LSC selfrenewal and survival. 9,10 Recent preclinical studies indicate that inhibiting the Wnt pathway is promising for AML treatment, 6,11 which implies that targeting the Wnt pathway may also eliminate the LSC population in AML.…”
Background: Canonical Wnt/β-catenin signaling is frequently dysregulated in acute myeloid leukemia (AML) and has been implicated in leukemogenesis. γ-catenin was previously demonstrated to be associated with the nuclear localization of β-catenin, the central mediator, and to exert oncogenic effects in AML; however, the underlying mechanisms remain unclear. Our study aimed to investigate the expression characteristics of γ-catenin in AML patients, explore the mechanisms by which γ-catenin regulates β-catenin, and discuss the feasibility of targeting γ-catenin for AML treatment. Methods: The mRNA expression levels of γ-catenin in AML patients were measured by qRT-PCR. Cell proliferation was examined via Cell Counting Kit-8 (CCK-8) assays. The expression levels of related proteins were measured via Western blotting. Specific siRNA was used to modulate the expression level of the γ-catenin gene. Apoptosis and cell cycle distribution were quantified by flow cytometry. The subcellular localization of γ-catenin and β-catenin was examined via immunofluorescence with a confocal laser scanning microscope. Results: Overexpression of γ-catenin was frequently observed in AML and correlated with poor prognosis. Consistent with this finding, suppression of γ-catenin in the AML cell line THP-1 induced growth inhibition, promoted apoptosis and blocked β-catenin nuclear translocation. Interestingly, γ-catenin knockdown sensitized THP-1 cells to cytotoxic chemotherapeutic agents such as cytarabine and homoharringtonine and further inhibited β-catenin nuclear localization. Moreover, our data implied the relationship between γ-catenin and GSK3β (whose effect on β-catenin is mediated by its own phosphorylation), which may be the principal mechanism underlying the anti-AML effect of γ-catenin inhibition. Conclusion: Taken together, our results revealed a potential role of γ-catenin in AML pathogenesis-mainly through the inhibition of GSK3β-mediated nuclear localization of β-catenin-and indicate that targeting γ-catenin might offer new AML treatments.
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