scholarly journals QLT0267, a small molecule inhibitor targeting integrin-linked kinase (ILK), and docetaxel can combine to produce synergistic interactions linked to enhanced cytotoxicity, reductions in P-AKT levels, altered F-actin architecture and improved treatment outcomes in an orthotopic breast cancer model

2009 ◽  
Vol 11 (3) ◽  
Author(s):  
Jessica Kalra ◽  
Corinna Warburton ◽  
Karen Fang ◽  
Lincoln Edwards ◽  
Tim Daynard ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Treatment Outcomes ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Cancer Model ◽  
Synergistic Interactions ◽  
Molecule Inhibitor ◽  
Breast Cancer Model ◽  
Integrin Linked Kinase

scholarly journals Combined administration of a small-molecule inhibitor of TRAF6 and Docetaxel reduces breast cancer skeletal metastasis and osteolysis

2020 ◽  
Vol 488 ◽  
pp. 27-39 ◽  
Author(s):  
Ryan T. Bishop ◽  
Silvia Marino ◽  
Giovana Carrasco ◽  
Boya Li ◽  
Richard J. Allen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Small Molecule ◽  
Skeletal Metastasis ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor ◽  
Combined Administration

QLT0267, a Small Molecule Inhibitor of ILK and FLT3 Is Cytotoxic to Acute Myeloid Leukemia (AML) ‘Stem Cells’ Detected in Immunodeficient Mice.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 950-950
Author(s):  
Andrew L Muranyi ◽  
Shoukat Dedhar ◽  
Donna E. Hogge
Keyword(s):  
Stem Cells ◽  
Small Molecule ◽  
Cell Cycle Progression ◽  
Small Molecule Inhibitor ◽  
Mouse Bone Marrow ◽  
Immunodeficient Mice ◽  
Akt Phosphorylation ◽  
Molecule Inhibitor ◽  
Integrin Linked Kinase

Abstract The phosphatidylinositol-3-kinase (PI-3K) and FMS-like tyrosine kinase 3 (FLT3) receptor signaling pathways are constitutively active in many AML blast samples suggesting these as therapeutic targets. Integrin linked kinase (ILK) is involved in Akt and GSK3 activation, key downstream effectors of the PI-3K pathway, and participates in the regulation of apoptosis, cell cycle progression, and tumour angiogenesis in many solid tumours. ILK is also expressed ubiquitously in AML blasts. In previous experiments to explore the effect of targeting ILK in AML, QLT0267, a small molecule inhibitor of ILK, was shown to be cytotoxic to AML blasts and colony forming cells (CFC) from some patient samples. Since AML samples containing the FLT3 internal-tandem duplication (ITD) were more susceptible to QLT0267-induced cell kill than FLT3 wildtype (WT) cells we tested the possibility that QLT0267 could inhibit FLT3 as well as ILK. In vitro kinase assays from 4 AML samples showed that QLT0267 produces equivalent inhibition of ILK and FLT3 (both WT and ITD) while Western blotting of 2 AML samples cultured with QLT0267 showed a dose and time dependant decrease in both FLT3 and Akt phosphorylation. 5 AML samples (4 FLT3-ITD, 1 FLT3 WT), were cultured for 24 h ± QLT0267, and assayed for AML CFC or 6-week suspension culture initiating cells (SC-IC). The mean percents kill for 20 and 50 μM QLT0267, respectively, were 92%, and 100% for AML-CFC and 71% and 92% for SC-IC. CD34+CD38− blasts (enriched for AML cells which engraft in immunodeficient mice) from these same samples were analyzed for expression of ILK, pGSK3, and FLT3. Intracellular staining detected ILK and pGSK3 protein in CD34+CD38− cells at levels similar to those present in other AML cell populations. QRT-PCR showed FLT-3 expression in CD34+CD38− cells from all 5 AML samples with 2 of these showing higher expression in this population than in the remainder of AML blasts. To determine if simultaneous targeting of ILK and FLT3 would kill AML progenitors that engraft in mice 4 AML samples (FLT3-ITD +) were cultured for 24 h ± QLT0267, and then injected IV into sublethally irradiated NOD/SCID or NOD/SCID IL2γRnull mice. As shown in the Table, treatment with 20 μM QLT0267 significantly reduced AML engraftment for 3 of 4 samples while the 50 μM dose was effective for 2 of the 3 samples tested (p<0.05, student t-test). Thus, combined targeting of ILK and FLT3 will kill AML cells, including candidate leukemic stem cells that sustain long-term engraftment in mice. Further preclinical evaluation of the potential therapeutic usefulness of this strategy is ongoing. QLT0267 (μM) 0 20 50 AML Sample % engraftment ± SD AML cells in mouse bone marrow
 Week 16 (n=) 1 86 ± 11
 (4) 53 ± 30
 (6) 2 ± 3
 (4) 2 46 ± 45
 (5) 3 ± 5
 (6) 0
 (2) 3 47 ± 40
 (5) 1 ± 2
 (4) 0
 (6) 4 90 ± 14
 (3) 1 ± 1
 (3) ND

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