Identifying novel strategies to re-engage the apoptotic pathway for the treatment of cancer
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In chapter two we demonstrate that in non-transformed cells multiple signalling pathways control TRAIL resistance and they act in a redundant manner. This is contrary, however, to the resistance mechanisms found in tumour cell types, which tend to rely on a single mechanism of resistance. Furthermore, inhibition or knockdown of the single overexpressed protein in a panel of tumour cells was sufficient to trigger TRAIL sensitivity. Therefore, the redundancy in resistance pathways in non-transformed cells may offer a safe therapeutic window for TRAIL-based combination therapies where selective sensitisation of the tumour to TRAIL can be achieved by targeting the single non-redundant resistance pathway. In chapter three we aimed to examine the role of TRAIL receptor-induced NF-kappaB activation driving TRAIL resistance. These efforts centred on the association of the adaptor proteins TRADD and TRAF2. In order to restore TRAIL sensitivity and overcome TRAIL resistance, the design of a molecular blocker which prevents the recruitment of the adaptor TRAF2 to TRADD was tested for its ability to uncouple DR4/DR5 mediated NF-kappaB activation and restore apoptotic signalling. Alongside this, the role of TRAF2 in TRAIL-induced NF-kappaB activation was examined through the generation of specific TRAF2 mutants deficient for either TRADD or cIAP1/cIAP2 binding in tumour cells. In chapter four we examine the role of the tumour microenvironment in AML treatment response. Using the bone marrow derived human cell line HS5; we examined the effects of stromal co-culture on drug responsiveness in both established AML tumour cell lines, and primary patient AML. We confirm that co-culture of AML cell lines with stromal HS5 cells induced expression of anti-apoptotic Bcl-2 family members, and resulted in marked resistance to single treatment with ABT-737 and cytarabine in AML cell lines and primary AML. Using a combination strategy we found that ABT-737 potently synergizes with the Cdc7/Cdk9 inhibitor PHA-767491 via transcriptional inhibition of Mcl-1 in Oci-AML3 cells. This combination also proved effective in primary AML, with both the whole cell population sensitised to cell death, and more importantly the leukemic stem cell (LSC) population.
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