The cytosolic protein, XIAP, is the major endogenous inhibitor of the caspase family of proteases involved in the execution phase of apoptosis. XIAP can antagonise the action of a number of different pro-apoptotic triggers including the therapeutic modalities of cytotoxic drugs and ionising radiation and its over-expression in Hodgkin's Lymphoma has been shown to be primarily responsible for the inability this tumour type to activate programmed cell death. The protein is now known to be over-expressed in a number of different tumours relative to normal tissue, reflecting possibly a more widespread role in many cancers in the inhibition of apoptosis and maintenance of the intrinsic drug resistance phenotype, and thus targeting XIAP represents a novel therapeutic strategy for rational anticancer drug design. Studies with knockout mice have shown that the absence of XIAP does not significantly affect the development of normal tissues and suggest that anti-sense knock down of XIAP would not have widespread toxicity to normal tissues. However, antisense knockdown of the XIAP protein in a non-small cell lung cancer (NSCLC) xenograft (H460) produced significant anti-tumour activity. In view of these and other favourable preclinical data, antisense knockdown of XIAP was accepted for multi-centre Phase I clinical evaluation in the United Kingdom, in a CRUK sponsored trial (NAC02/03, Cancer Research UK, 2002) with DCU as the lead centre. CEP is involved in the development and implementation of validated pharmacodynamic (PD) endpoint assays. These assays help to determine the biological efficacy of the antisense treatment in the target tissue - the patients tumour. Studies undertaken this year include measurement of M65 and M30 and Nucleosomal DNA (indicators of apoptosis) and other types of cell death.
Immunohistochemistry measurements of active caspase 3 and cleaved PARP have been also undertaken on available pre and post biopsies. The initial 7 day infusion study was extended to include a 3 day infusion protocol. Currently both the 3 and 7 day trials have finished. Results from these studies were sufficiently encouraging to prompt a third protocol exploring a 2hr infusion. This study is currently still ongoing. Data from both the 7 day and 3 day studies is currently being compiled and reported. CEP is also evaluating combinations of conventional anti-cancer drugs with those targeted at IAPs in vitro and in vivo.