Targeting cellular FLICE-like inhibitory protein as a novel approach to the treatment of Hodgkin’s lymphoma

Abstract

Hodgkin's lymphoma is one of the most common lymphoid cancers, particularly among young adults. Although there have been dramatic improvements in the treatment of Hodgkin's lymphoma, leading to high cure rates in some groups, current combination chemotherapy regimes are associated with significant secondary complications in long-term survivors. Furthermore, although a proportion of patients with Hodgkin's lymphoma will be cured, there still remains a significant rate of relapse and also a smaller proportion of poor responders who will go on to die of their disease. Therefore, developments in the treatment of Hodgkin's lymphoma must be directed at improving cure rates and reducing the burden of secondary complications. In recent years, the underlying pathogenesis of Hodgkin's lymphoma has become better understood. In particular, it is emerging that a key pathogenic event in Hodgkin's lymphoma is protection from Fas-induced cell death. Recent studies by the authors' group, and others, have demonstrated that this is, in part, due to the expression by Hodgkin/Reed-Sternberg cells of the cellular Fas-associated death domain-like IL-1 converting enzyme (FLICE)-like inhibitory protein molecule, a potent inhibitor of Fas-induced death. In this review, the role of cellular FLICE-like inhibitory protein in the pathogenesis of Hodgkin's lymphoma will be explored and also the possibility of targeting this molecule in order to provide an alternative and potentially safe approach to the treatment of Hodgkin's lymphoma will be investigated.

Contribution of the Epstein–Barr virus to the molecular pathogenesis of Hodgkin lymphoma

“…c-FLIP is a proximal negative regulator of CD95-induced apoptosis that interferes with the formation of the death inducing signalling complex (DISC) required for death receptor induced death. A number of studies have shown that c-FLIP is highly expressed in HL-derived cell lines and primary HRS cells 68 69 71 75. We showed that c-FLIP down-regulation was accompanied by the spontaneous death of HL cells, even in the absence of challenge with Fas agonistic antibody, CH11 76.…”

“…In vitro studies performed in our own laboratory and by others have demonstrated that HL-derived cell lines are resistant to Fas-mediated apoptosis 68 – 71. It is well established that HRS cells express Fas,70 72 73 and the rare occurrence of mutations in the FAS gene suggests that the general resistance of HRS cells to Fas-induced death is due to defects further downstream in the death receptor pathway 74 75.…”

Current Status of siRNA Delivery Technology and siRNA Drug Development

“…Many candidate genes for therapeutic use of siRNA in cancer were reported previously [3,102]. There are many gene mutations in cancer cells: Several single nucleotide mutant forms of p53 and ras are frequently mutated in human cancer and chromosomal translocation in leukaemia and lymphoma are well known [3,103,104]. Many gene products functionally associated with the growth and malignancy of cancers in vitro and in vivo, e.g.…”

Current Status of siRNA Delivery Technology and siRNA Drug Development

“…There are many gene mutations in cancer cells: Several single nucleotide mutant forms of p53 and ras are frequently mutated in human cancer and chromosomal translocation in leukaemia and lymphoma are well known [3,103,104]. Many gene products functionally associated with the growth and malignancy of cancers in vitro and in vivo, e.g.…”