Survivin-directed Anticancer Therapies – A Review of Pre-clinical Data and Early-phase Clinical Trials

European Oncology, 2010;6(1):10-4

Abstract:

Survivin, the smallest member of the inhibitor-of-apoptosis family, is a promising target for anticancer therapies. It plays key roles in apoptosis and the cell cycle, and has been shown to be upregulated in many cancer types while being minimally expressed in normal adult tissue. A number of survivin-directed anticancer therapies are currently in development, including transcriptional repressors, antisense oligonucleotides, hammerhead ribozymes, small interfering RNAs (siRNAs), dominant-negative mutants, small molecular inhibitors, cyclin-dependent kinase (CDK) inhibitors and immunotherapies. This article reviews the roles of survivin in mitosis and apoptosis, its regulation and the pre-clinical and clinical data on the emerging survivin-directed therapies.
Keywords: Survivin, apoptosis, cell cycle, inhibitor-of-apoptosis proteins, YM-155, EM-1421, antisense oligonucleotide, LY2181308, ribozyme, small interfering RNA, dominant negative mutant, Shepherdin, cyclin-dependent kinase inhibitor, clinical trials
Disclosure: Helen Doolittle and Armand Morel have no conflicts of interest to declare. Denis Talbot has in the past received an unrestricted grant from Lilly and honoraria for attending Lilly Oncology advisory boards; he has not received funding in relation to writing this article.
Received: February 15, 2010 Accepted March 16, 2010 Citation European Oncology, 2010;6(1):10-4
Correspondence: Denis Talbot, Oxford University Department of Medical Oncology, Cancer and Haematology Centre, Churchill Hospital, Oxford, OX3 7LJ, UK. E: denis.talbot@medonc.ox.ac.uk

New cancer treatments continue to move away from traditional cytotoxic chemotherapy to more specific and targeted therapies. One of the many striking examples of successful targeted therapy came from the identification of the bcr-abl fusion protein, the driving oncogenic force in chronic myeloid leukaemia (CML).1 Imatinib mesylate (Gleevec) was designed as a competitive inhibitor of the bcr-abl fusion protein,thus reversing the malignant CML phenotype. Although most other cancer types have more than one pathway involved, research is now focused on identifying critical up- or downregulated pathways andselectively targeting key molecules responsible for perpetuating the oncogenic state. One such promising target is survivin, a small 16.5kDa protein belonging to the inhibitor-of-apoptosis (IAP) family.2 Interest in survivin stems from its pattern of expression: it is upregulated in almost all tumour types while being minimally expressed in terminally differentiated tissues.3 Moreover, it plays a key role in both apoptosis and control of cell-cycle progression, and in tumours its expression is associated with poorer prognosis and increased treatment resistance.4 A number of strategies to inhibit survivin expression are being evaluated in the pre-clinical setting and some survivin-targeted therapies have now reached first-in-human trials. This article aims to review the role of survivin at a cellular and molecular level in normal and malignant tissues, the rationale for targeting the protein and the pre-clinical and early clinical data on survivin inhibitors.

Structure and Function of Survivin

The smallest member of the IAP family, survivin is composed of a single baculovirus IAP repeat (BIR) domain and an extended α-helical coiledcoil domain at the carboxy terminus5 (see Figure 1). It functions as a homodimer, requiring the BIR domain for dimerisation and recruitment of other proteins such as caspase 3, p21 and Cdk4.6 Differential splicing of the survivin gene pre-messenger RNA (mRNA) yields five distinct proteins: survivin (wild-type), survivin-ΔEx3, survivin-2β,7 survivin- 3β8 and survivin-2α.9 While wild-type survivin is often the predominant transcript, these survivin variants have been shown to have distinct functions and be of prognostic significance,10 e.g. delta Exon 3 and survivin-3β are cytoprotective,11 while survivin-2α and survivin-2β are pro-apoptotic.7 Delta Exon 3 has been associated with a poorer prognosis, higher stage or more aggressive disease in several tumour types,12,13 while low levels of survivin-2β correlate with high-stage gastric cancer10 and poorer prognosis in non-small-cell lung cancer (NSCLC).13

Role of Survivin in Apoptosis

Many studies have shown that survivin opposes both intrinsic and extrinsic mediators of apoptosis.4 Like most other IAPs, it acts upstream of effector caspases rather than through direct caspase inhibition.14 In the cytosol, survivin associates with hepatitis B X-interacting protein (HBXIP) and the complex binds to pro-caspase 9, preventing its recruitment and activation by the apoptosome.15 Another mechanism involves the sequestration of second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with low pI (Smac/DIABLO). Smac/DIABLO is a mitochondrial pro-apoptotic signal that binds X-linked IAP (XIAP), thereby preventing apoptosis inhibition. Survivin has been shown to prevent the release of Smac/DIABLO from the mitochondria, leaving XIAP free to inhibit caspase activity.16 Lastly, survivin can also bind directly to XIAP, stabilising it against degradation and resulting in inhibition of apoptosis.17

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Keywords: Survivin, apoptosis, cell cycle, inhibitor-of-apoptosis proteins, YM-155, EM-1421, antisense oligonucleotide, LY2181308, ribozyme, small interfering RNA, dominant negative mutant, Shepherdin, cyclin-dependent kinase inhibitor, clinical trials
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