Survivin-directed Anticancer Therapies – Pre-clinical Data and Early-phase Clinical Trials
Role of Survivin in the Cell Cycle
Survivin is involved with all stages of the cell cycle from spindle formation to chromosome separation and cytokinesis. It functions, in part, as a member of the chromosomal passenger complex (CPC).18 In addition to survivin, the CPC comprises Aurora kinase B (AURKB) and borealin and inner centromere protein (INCENP), and has a major role in several aspects of cell-cycle control including spindle formation, kinetochore-microtubule attachments, the spindle checkpoint and cytokinesis.18,19
Survivin targets the CPC to various locations during cell
division by means of its different domains. Survivin’s BIR domain localises the CPC to the centromeres, whereas its C-terminus domain localises it to the central spindle and mid-body.19
At the spindle
checkpoint, survivin plays a key role as part of the CPC in retaining the anaphase-promoting complex/cyclosome (APC/C) inhibitor BubR1 at the kinetochores until correct microtubule attachments have been achieved.20
Survivin also operates independently of the CPC. It binds
directly to microtubules in metaphase and anaphase, and is involved in regulation of microtubule dynamics.21
Regulation of Survivin
The survivin gene is regulated by a number of transcription factors including E2F, Sp1, β-catenin, activated T-cell factor (TCF), signal transducer and activator of transcription (Stat)-3, hypoxia-inducible factor-1 alpha (HIF-1α), and heat shock protein (Hsp) 90.22
Factors
upstream also play an important regulatory role. One study found that in normal melanocytes, p53 and retinoblastoma (Rb) are required to repress survivin transcription, with Rb exerting its effects through E2F and p53 repressing Sp1-mediated expression.23
Post-translational
modifications also play an important regulatory role. Phosphorylation of Thr34 by p34cdc2-cyclin B1 slows down survivin clearance by the proteasome.22
cell-cycle activities, while phosphorylation of Ser20 (by protein kinase A [PKA]) facilitates the interaction of survivin with XIAP.24,25
Several sites of
ubiquitination have also been identified and these include Lys23, Lys62, Lys78 and Lys79.26
survivin, necessary to prevent proteasomal degradation.27
Survivin and Cancer
Survivin is almost undetectable in most adult tissues, and expression is largely limited to developing embryos and haematopoietic, epithelial and gonadal cell lines, where expression is often cell-cycle-dependent.3 However, survivin over-expression has been reported in nearly all human malignancies.14
In most cases, this results from non-cell-cycle-
dependent mechanisms driving survivin gene transcription. Three key intracellular pathways converge on the survivin promoter: the phosphatidylinositide 3,4,5-triphosphate kinase (PI3k)/Akt pathway,28 the Janus kinase (JAK)/Stat-3 pathway29 pathway.30
and the TCF/β-catenin
The upregulation of these pathways is either in response to growth factors such as epidermal growth factor (EGF),31
6 or granulocyte-macrophage colony-stimulating factor (GM-CSF),32 p53,34
interleukin (IL)- or
through downregulation of tumour suppressors such as adenomatous polyposis coli (APC),33
and fragile histidine triad gene (FHIT).36
promyelocytic leukaemia protein (PML)-435 In fact, all of the best
characterised tumour suppressor networks, such as p53, target the survivin gene, thus underscoring survivin’s importance in malignancy.37
Methods of Targeting Survivin and Pre-clinical Results
By knocking out survivin, multiple networks of cell proliferation and cytoprotection can be simultaneously disrupted. Direct survivin
EUROPEAN ONCOLOGY
Transcriptional Inhibition
Small molecule transcriptional repressors have been developed. These include YM-155 and EM-1421 (tetra-O-methyl nordihydro-guaiaretic acid, terameprocol). YM-155 is an imidazolium-based molecule that inhibits survivin gene transcription through promoter binding, with consequent pro-apoptotic and antitumour effects on prostate cancer models.38
tolerated,39,40
Phase I trials have demonstrated that YM-155 is well and a phase II trial in 37 patients with previously treated
advanced NSCLC reported two (5%, 95% confidence interval [CI] 1–18%) partial responses (PRs) and 14 (38%) patients achieving stable disease (SD), resulting in a disease control rate of 43% (95% CI 27–61%). Median duration of progression-free survival (PFS) was 1.7 months (95% CI 1.3 to 2.8 months), and median duration of overall survival (OS) was 6.6 months (95% CI 4–12.2 months). Treatment was well-tolerated.41
However, another phase II study in 34 chemotherapy-
naïve patients with unresectable stage III or IV melanoma reported only one PR, thus failing to meet its pre-specified primary end-point for
11
Finally, Hsp90 acts as an important chaperone for
Protein degradation Amino acids
Phosphorylation of Thr117 (by AURKB) regulates survivin’s
Dimer interface 6–10
Dimer interface 89–102
Figure 1: Survivin Protein Structure and Function
PKA
P
Ser20
p34cdc
2-cyclin B1
P
Thr34 15-89 BIR domain
P
Thr117
100–140 Coiled-coil domain AURKB
Functions:
• Inhibition of apoptosis • Recruitment of other proteins • Localisation of CPC to centrometres
Functions: • Microtuble binding
• Localisation of CPC to central spindle and mid-body
This figure shows survivin’s functional domains, phosphorylation sites and sites of dimer interface. AURKB = Aurora kinase B; BIR = baculovirus inhibitor of apoptosis repeat; CPC = chromosomal passenger complex; PKA = protein kinase A.
Figure 2: Inhibition Strategies Targeting Survivin
Survivin gene Transcription Survivin mRNA Translation Survivin protein
Promoter-dependent vectors: Surv.CRA, surDN, BikDD
Small molecules: YM-155, EM-1421
Antisense oligonucleotides: LY2181308, SPC-3042
Hammerhead ribozyme siRNA
Dominant negative mutants: T34A, C84A, surDN
Hsp90 inhibitors: Shepherdin, Shepherdin[79–83], AICAR
CDK inhibitors: flavopiridol, purvalanol A, NU6140
CDK = cyclin-dependent kinase; Hsp90 = heat shock protein 90.
inhibition has been investigated at several levels: gene transcription, translation and protein degradation. Additionally, gene therapies and immunotherapies are in development (see Figure 2 and Table 1).
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