Survivin-directed Anticancer Therapies – Pre-clinical Data and Early-phase Clinical Trials
in vivo experiments demonstrated that survivin C84A reduced both tumour growth and angiogenesis, as well as enhancing the effects of 5-fluorouracil.64
Due to the survivin protein’s need for Hsp90 for
stability, the peptidomimetic Shepherdin was developed to disrupt this interaction by interacting with the ATP-binding pocket on Hsp90. Early in vitro experiments showed that Shepherdin induces cell death within tumour cells, while sparing normal cells.65
In both breast cancer
and acute myeloid leukaemia (AML) mouse xenograft models, Shepherdin was well-tolerated and inhibited tumour growth.65,66
After
it was shown that Shepherdin residues 79–83 were essential for Hsp90 binding, a five-residue peptide called Shepherdin[79–83] with this same sequence was synthesised. Studies in AML cell lines showed rapid and complete killing of AML cell types and myeloblasts, but no effect of Shepherdin[79–83] on normal mononuclear cells.65 The non-peptidic small molecule 5-aminoimidazole-4-carboxamide-1- beta-D-ribofuranoside (AICAR) is another inhibitor of Hsp90. It mimics Shepherdin, binding the Hsp90 N-terminal domain. It has been shown to exert antiproliferative and proapoptotic activity in multiple tumour cell lines while having no effect on normal human fibroblasts.67
Cyclin-dependent kinase (CDK) inhibitors mediate their antitumour effects in part through their actions on survivin. Inhibition of p34cdc2- cyclin B1 prevents phosphorylation of survivin (Thr34), thereby reducing protein stability. In human hepatocellular carcinoma cells, flavopiridol was shown to increase TRAIL-induced apoptosis by upregulation of TRAIL receptors and downregulation of survivin.68 Purvalanol A, another CDK inhibitor, was also shown to induce apoptosis by inhibiting the JAK/Stat-3 pathway in MKN45 cells.69
A
novel CDK inhibitor, NU6140, was shown to induce cell-cycle arrest and increase apoptosis in a concentration-dependent manner. Moreover, a significant synergistic effect was observed when combining NU6140 and paclitaxel in HeLa cervical carcinoma cells.70
Targeting the Survivin Promoter
The high level of survivin expression in tumour cells has led to the idea of using the survivin promoter to drive expression of therapeutic genes, an approach still in early pre-clinical development. In 2005 Kamizono et al.71
reported having constructed a survivin-responsive
conditionally replicating adenovirus (Surv.CRA), in which expression of the early region 1A (E1A) gene was regulated by the survivin promoter. Another group modified the mifepristone/RU486-regulated system to express a dominant-negative mutant of survivin (surDN) in colorectal tumour cells.72
Sher et al.73 constructed a plasmid
containing a Bcl2 interacting killer (Bik) mutant gene, BikDD, whose expression was driven by the survivin promoter and resulted in selective killing of lung cancer cells both in vitro and in vivo.
Immunotherapy
A number of research groups have tested survivin-directed immunological approaches in pre-clinical models. For example, a survivin DNA vaccine was evaluated in murine pancreatic and lymphoma models, and was found to significantly slow tumour growth and prolong survival through increased lymphocyte infiltration at the tumour sites.74
In an NSCLC mouse model, oral delivery of a DNA vaccine
triggered activation of antigen-presenting dendritic cells (DCs) and a cytotoxic T-lymphocyte (CTL) response, which resulted in elimination or suppression of pulmonary metastases.75
Another group developed a
novel mimovirus vaccine, consisting of a cationic peptide containing a survivin CTL epitope and a plasmid encoding the murine IL-15 gene. The mimovirus was shown to inhibit tumour growth and prolong life in a
EUROPEAN ONCOLOGY
Another technique involves inducing survivin-specific CTLs with DCs. One group transduced DCs with the survivin gene via an adenoviral vector, and used these to induce CTLs with cytotoxic activity in urological cancer cell lines.81
In a phase I trial, a vaccination consisting of
DCs loaded with five different HLA-A*0201-restricted peptides derived from prostate-cancer-associated antigens including survivin was evaluated. Of the eight patients with hormone-refractory prostate cancer treated, there was one PR and three patients had stable prostate-specific antigen (PSA) values or decelerated PSA increases. No side effects were noted other than local skin reactions.82
Conclusions
Because of its critical mitotic and anti-apoptotic roles, as well as its high levels of expression in many types of cancer, survivin is an excellent therapeutic target. A wide variety of strategies have been employed to reduce survivin activity, and strong pre-clinical data have led to early-phase clinical trials, which have thus far not reported any significant toxicities. The exact extent of the antitumour effect of these different strategies will become clear as data from phase II and III trials become available. If efficacy is demonstrated, survivin-directed therapies could be incorporated into a broad spectrum of oncological practice either as single agents or, more likely, in combination with existing chemotherapeutics, particularly those that exert their effects through apoptosis. Additionally, tumour survivin expression and change following therapy have the potential for use as predictive biomarkers to identify those patients most likely to benefit. n
Helen Doolittle is a Researcher for the North West Thames Academic Foundation Programme at Hammersmith Hospital, Imperial College, London, where she has recently undertaken a research project into multiple myeloma. She graduated from Oxford University with degrees in medical sciences (first class) and in medicine and surgery (distinction). It was here that she first developed her interest in oncology at both the basic science and the translational research level.
Armand Morel is a Clinical Research Assistant in the Oxford Lung Cancer Group at the Churchill Hospital, University of Oxford. His research focuses on molecularly targeted agents as well as other chemotherapy regimens. He has completed two years towards a medical degree at The University of Texas Health Science Centre Medical School in Houston.
mouse model.76
vaccinations have been used in colorectal cancers,77 and breast cancers,79
Survivin vaccines are now moving into the clinic. Peptide urothelial cancers78
all of which have been well tolerated. In one case
report, a patient with refractory pancreatic cancer achieved complete remission for eight months after receiving peptide vaccinations consisting of a modified HLA-A2 restricted survivin (96–104) epitope.80
Denis Talbot is a Consultant Medical Oncologist and Reader in Cancer Medicine at the University of Oxford. He leads the Oxford Cancer Centre neuroendocrine tumour and thoracic oncology research groups. His research focuses on proof of concept of mechanism of molecularly targeted agents directed against cell-cycle regulatory proteins and DNA repair. He is a member of the UK Specialist Advisory Committee for Medical Oncology, the Leukaemia Research Scientific Advisory
Board, the Cancer Research UK New Agents Committee and the Clinician Scientist Advisory Board. After graduating in biochemistry he completed a PhD in pharmacology before studying medicine at the University of Cambridge.
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