Cancer continues to drive the identification and development of new therapeutic strategies. LeadDiscovery has focussed on a number of these over recent months. Particularly exciting are the endogenous inhibitors of apoptosis (click here for more); histone deacetylase inhibitors (access our recent dossier on this field here); and the retinoids (click here for more). Oncolytic viruses represent a further approach to cancer with considerable potential. Although the cytotoxic effects of viruses are usually viewed in terms of pathogenicity, it is possible to harness this activity for therapeutic purposes. In particular, viral genomes are highly versatile, and can be modified to direct their cytotoxicity towards cancer cells. To our knowledge there are almost 20 such oncolytic virus-based therapeutics in development by the pharma/biotech sector. Although most of these are in preclinical development, therapies from Cell Genesys, Crusade, Medigene and Oncolytics are more advanced.

The use of replication-competent gene therapy viruses, which have a cytolytic cycle, has emerged as a viable strategy to specifically kill tumor cells and enhance adjuvant therapeutic gene transfer by viral spread throughout the tumor. The development of vectors whose replication is dependent upon microenvironmental constraints specific to tumor growth rather than cell-intrinsic gene expression profiles or genetic alterations would be particularly useful.

Hypoxia is an integral component of the tumor microenvironment that develops in most solid tumors regardless of their origin, location, or genetic alterations and arises from the rapid growth of the tumor relative to its vascular supply. Since hypoxia is a major factor in conferring resistance of cancer cells to radio- and chemo-therapies, selecting tumor clones of high malignancy, predisposing tumors to metastasis, the development of novel therapeutic strategies that can target hypoxic areas of tumors is important. Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that mediates responses to hypoxia by binding to a hypoxia-response element (HRE) present within target genes and the HIF/HRE system can therefore be utilized to specifically target therapeutic gene expression to tumors.

Recently Dawn Post and Erwin Van Meir from Emory University examined the potential use of this system to conditionally regulate the replication of an adenovirus, thereby creating a novel type of oncolytic therapy vector, hypoxia/HIF-dependent replicative adenovirus (HYPR-Ad), that targets cells with activated HIF, such as hypoxic cells. Dependency on hypoxia was brought about by reintroducing E1 genes (this is essential for replication) into a replication deficient virus. The E1A gene was under the regulation of a bi-directional hypoxia/HIF-responsive promotor; the E1B gene was restored with its endogenous regulatory elements. This HYPR-Ad was highly effective at causing cytolysis of human foreskin fibroblasts maintained under hypoxic but not normoxic conditions. In contrast a control virus lacking the hypoxia/HIF-responsive promotor was unable to target hypoxic cells, producing cytolysis independent of oxygen saturation. Consistent with this effect HYPR-Ad was able to effectively kill each member of a panel of brain tumor cells when exposed to hypoxia.

This study and the further development of oncolytic viruses such as HYPR-Ad has immense therapeutic potential not only against tumors that develop a hypoxic environment but also against cancer cells with active HIF under normoxic conditions. Such an approach may be expected to be useful in a wide range of tumors since unlike other therapies efficacy is relatively independent of tumor genotype. In addition cytolytic activity may be expected to be directed against tumor cells as well as adjacent cells which may be important since the neovasculature may be compromised limiting delivery.

Perhaps even more exciting is the possibility of developing HYPR-Ad-like viruses that deliver genes with antitumor properties. Such viruses may be expected to preferentially express such genes in hypoxic tumors conferring specificity. Furthermore if such genes were to inhibit angiogenesis, a situation of synergy may be expected.

Entry date Friday, June 27, 2003

Adapted from Post & Van Meir, Oncogene. 2003 Apr 10;22(14):2065-72

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