In the US, like much of the developed world, cancer is the second most common cause of death after cardiovascular disease. Together between 1970 and 1994, Lung, Colon, Breast, Prostate and Pancreatic cancers claimed more than 5 million lives in the US alone. Considering these statistics and the often sub-optimal treatment options, it is unsurprising that anti-cancer drugs have received more attention from the pharmaceutical industry than any other drugs. Cancer is characterized by uncontrolled proliferation and in most cases reduced apoptosis. Despite the attractiveness of proapoptotic strategies and the level of research focussing on the development of such drugs clinical progress has been disappointing to date. Thus the search for effective targets continues. One such target is the sigma-2 receptor. Field-leading researchers at the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health and at Howard University have played a major role in establishing a proof of concept for the development of anti-cancer sigma-2 receptor agonists. Early data showed that a variety of neuroleptics were able to kill glioma cells and that the rank order potency suggested that this was mediated by sigma receptors. Later studies demonstrated the high density expression of sigma receptors by a wide variety of cancer cell lines and hence this group has developed high affinity radioligands for sigma receptors. These molecules showed potential for cancer imaging, however they may also represent lead radioimmunotherapeutics (Click here for our recent dossier "Targeted immunotherapy as an evolving strategy for the treatment of primary, residual and metastatic cancer"). The cytotoxic effects of sigma ligands were found to be mediated specifically by the sigma-2 receptor subtype. Further pharmacological assessment demonstrated that sigma-2 agonists were able to increase intracellular Ca2+ levels. This has been used as a strategy for inducing apoptosis in cancer cells (Click here for an overview of this target) and indeed one of the most recent publications from this group clearly demonstrated the therapeutic potential of sigma-2 receptor agonists. The sigma-2 subtype-selective agonists CB-64D and CB-184 produced dose-dependent cytotoxicity in antineoplastic sensitive and resistant breast cancer cells. This effect was independent of p53 genotype, caspase activation and drug-resistance phenotype. Cell death was shown to occur via apoptosis. Furthermore CB-184 was able to increase the sensitivity of cells to doxorubicin or actinomycin D, even if the cells displayed resistance to these standard chemotherapies in the absence of sigma-2 receptor stimulation. These findings suggest the involvement of a novel p53- and caspase-independent apoptotic pathway used by sigma-2 receptors, which is distinct from mechanisms used by some DNA-damaging, antineoplastic agents and other apoptotic stimuli. These observations further suggest that sigma-2 receptors may be targets that can be therapeutically exploited in the treatment of both drug-sensitive and drug-resistant metastatic tumors. This field represents a novel area of cancer therapeutics since none of the sigma receptor agonists currently in development are indicated as anticancer drugs. Collaboration with this group could therefore result in dramatic therapeutic and commercial results.

Safety and Immunogenicity of ALVAC vCP1452 and Recombinant gp160 in Newly Human Immunodeficiency Virus Type 1-Infected Patients Treated with Prolonged Highly Active Antiretroviral Therapy

Interested in collaborating with this group? Contact leaddiscovery@bioportfolio.co.uk