Development of oncolytic adenoviruses for targeting of androgen-independent prostate cancers: enhancement of anti-tumour efficacy by combination therapies.
Gunnel Halldén, Queen Mary, University of London

Prostate cancer is a major cause of death in men. In early stages, progression can be prevented by hormone-deprivation, cytotoxic drugs and radiation therapies but later almost all cancers develop hormone-independent growth, refractory to hormone-ablation therapies. These late-stage hormone-refractory prostate cancers also become resistant to all current therapies.

Dr Gunnel Hallden at Barts

Therefore, no effective treatment is currently available for this patient group and new therapies are needed. Adenoviruses can be engineered to specifically target cancer cells and are developed as anti-tumour agents. Several engineered viruses (mutants) have been constructed that can efficiently kill tumour cells while leaving normal cells unharmed. Data from numerous clinical trials are promising, demonstrating no cross-resistance with other therapies and limited toxicity.

The aim of our research is to develop more potent viruses that are capable of selectively multiplying in prostate cancer cells to destroy tumour masses by a burst of viral replication with minimal toxicity in normal cells. Various modifications of the viral genome will be made including deletions and insertions of cytotoxic genes and regulatory elements. Genes essential for viral replication in normal cells and genes responsible for defence against the host immune response as well as genes coding for cytotoxic agents will be evaluated in combination with drugs used in the clinic. In addition, we are targeting the interactions of cellular regulatory proteins with the androgen receptor to inhibit receptor function and suppress tumour cell growth. The androgen receptor is often overactive in late-stage prostate cancers and specific protein sequences that inhibit receptor activity can be identified and inserted into our mutant viruses. The most promising prostate-cancer specific adenoviral mutants will be extensively evaluated in cells in culture and in vivo models. Special attention will be on conditions for synergistic (more than additive) interactions with standard chemotherapy.

The overall goal of our research is to develop potent anti-cancer viral mutants that specifically target late-stage refractory prostate cancers that can be evaluated in clinical trials for potential future therapeutic applications. Similar oncolytic viral mutants have already been demonstrated to be safe, have low toxicity and do not develop cross-resistance with standard cancer therapies.

Project commenced
March 2006

Length of project
3 years

Amount Supported
£96,000