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RAD001 (everolimus) improves the efficacy of replicating adenoviruses that target colon cancer
Krisztian Homicsko1, Alexander Lukashev, Richard D Iggo
1National Center of Competence in Research Molecular Oncology, Swiss Institute for Experimental Cancer Research (ISREC), Epalinges, Switzerland.
Abstract:
Selectively replicating adenoviruses have the potential to cure cancer but have shown little efficacy in clinical trials. We have tested the ability of the mTOR kinase inhibitor RAD001 (everolimus) to enhance the response of xenografts to an oncolytic adenovirus. The virus has Tcf sites inserted in the early viral promoters and replicates selectively in cells with activation of the Wnt signaling pathway. To enhance tumor cell infection, an integrin targeting peptide (CDCRGDCFC) was inserted into the fiber gene of the virus. RAD001 combines three useful properties: it inhibits tumor cell growth directly, blocks angiogenesis, and suppresses the immune response. RAD001 does not block viral protein expression, DNA replication, or cytopathic effect in tumor cells in vitro. After 6 weeks of daily RAD001 treatment, ongoing viral DNA replication could be detected in tumor xenografts, showing that RAD001 does not inhibit virus replication in vivo. I.v. injection of virus alone produced a small delay in xenograft growth, whereas combination therapy substantially prolonged the survival of the mice. We suggest that collapsing the tumor vasculature after the initial infection traps the virus and facilitates local spread within the tumor. Unlike conventional drugs, which require continued access to the tumor through the vascular system, oncolytic viruses are in principle less sensitive to late reductions in perfusion because they are produced locally within the tumor.
Insights
Combining an oncolytic adenovirus with RAD001 (everolimus) significantly improved cancer treatment in mice. This combination therapy enhanced viral replication and prolonged survival, offering a promising new strategy for cancer therapy.
Area of Science:
- Oncology
- Virology
- Pharmacology
Background:
- Selectively replicating adenoviruses show potential for cancer treatment but have limited clinical efficacy.
- The mTOR kinase inhibitor RAD001 (everolimus) has direct anti-tumor effects, inhibits angiogenesis, and suppresses immune responses.
Purpose of the Study:
- To evaluate the efficacy of combining an oncolytic adenovirus with RAD001 in enhancing cancer xenograft response.
- To assess the impact of RAD001 on viral replication and anti-tumor activity in vivo.
Main Methods:
- Developed a modified oncolytic adenovirus with Tcf sites for Wnt pathway-selective replication and an integrin-targeting peptide for enhanced infection.
- Administered daily RAD001 treatment to tumor xenografts in mice.
- Assessed viral DNA replication, tumor growth, and survival rates in treated and control groups.
Main Results:
- RAD001 did not inhibit viral protein expression, DNA replication, or cytopathic effects in tumor cells in vitro.
- Ongoing viral DNA replication was detected in tumor xenografts after 6 weeks of RAD001 treatment.
- Combination therapy substantially prolonged mouse survival compared to virus injection alone.
Conclusions:
- The combination of RAD001 and an oncolytic adenovirus is a potent anti-cancer strategy.
- RAD001 enhances the efficacy of oncolytic adenoviruses by supporting viral replication within tumors.
- The study suggests that oncolytic viruses, when combined with RAD001, can overcome limitations of conventional cancer therapies.
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