Elevated temperature enhances success of viral cancer therapy

July 18, 2005

A therapeutic approach for battling cancer that is based on infection with a specially designed virus similar to the one that causes the common cold has shown promise in clinical trials. Now, new research suggests that fever might be a useful weapon in the fight as well. The study, published in the July issue of Cancer Cell, demonstrates that tumor cells are even more sensitive to viral therapy after they have been incubated at an elevated temperature. The findings could have a significant impact on the future success of viral strategies for cancer therapy.

ONYX-015 is a mutated adenovirus that undergoes selective replication in tumor cells until the cells become so full of virus that they burst and die. The virus is modified so that it only copies itself in tumor cells and is safe for normal cells. In clinical trials, ONYX-015 was a successful therapy for many cancer patients, but the success varied considerably for reasons that were not well understood. Dr. Clodagh C. O'Shea and colleagues from the Cancer Research Institute at the University of California, San Francisco examined why ONYX-015 did not undergo replication in some cancer cells and if it might be possible to sensitize tumor cells to ONYX-015 therapy.

The researchers demonstrated that resistant tumor cells fail to complete an RNA export function that is necessary for ONYX-015 replication. Interestingly, when a cellular heat shock response was induced in the resistant tumor cells, either pharmacologically or by incubating the cells at an elevated temperature similar to that experienced by humans when they have a fever, the RNA export function was restored. Therefore, induction of the heat shock response could rescue ONYX-015 replication in resistant tumor cells.

According to Dr. O'Shea, "Our data suggest that a clinical strategy that does not advocate the use of pharmacological agents to suppress fever would favor the tumor-selective replication of ONYX-015. This study indicates that induction of a heat shock response by pharmacological agents (that could potentially be administered systemically) or local hyperthermia, could greatly augment and broaden ONYX-015's clinical utility as a cancer therapy."
-end-
The researchers include Clodagh C. O'Shea, Conrado Soria, Bridget Bagus, and Frank McCormick of the Cancer Research Institute at University of California, San Francisco. This work was supported, in part, by UC Discovery grant bio-02-10242. F.M. is a shareholder in ONYX Pharmaceuticals.

Clodagh C. O'Shea, Conrado Soria, Bridget Bagus, and Frank McCormick: "Heat shock phenocopies E1B-55K late functions and selectively sensitizes refractory tumor cells to ONYX-015 oncolytic viral therapy" Publishing in Cancer Cell, Vol. 8, July 2005, pages 61-74 . DOI 10.1016/j.ccr.2005.06.009 www.cancercell.org

Cell Press

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