Chemoprevention by perillyl alcohol coupled with viral gene therapy reduces pancreatic cancer pathogenesis

Abstract

Pancreatic cancer is one of the deadliest of cancers. Even with aggressive therapy, the 5-year survival rate is <5%, mandating development of more effective treatments. Melanoma differentiation -associated gene-7/interleukin-24 (mda-7/IL-24) shows potent antitumor activity against most cancers displaying safety with significant clinical efficacy. However, pancreatic cancer cells display inherent resistance to mda-7/IL-24 that is the result of a ''protein translational block'' of mda-7/IL-24 mRNA in these tumor cells. We now show that a dietary supplement perillyl alcohol (POH) has significant chemopreventive effects for pancreatic cancer and, when coupled with adenovirus-mediated mda-7/IL-24 gene therapy (Ad.mda-7), effectively eliminates s.c. and i.p. xenografts of human pancreatic cancer cells in nude mice, promoting enhanced survival. The combination of POH and Ad.mda-7 efficiently abrogates the mda-7/IL-24 protein translational block, resulting in MDA-7/IL-24 protein production and growth suppression. Of direct translational relevance, clinically achievable concentrations of POH with Ad.mda-7, both of which have been found safe and without toxic effects in human trials, were used. This novel and innovative approach combining a dietary agent and a virally delivered therapeutic cytokine provides a means of both preventing and treating human pancreatic cancer with significant clinical translational potential.

Perillyl Alcohol for the Treatment of Temozolomide-Resistant Gliomas

“…POH has been shown to inhibit tumor growth in different solid tumor systems (11)(12)(13)(14)(15). As angiogenesis is a Cho et al…”

Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24

“…Recent studies by Lebedeva et al 88,89 showed that a combination of agents with complementary mechanisms of action proved more efficacious than administering a single agent in the therapy of pancreatic cancer. Perillyl alcohol (POH) is a naturally occurring nonnutritive dietary monoterpene and currently being tested in phase I and II clinical trials in patients with refractory solid malignancies.…”

“…94,95 In the majority of these experiments, animals were subjected to POH treatment after tumors developed. However, Lebedeva et al 88 showed that POH exhibited significant chemo-preventive effects in mice models of pancreatic cancer using human pancreatic adenocarcinoma cells. These studies used low doses of POH because high doses of POH that were effective in animal models induced extreme gastroenterotoxicity when applied in humans.…”

“…The safety of both POH and Ad.mda-7 has been confirmed by clinical trials and studies in animal models also revealed that this combination profoundly inhibited pancreatic cancer xenografts in nude mice. 88 These exciting observations pave the way for future clinical evaluation of POH and Ad.mda-7 combination therapy in the near future to determine if this approach has efficacy in patients…”

“…15 Those include (1) enhanced effectiveness of CTV adenoviruses in nude mice containing human melanoma, 100 breast, 78 colorectal 101 or therapy-resistant prostate 99 tumors in comparison with non-replicating adenoviruses Ad.mda-7, (2) augmentation of the antitumor properties of mda-7/IL-24 in combination with radiation, chemotherapy or monoclonal antibody therapy, 20,103 and (3) chemopreventive and enhanced antitumor effects of mda-7/IL-24 in combination with dietary agents that promote ROS production in pancreatic tumors. 88,89 Additionally, approaches that facilitate delivery of mda-7/IL-24 to the tumor microenvironment and tumor cells, including the use of stem cells and dendritic cells, offer promise for increasing therapeutic index of this novel cytokine. 15 All of these approaches merit future research efforts and will require further study to define ways of expanding the utility of mda-7/IL-24 as a cancer gene therapeutic.…”