Pancreatic ductal adenocarcinoma (PC) represents one of the most lethal and aggressive human malignancies and the fourth most common cause of cancer-related deaths in the US with 15% survival when the disease is organ confined, and only 4% when presenting with metastatic disease. In ~90% of PC, the K-ras oncogene is mutated. An obstacle to understanding the pathogenesis of this neoplasm has been the lack of suitable murine models that recapitulate the human condition. This impediment has now been diminished by the development of murine models that utilize a combination of targeted KrasG12D expression in the pancreas and Ink4a/Arf deficiency to develop pancreatic intraepithelial neoplasias (PanINs), which mimic the human disease, progressing rapidly to highly invasive and metastatic cancers. This model is ideally suited for designing and testing novel therapeutic/preventive approaches for this universally fatal human malignancy. We previously cloned melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), a novel member of the IL-10-related cytokine gene family with unique cancer-specific apoptosis-inducing properties. Recent Phase I/II clinical trials confirm its safety and efficacy in humans with advanced carcinomas and melanomas. Unexpectedly, ectopic expression of mda-7/IL-24 in PC cells is ineffective in inducing apoptosis because of a 'translational block'induced by K- ras that delimits association of mda-7/IL-24 mRNA with polysomes. When K-ras expression or its downstream MEK1/MEK2 pathway is inhibited or a reactive oxygen species (ROS) inducer is applied, mda-7/IL-24 mRNA is converted into protein and apoptosis is induced. Recent intriguing preliminary studies show that a dietary monoterpene, perillyl alcohol (POH), facilitates the apoptosis-promoting effects of mda- 7/IL-24 in PC cells. This study provides a first example of a synergistic interaction between a dietary agent and gene therapy in controlling the growth of an aggressive and currently untreatable cancer, such as PC. We currently plan to: i. Analyze the combinatorial effects of Ad.mda-7 and POH on the invasiveness and metastasis of a series of mutant and wild type K-ras PC cells;ii. Elucidate the molecular mechanisms of apoptosis-induction by Ad.mda-7 and POH;iii study the efficacy of mda-7/IL-24 and POH in inhibiting PC development and progression in transgenic PC animal models. We also are developing a compound transgenic mouse overexpressing mda-7/IL-24 in the pancreas to directly confirm that in situ generated mda-7/IL-24 will cooperate with POH in preventing PC development. The studies we propose will provide important information of direct relevance for future efforts designed to translate into patients an effective combination of dietary compounds with a novel cancer-specific apoptosis- inducing cytokine for the chemoprevention and potentially therapy of PC.

Public Health Relevance

Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a pleotrophic tumor suppressor molecule that exhibits the unique property of inducing apoptosis only in cancer cells. Dietary monoterpenes, such as perillyl alcohol (POH) also exhibit anti- tumor properties. The present proposal describes a combinatorial approach of a dietary agent (POH) and adenovirus-based gene therapy, expressing mda-7/IL-24, as chemopreventive and therapeutic regimens for one of the deadliest neoplasms, pancreatic cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA127641-04
Application #
8270513
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Ross, Sharon A
Project Start
2009-06-25
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$300,907
Indirect Cost
$99,632
Name
Virginia Commonwealth University
Department
Genetics
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Shapiro, Brian A; Vu, Ngoc T; Shultz, Michael D et al. (2016) Melanoma Differentiation-associated Gene 7/IL-24 Exerts Cytotoxic Effects by Altering the Alternative Splicing of Bcl-x Pre-mRNA via the SRC/PKCδ Signaling Axis. J Biol Chem 291:21669-21681
Bacolod, Manny D; Das, Swadesh K; Sokhi, Upneet K et al. (2015) Examination of Epigenetic and other Molecular Factors Associated with mda-9/Syntenin Dysregulation in Cancer Through Integrated Analyses of Public Genomic Datasets. Adv Cancer Res 127:49-121
Talukdar, Sarmistha; Emdad, Luni; Das, Swadesh K et al. (2015) Noninvasive approaches for detecting and monitoring bladder cancer. Expert Rev Anticancer Ther 15:283-94
Sarkar, Siddik; Quinn, Bridget A; Shen, Xuening et al. (2015) Reversing translational suppression and induction of toxicity in pancreatic cancer cells using a chemoprevention gene therapy approach. Mol Pharmacol 87:286-95
Das, Swadesh K; Menezes, Mitchell E; Bhatia, Shilpa et al. (2015) Gene Therapies for Cancer: Strategies, Challenges and Successes. J Cell Physiol 230:259-71
Quinn, Bridget A; Dash, Rupesh; Sarkar, Siddik et al. (2015) Pancreatic Cancer Combination Therapy Using a BH3 Mimetic and a Synthetic Tetracycline. Cancer Res 75:2305-15
Sarkar, S; Azab, B; Quinn, B A et al. (2014) Chemoprevention gene therapy (CGT) of pancreatic cancer using perillyl alcohol and a novel chimeric serotype cancer terminator virus. Curr Mol Med 14:125-40
Dash, Rupesh; Bhoopathi, Praveen; Das, Swadesh K et al. (2014) Novel mechanism of MDA-7/IL-24 cancer-specific apoptosis through SARI induction. Cancer Res 74:563-74
Bhoopathi, Praveen; Quinn, Bridget A; Gui, Qin et al. (2014) Pancreatic cancer-specific cell death induced in vivo by cytoplasmic-delivered polyinosine-polycytidylic acid. Cancer Res 74:6224-35
Azab, Belal M; Dash, Rupesh; Das, Swadesh K et al. (2014) Enhanced prostate cancer gene transfer and therapy using a novel serotype chimera cancer terminator virus (Ad.5/3-CTV). J Cell Physiol 229:34-43

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