Title:Chemoprevention Gene Therapy (CGT) of Pancreatic Cancer Using Perillyl Alcohol and a Novel Chimeric Serotype Cancer Terminator Virus
Volume: 14
Issue: 1
Author(s): S. Sarkar, B. Azab, B.A. Quinn, X. Shen, P. Dent, A.L. Klibanov, L. Emdad, S.K. Das, D. Sarkar and P.B. Fisher
Affiliation:
Keywords:
Cancer terminator virus expressing mda-7/IL-24 (CTV-M7), chemoprevention gene therapy (CGT),
endoplasmic reticulum stress (ER-stress), melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24),
microbubble (MB), pancreatic ductal adenocarcinoma (PDAC), perillyl alcohol (POH), ultrasound-targeted
microbubble-destruction (UTMD).
Abstract: Conditionally replication competent adenoviruses (Ads) that selectively replicate in cancer cells and
simultaneously express a therapeutic cytokine, such as melanoma differentiation associated gene-
7/Interleukin-24 (mda-7/IL-24), a Cancer Terminator Virus (CTV-M7), hold potential for treating human
cancers. To enhance the efficacy of the CTV-M7, we generated a chimeric Ad.5 and Ad.3 modified fiber
bipartite CTV (Ad.5/3-CTV-M7) that can infect tumor cells in a Coxsackie Adenovirus receptor (CAR)
independent manner, while retaining high infectivity in cancer cells containing high CAR. Although mda-7/IL-24
displays broad-spectrum anticancer properties, pancreatic ductal adenocarcinoma (PDAC) cells display an
intrinsic resistance to mda-7/IL-24-mediated killing due to an mda-7/IL-24 mRNA translational block. However,
using a chemoprevention gene therapy (CGT) approach with perillyl alcohol (POH) and a replication
incompetent Ad to deliver mda-7/IL-24 (Ad.mda-7) there is enhanced conversion of mda-7/IL-24 mRNA into
protein resulting in pancreatic cancer cell death in vitro and in vivo in nude mice containing human PDAC
xenografts. This combination synergistically induces mda-7/IL-24-mediated cancer-specific apoptosis by
inhibiting anti-apoptotic Bcl-xL and Bcl-2 protein expression and inducing an endoplasmic reticulum (ER) stress
response through induction of BiP/GRP-78, which is most evident in chimeric-modified non-replicating Ad.5/3-
mda-7- and CTV-M7-infected PDAC cells. Moreover, Ad.5/3-CTV-M7 in combination with POH sensitizes
therapy-resistant MIA PaCa-2 cell lines over-expressing either Bcl-2 or Bcl-xL to mda-7/IL-24-mediated
apoptosis. Ad.5/3-CTV-M7 plus POH also exerts a significant antitumor ‘bystander’ effect in vivo suppressing
both primary and distant site tumor growth, confirming therapeutic utility of Ad.5/3-CTV-M7 plus POH in PDAC
treatment, where all other current treatment strategies in clinical settings show minimal efficacy.
