Title:Chemoprevention Gene Therapy (CGT): Novel Combinatorial Approach for Preventing and Treating Pancreatic Cancer
VOLUME: 13 ISSUE: 7
Author(s):S. Sarkar, B. M. Azab, S. K. Das, B. A. Quinn, X. Shen, R. Dash, L. Emdad, S. Thomas, S. Dasgupta, Z.-Z. Su, X.-Y. Wang, D. Sarkar and P. B. Fisher
Affiliation:Department of Human & Molecular Genetics, Virginia Commonwealth University, School of Medicine, 1101 East Marshall Street, Sanger Hall Building, Room 11- 015, Richmond, VA 23298-0033, USA.
Keywords:Cancer terminator virus (CTV), chemoprevention, conditionally replication-competent adenovirus
(CRCA), gene therapy, K-RAS, mda-7/IL-24, pancreatic ductal adenocarcinoma (PDAC).
Abstract:Pancreatic cancer remains one of the deadliest of all cancers despite aggressive surgical treatment
combined with adjuvant radiotherapy and chemotherapy. Chemoresistance and radioresistance are the
principal causes of failure of pancreatic cancer patients to respond to therapy. Conditionally replicationcompetent
adenovirus (CRCA)-based cancer gene therapy is an innovative strategy for treating cancers
displaying inherent resistance to treatment. Limitations of current adenovirus (Ad)-based gene therapies for
malignant tumors include lack of cancer-specificity, and effective and targeted delivery. To remedy this
situation, CRCAs have been designed that express E1A, necessary for Ad replication, under the control of a
cancer-specific progression elevated gene-3 promoter (PEG-Prom) with concomitant expression of an
immunomodulatory cytokine, such as mda-7/IL-24 or interferon-γ (IFN-γ), under the control of a ubiquitous and
strong cytomegalovirus promoter (CMV-Prom) from the E3 region. These bipartite CRCAs, when armed with a
transgene, are called cancer terminator viruses (CTVs), i.e., Ad.PEG-E1A-CMV-mda-7 (CTV-M7) and
Ad.PEG-E1A-CMV-IFN-γ (CTV-γ), because of their universal effectiveness in cancer treatment irrespective of
p53/pRb/p16 or other genetic alterations in tumor cells. In addition to their selective oncolytic effects in tumor
cells, the potent ‘bystander antitumor’ properties of MDA-7/IL-24 and IFN-γ embody the CTVs with expanded
treatment properties for both primary and distant cancers. Pancreatic cancer cells display a “translational
block” of mda-7/IL-24 mRNA, limiting production of MDA-7/IL-24 protein and cancer-specific apoptosis.
Specific chemopreventive agents abrogate this “translational block” resulting in pancreatic cancer-specific
killing. This novel chemoprevention gene therapy (CGT) strategy holds promise for both prevention and
treatment of pancreatic cancers where all other strategies have proven ineffective.
