Molecular target-based therapy of pancreatic cancer.
Pancreatic cancer is genetically complex, and without effective therapy. Mutations in the Kirsten-ras (K-ras) oncogene occur early and frequently (approximately 90%) during pancreatic cancer development and progression. In this context, K-ras represents a potential molecular target for the therapy of this highly aggressive cancer. We now show that a bipartite adenovirus expressing a novel cancer-specific apoptosis-inducing cytokine gene, mda-7/interleukin-24 (IL-24), and a K-ras AS gene, but not either gene alone, promotes growth suppression, induction of apoptosis, and suppression of tumor development mediated by K-ras mutant pancreatic cancer cells. Equally, the combination of an adenovirus expressing mda-7/IL-24 and pharmacologic and genetic agents simultaneously blocking K-ras or downstream extracellular regulated kinase 1/2 signaling also promotes similar inhibitory effects on the growth and survival of K-ras mutant pancreatic carcinoma cells. This activity correlates with the reversal of a translational block in mda-7/IL-24 mRNA in pancreatic cancer cells that limits message association with polysomes, thereby impeding translation into protein. Our study provides support for a "dual molecular targeted therapy" involving oncogene inhibition and selective cancer apoptosis-inducing gene expression with potential for effectively treating an invariably fatal cancer.
Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Irina V
IV
Lebedeva
Devanand
D
Sarkar
Zao-Zhong
ZZ
Su
Rahul V
RV
Gopalkrishnan
Mohammad
M
Athar
Aaron
A
Randolph
Kristoffer
K
Valerie
Paul
P
Dent
Paul B
PB
Fisher
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D011905:Genes, ras; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007378:Interleukins / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
D007378:Interleukins; D020928:Mitogen-Activated Protein Kinases; D012333:RNA, Messenger; D000099180:Interleukin-24