Potent antitumor effect of tumor microenvironment‐targeted oncolytic adenovirus against desmoplastic pancreatic cancer

Abstract

Pancreatic cancer is a leading cause of cancer-related death. Desmoplastic pancreatic tumors exhibit excessive extracellular matrix (ECM) and are thus highly resistant to anticancer therapeutics, since the ECM restricts drug penetration and dispersion. Here, we designed and generated two hypoxia-responsive and cancer-specific hybrid promoters, H(mT)E and H(E)mT. Transgene expression driven by each hybrid promoter was markedly higher under hypoxic conditions than normoxic conditions. Moreover, H(E)mT-driven transgene expression was highly cancer-specific and was superior to that of H(mT)E-driven expression. A decorin-expressing oncolytic adenovirus (Ad; oH(E)mT-DCN) replicating under the control of the H(E)mT promoter induced more potent and highly cancer-specific cell death compared with its cognate control oncolytic Ad, which harbored the endogenous Ad E1A promoter. Moreover, oH(E)mT-DCN exhibited enhanced antitumor efficacy compared with both the clinically approved oncolytic Ad ONYX-015 and its cognate control oncolytic Ad lacking DCN. oH(E)mT-DCN treatment also attenuated the expression of major ECM components, such as collagen I/III, elastin and fibronectin and induced tumor cell apoptosis, leading to extensive viral dispersion within orthotopic pancreatic tumors and pancreatic cancer patient-derived tumor spheroids. Collectively, these findings demonstrate that oH(E)mT-DCN exhibits potent antitumor efficacy by degrading the ECM and inducing apoptosis in a multifunctional process. This process facilitates the dispersion and replication of oncolytic Ad, making it an attractive candidate for the treatment of aggressive and desmoplastic pancreatic cancer.Pancreatic cancer is the fourth leading cause of cancerrelated death in Europe and the United States.1 Only 10-20% of all patients with pancreatic cancer are resectable at presentation. The US National Cancer Institute recently reported that the overall 5-year relative survival rate for 2002-2008 was 5.8%, and nearly 90% of all patients were dead 1 year after diagnosis, with a median survival of <6 months. 2,3 One experimental treatment option of particular interest for pancreatic cancer is oncolytic virotherapy, which uses viral vectors to preferentially replicate in tumor cells and induce cancer cell death. Among the various viral vectors that have been tested, adenovirus (Ad) has been most extensively used in gene therapy applications, and sufficient data from randomized clinical trials support its safety in patients. 4-6Although oncolytic Ad-mediated cancer gene therapy is highly promising, significant therapeutic efficacy of oncolytic Ad for the treatment of localized tumors has not yet been achieved in clinical trials; thus, further improvements are needed. 7,8 Hypoperfusion and desmoplasia are two prominent features of pancreatic cancer that attenuate the therapeutic efficacy of cancer therapeutics.9 Aberrant extracellular matrix (ECM) functions as a protective layer that prevents drug penetration and diffusion into the pancreatic tumors, contributing t...

Decorin‐mediated oncosuppression – a potential future adjuvant therapy for human epithelial cancers

“…Additionally, decorin inhibited the expression and accumulation of ECM macromolecules such as collagen types I and III, elastin and fibronectin, thus attenuating the desmoplastic reaction surrounding pancreatic cancer cells (Li et al, ). This was demonstrated in both orthotopic pancreatic tumours as well as in pancreatic cancer patient‐derived tumour spheroids (Li et al, ). The use of 3D tumour spheroids provide an approach that mimics the tumour micro‐environment of the cancer including its ECM macromolecules and the cellular heterogeneity, more closely than animal models.…”

“…In desmoplasia, the tumour mass becomes surrounded by a dense fibrotic tissue rich in ECM macromolecules such as collagen, proteoglycans and hyaluronan. It is typically detected in different cancers, particularly in pancreatic cancer, where it can considerably hinder the targeting of therapeutic drugs to cancer cells (Li et al, ).…”

“…As mentioned above, TGF‐β is the first growth factor that was shown to be sequestered and its activity inhibited by decorin (Yamaguchi et al, ). Just recently, transduction of pancreatic cancer cells with oncolytic adenoviral decorin vector was shown to suppress the expression of TGF‐β resulting in suppression of growth of cancer cells and induction of their apoptosis (Li et al, ). Additionally, decorin inhibited the expression and accumulation of ECM macromolecules such as collagen types I and III, elastin and fibronectin, thus attenuating the desmoplastic reaction surrounding pancreatic cancer cells (Li et al, ).…”

“…Just recently, transduction of pancreatic cancer cells with oncolytic adenoviral decorin vector was shown to suppress the expression of TGF‐β resulting in suppression of growth of cancer cells and induction of their apoptosis (Li et al, ). Additionally, decorin inhibited the expression and accumulation of ECM macromolecules such as collagen types I and III, elastin and fibronectin, thus attenuating the desmoplastic reaction surrounding pancreatic cancer cells (Li et al, ). This was demonstrated in both orthotopic pancreatic tumours as well as in pancreatic cancer patient‐derived tumour spheroids (Li et al, ).…”

“…This is based on the nature of oncolytic viruses, as they replicate within cells and execute the lytic life cycle of viruses, resulting in cellular death. However, the use of oncolytic viruses can improve penetration and viral spread in the cancer tissue due to ECM disruption (Li et al, ). Tissue penetration can be problematic specifically in cancers like pancreatic cancer, where the cancer tissue is often surrounded by a pronounced accumulation of ECM macromolecules (Li et al, ).…”