A novel translational approach for human malignant pleural mesothelioma: heparanase-assisted dual virotherapy

Abstract

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that is related to asbestos exposure. MPM is characterized by rapid and diffuse local growth in the thoracic cavity, and it has a poor prognosis because it is often refractory to conventional therapy. Although MPM is an extraordinarily challenging disease to treat, locoregional virotherapy may be useful against this aggressive disease because of the accessibility by intrapleural virus delivery. In this study, we show that telomerasespecific, replication-selective adenovirus OBP-301 can efficiently infect and kill human mesothelioma cells by viral replication. Intrathoracic administration of virus significantly reduced the number and size of human mesothelioma tumors intrathoracically implanted into nu/nu mice. A high-definition, fluorescence optical imaging system with an ultra-thin, flexible fibered microprobe clearly detected intracellular replication of green fluorescent protein-expressing oncolytic virus in intrathoracically established mesothelioma tumors. As the extracellular matrix (ECM) may contribute to the physiological resistance of a solid tumor by preventing the penetration of therapeutic agents (including oncolytic viruses), we also examined whether the co-expression of heparanase, an endoglucuronidase capable of specifically degrading heparan sulfate, that influences the physiological barrier to macromolecule penetration, can modify the permeability of the ECM, resulting in profound therapeutic efficacy. Co-injection of OBP-301 and a replication-defective adenovirus (Ad-S/hep)-expressing heparanase resulted in more profound antitumor effects without apparent toxicity in an orthotopic pleural dissemination model. Our results suggest that intrathoracic dual virotherapy with telomerase-specific oncolytic adenovirus in combination with heparanase-expressing adenovirus may be efficacious in the prevention and treatment of pleural dissemination of human malignant mesothelioma.

Strategies to Enhance Viral Penetration of Solid Tumors

“…When tested in highly metastatic tumor models neither relaxin-induced MMP expression nor expression of heparanase, hyaluronidase, or decorin increased metastasis. On the contrary, coadministration or expression of these enzymes with oncolytic virus reduced metastasis in the models tested Ganesh et al, 2008;Choi et al, 2010;Watanabe et al, 2010). Still, this risk must always be considered when examining the therapeutic potential of agents that degrade the ECM in solid tumors.…”

“…The intratumoral administration of a replicating oncolytic adenovirus along with a nonreplicating adenovirus expressing heparanase resulted in increased viral spread within tumor spheroids, reduced tumor growth, and a significant improvement in survival in a malignant plural human mesothelioma mouse model in vivo (Watanabe et al, 2010). In general, targeting the ECM is an effective strategy used to increase viral diffusion throughout solid tumors.…”

Management of malignant pleural effusion by suicide gene therapy in advanced stage lung cancer: a case series and literature review

“…43,45,50,51 It has been previously investigated that chondroitin sulfates and proteoglycans/glycosaminoglycans that exist within the pleural effusion interact with the vector in the solution and not with the target cells and therefore inhibit the treatment. 52,53 Although, an enzymatic pre-treatment was proposed, further investigation of the molecular pathways of MPE discouraged this approach.…”

Controlling the evolution of resistance

“…These viruses are used either alone, for their direct cytotoxic effects on the tumor [33], [3], or in combination, enhancing tumor susceptibility to a secondary chemotherapy [50], [55], [11],[48], [57], [58]. These viruses are usually variants of naturally occurring viruses.…”