Advantages of Using Paclitaxel in Combination with Oncolytic Adenovirus Utilizing RNA Destabilization Mechanism

Abstract

Oncolytic virotherapy is a novel approach to cancer therapy. Ad-fosARE is a conditionally replicative adenovirus engineered by inserting AU-rich elements (ARE) in the 3’-untranslated region of the E1A gene. In this study, we examined the oncolytic activity of Ad-fosARE and used it in a synergistic combination with the chemotherapeutic agent paclitaxel (PTX) for treating cancer cells. The expression of E1A was high in cancer cells due to stabilized E1A-ARE mRNA. As a result, the efficiency of its replication and cytolytic activity in cancer cells was higher than in normal cells. PTX treatment increased the cytoplasmic HuR relocalization in cancer cells, enhanced viral replication through elevated E1A expression, and upregulated CAR (Coxsackie-adenovirus receptor) required for viral uptake. Furthermore, PTX altered the instability of microtubules by acetylation and detyrosination, which is essential for viral internalization and trafficking to the nucleus. These results indicate that PTX can provide multiple advantages to the efficacy of Ad-fosARE both in vitro and in vivo, and provides a basis for designing novel clinical trials. Thus, this virus has a lot of benefits that are not found in other oncolytic viruses. The virus also has the potential for treating PXT-resistant cancers.

Interferon‐expressing oncolytic adenovirus + chemoradiation inhibited pancreatic cancer growth in a hamster model

“…Microtubule networks are important for adenovirus entry, nuclear tracking, and the development of replication 37 . PTX is also known to affect the instability of microtubules by acetylation and detyrosination, which is essential for viral internalization and trafficking to the nucleus 38 . Recent papers reported the efficacy of the combination of OAd with PTX 38,39 .…”

Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy

“…Triple combination of chemotherapy, ICB therapy, and OVT has been applied in the clinic because synergistic efficacy has been reported between OVs and some chemical agents such as gemcitabine and paclitaxel [ 140 , 141 ]. Recently, this triple combination strategy was applied in a phase Ib trial treating patients with unresectable PDAC.…”

Evolving Role of Oncolytic Virotherapy: Challenges and Prospects in Clinical Practice

“…A growing list of conventional chemotherapy regimens, including gemcitabine, infusional fluorouracil, leucovorin, and oxaliplatin, paclitaxel, and cisplatin are being investigated as combination therapy with a variety of OVs. [20][21][22][23] Radiation therapy. Another modality of interest for combination treatment with OVs is external beam radiotherapy (XRT).…”