Oncolytic viral therapy as a novel potential solution for treatment of pancreatic cancer

Abstract

Pancreatic cancer (PC) remains one of the most formidable malignancies, with survival rates showing minimal improvement over the years despite progress in chemotherapy, targeted treatments, and radiation therapy. The development of targeted agents and chemotherapy for cancer treatment has only moderately influenced clinical results and has not significantly altered 5-year survival rates. However, with the rapid discovery of the genetic and molecular functions underlying PC, new opportunities for targeted therapies are emerging. One promising approach is oncolytic viral therapy, which has shown potential as a targeted agent for the treatment of pancreatic cancer. Based on the available evidence, oncolytic viral therapy appears to be a viable treatment option for pancreatic cancer. In the present narrative review, we explore oncolytic viruses in detail, and their potential applications in cancer therapy as a future alternative treatment are investigated.

Keywords: Chemoresistance; Immunotherapy; Oncolytic viral treatment; Pancreatic cancer; Therapeutic Targets.

Figure 1

Signaling pathways controlling normal cell function. Fig 1a) K-Ras: KRAS, a key gene in the RAS family, drives cell growth through the MAPK and PI3K/Akt pathways. Mutations, present in over 80% of pancreatic cancers, lead to chemotherapy resistance and tumor progression, but effective inhibitors remain challenging to develop. Fig 1b) PI3K: The PI3K pathway, activated by KRAS mutations or growth factors, supports cancer cell survival and is linked to chemo- and radiotherapy resistance in PDAC. Fig 1c) TGF-β: TGF-β acts as a tumor suppressor early but promotes metastasis in advanced stages via EMT. Its upregulation in pancreatic cancer correlates with poor prognosis, though clinical targeting has shown limited success. Fig 1d) MAPK: The MAPK pathway, disrupted in pancreatic cancer through KRAS mutations, drives disease progression. Targeting its downstream effects shows therapeutic promise. Fig 1e) Wnt: The Wnt/B-catenin pathway promotes EMT, tumor growth, and apoptosis resistance in pancreatic cancer, maintaining cancer stem cells and supporting the tumor microenvironment (37, 38). Fig 1f) Notch: Notch signaling, critical for cell proliferation and EMT, drives pancreatic cancer progression and chemoresistance, making it a potential therapeutic target.

Figure 2

Oncolytic DNA Viruses Involved in the Treatment of Pancreatic Cancer. Fig.2a) Adenovirus: A double-stranded DNA virus used in cancer treatment. Modified versions like ONYX-015 (E1B-deleted) and Oncorine selectively target cancer cells with p53 mutations. Engineered adenoviruses with tumor-specific promoters and enhanced infectivity (e.g., desmoglein2 targeting) show improved efficacy. Therapeutic genes like IL24 are being incorporated for immune modulation. Fig.2b) Oncolytic Herpes Simplex Virus (HSV): HSV-1 and HSV-2 are modified to replicate in cancer cells while sparing normal ones. Deletions in genes such as γ34.5 (e.g., R3616) and ICP6 (e.g., hrR3) enhance selectivity and efficacy. Some HSV strains (e.g., OncoVex GM-CSF) express immune-stimulating genes like GM-CSF. Studies indicate synergistic effects with chemotherapy and radiation. Fig.2c) Poxviruses: Enveloped double-stranded DNA viruses like vaccinia and myxoma virus (MYXV) show promise. Vaccinia expressing anti-angiogenic proteins or survivin inhibitors improves outcomes in combination with chemotherapy. MYXV enhances survival, especially with gemcitabine. Engineered poxviruses (e.g., PANVAC-V) also induce strong immune responses. Fig.2d) Parvovirus: Small, non-enveloped DNA viruses (e.g., H-1PV) are inherently oncolytic, replicating in dividing cancer cells. In pancreatic cancer, they exhibit direct oncolysis, immune activation, and synergy with gemcitabine, enhancing natural killer (NK) cell activity.

Figure 3

Oncolytic RNA Viruses Involved in the Treatment of Pancreatic Cancer. Fig.3a) Measles Virus: The measles virus targets cancer cells through overexpressed CD46. Modified strains, like MV-NIS, showed tumor regression in pancreatic cancer models but lacked synergy with radiotherapy. Another variant, MVPNPantiPSCA, targets PSCA in pancreatic cancer and uses a suicide gene to activate fludarabine, proving effective even against gemcitabine-resistant tumors. Fig.3b) Reovirus: Reovirus exploits KRAS mutations (common in pancreatic cancer) to replicate in cancer cells. In animal models, it reduced tumor size and ascites. Reolysin®, a reovirus-based therapy, is undergoing phase II trials for pancreatic cancer.