Cellular Oncology

, Volume 39, Issue 3, pp 279–286

Tumor-specific promoter-driven adenoviral therapy for insulinoma

Authors

  • Alan Wei-Shun Tseng
    • The Research Institute for Children, Children’s Hospital
    • Department of Biochemistry and Molecular BiologyLouisiana State University Health Sciences Center
  • Chiachen Chen
    • The Research Institute for Children, Children’s Hospital
    • Laboratory of Diana Helis Henry Medical Research Foundation
  • Mary B. Breslin
    • The Research Institute for Children, Children’s Hospital
    • Laboratory of Diana Helis Henry Medical Research Foundation
    • Department of PediatricsLouisiana State University Health Sciences Center
    • The Research Institute for Children, Children’s Hospital
    • Laboratory of Diana Helis Henry Medical Research Foundation
    • Department of PediatricsLouisiana State University Health Sciences Center
    • Department of GeneticsLouisiana State University Health Sciences Center
Original Paper

DOI: 10.1007/s13402-016-0274-8

Cite this article as:
Tseng, A.W., Chen, C., Breslin, M.B. et al. Cell Oncol. (2016) 39: 279. doi:10.1007/s13402-016-0274-8

Abstract

Background

Insulinomas are the most common type of neuroendocrine (NE) pancreatic islet tumors. Patients with insulinomas may develop complications associated with hyperinsulinemia. To increase the treatment options for insulinoma patients, we have tested a conditionally replicating adenovirus that has been engineered in such a way that it can specifically express therapeutic genes in NE tumors.

Methods

We used a promoter-specific adenoviral vector delivery system that is regulated by an INSM1 (insulinoma-associated-1) promoter, which is silent in normal adult tissues but active in developing NE cells and tumors. Through a series of modifications, using an insulator (HS4) and neuron-restrictive silencer elements (NRSEs), an oncolytic adenoviral vector was generated that retains tumor specificity and drives the expression of a mutated adenovirus E1A gene (Δ24E1A) and the herpes simplex virus thymidine kinase (HSV-tk) gene. The efficacy of this vector was tested in insulinoma-derived MIN, RIN, βTC-1 and pancreatic (Panc-1) cells using in vitro cell survival and in vivo tumor growth assays.

Results

Using in vitro insulinoma-derived cell lines and an in vivo subcutaneous mouse tumor model we found that the INSM1 promoter-driven viruses were able to replicate specifically in INSM1-positive cells. INSM1-specific HSV-tk expression in combination with ganciclovir treatment resulted in dose-dependent tumor cell killing, leaving INSM1-negative cells unharmed. When we combined the INSM1-promoter driven HSV-tk with Δ24E1A and INSM1p-HSV-tk (K5) viruses, we found that the co-infected insulinoma-derived cells expressed higher levels of HSV-tk and exhibited more efficient tumor suppression than cells infected with INSM1p-HSV-tk virus alone.

Conclusions

INSM1 promoter-driven conditionally replicating adenoviruses may serve as a new tool for the treatment of insulinoma and may provide clinicians with additional options to combat this disease.

Keywords

INSM1InsulinomaOncolyticEndocrine tumorGene therapy

Abbreviations

NE

neuroendocrine

INSM1

insulinoma-associated-1

NRSEs

neuronal restrictive silencer elements

IRES

internal ribosomal entry site

HSV-tk

herpes simplex virus thymidine kinase

GCV

ganciclovir

DMEM

Dulbecco Modified Eagle Medium

MOI

multiplicities of infection

CAR

coxsackievirus and adenovirus receptor

Copyright information

© International Society for Cellular Oncology 2016