A First-Generation Multi-Functional Cytokine for Simultaneous Optical Tracking and Tumor Therapy

Authors

Shawn Hingtgen, Harvard Medical School
Randa Kasmieh, Harvard Medical School
Elizabeth Elbayly, Harvard Medical School
Irina Nesterenko, Harvard Medical School
Jose-Luiz Figueiredo, Harvard Medical School
Rupesh Dash, Virginia Commonwealth University
Devanand Sarkar, Virginia Commonwealth UniversityFollow
David Hall, Boston University
Dima Kozakov, Boston University
Sandor Vajda, Boston University
Paul B. Fisher, Virginia Commonwealth UniversityFollow
Khalid Shah, Harvard Medical School

Document Type

Article

Original Publication Date

2012

Journal/Book/Conference Title

PLOS ONE

Volume

7

DOI of Original Publication

10.1371/journal.pone.0040234

Comments

Originally Published at http://dx.doi.org/10.1371/journal.pone.0040234

Date of Submission

November 2014

Abstract

Creating new molecules that simultaneously enhance tumor cell killing and permit diagnostic tracking is vital to overcoming the limitations rendering current therapeutic regimens for terminal cancers ineffective. Accordingly, we investigated the efficacy of an innovative new multi-functional targeted anti-cancer molecule, SM7L, using models of the lethal brain tumor Glioblastoma multiforme (GBM). Designed using predictive computer modeling, SM7L incorporates the therapeutic activity of the promising anti-tumor cytokine MDA-7/IL-24, an enhanced secretory domain, and diagnostic domain for non-invasive tracking. In vitro assays revealed the diagnostic domain of SM7L produced robust photon emission, while the therapeutic domain showed marked anti-tumor efficacy and significant modulation of p38MAPK and ERK pathways. In vivo, the unique multi-functional nature of SM7L allowed simultaneous real-time monitoring of both SM7L delivery and anti-tumor efficacy. Utilizing engineered stem cells as novel delivery vehicles for SM7L therapy (SC-SM7L), we demonstrate that SC-SM7L significantly improved pharmacokinetics and attenuated progression of established peripheral and intracranial human GBM xenografts. Furthermore, SC-SM7L anti-tumor efficacy was augmented in vitro and in vivo by concurrent activation of caspase-mediated apoptosis induced by adjuvant SC-mediated S-TRAIL delivery. Collectively, these studies define a promising new approach to treating highly aggressive cancers, including GBM, using the optimized therapeutic molecule SM7L.

Rights

Copyright: © 2012 Hingtgen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Is Part Of

VCU Human and Molecular Genetics Publications