A first-generation multi-functional cytokine for simultaneous optical tracking and tumor therapy.
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.
Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Shawn
S
Hingtgen
Randa
R
Kasmieh
Elizabeth
E
Elbayly
Irina
I
Nesterenko
Jose-Luiz
JL
Figueiredo
Rupesh
R
Dash
Devanand
D
Sarkar
David
D
Hall
Dima
D
Kozakov
Sandor
S
Vajda
Paul B
PB
Fisher
Khalid
K
Shah
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000188:drug therapy* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D018450:Disease Progression; D016503:Drug Delivery Systems; D005909:Glioblastoma / Q000175:diagnosis* / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007378:Interleukins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D055620:Optical Phenomena; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D000099180:Interleukin-24
D000970:Antineoplastic Agents; D007378:Interleukins; D000099180:Interleukin-24