INVESTIGADORES
CANDOLFI Marianela
artículos
Título:
Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics
Autor/es:
MARIANELA CANDOLFI; WEIDONG XIONG; KADER YAGIZ; CHUNYAN LIU; AKM GHULAM MUHAMMAD; MARIANA PUNTEL; DAVID FOULAD; ALI ZADMEHR; GABRIELLE E ALZADEH; KURT M KROEGER; MATTHEW TESARFREUND; SHARON LEE; WALDEMAR DEBINSKI; D SAREEN; CLIVE N SVENDSEN; RONALD RODRIGUEZ; PEDRO R LOWENSTEIN; MARIA G CASTRO
Revista:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Editorial:
NATL ACAD SCIENCES
Referencias:
Año: 2010 p. 20021 - 20026
ISSN:
0027-8424
Resumen:
Restricting the cytotoxicity of anticancer agents by targeting receptors exclusively expressed on tumor cells is critical when treating infiltrative brain tumors such as glioblastoma multiforme (GBM). GBMs express an IL-13 receptor (IL13Rα2) that differs from the physiological IL4R/IL13R receptor. We developed a regulatable adenoviral vector (Ad.mhIL-4.TRE.mhIL-13-PE) encoding a mutated human IL-13 fused to Pseudomonas exotoxin (mhIL-13-PE) that specifically binds to IL13Rα2 to provide sustained expression, effective anti-GBM cytotoxicity, and minimal neurotoxicity. The therapeutic Ad also encodes mutated human IL-4 that binds to the physiological IL4R/IL13R without interacting with IL13Rα2, thus inhibiting potential binding of mhIL-13-PE to normal brain cells. Using intracranial GBM xenografts and syngeneic mouse models, we tested the Ad. mhIL-4.TRE.mhIL-13-PE andtwo protein formulations, hIL-13-PE used in clinical trials (Cintredekin Besudotox) and a second-generation mhIL-13-PE. Cintredekin Besudotox doubled median survival without eliciting long-term survival and caused severe neurotoxicity; mhIL-13-PE led to ∼40% long-term survival, eliciting severe neurological toxicity at the high dose tested. In contrast, Ad-mediated delivery of mhIL-13-PE led to tumor regressionandlong-termsurvival in over 70% of the animals, without causing apparent neurotoxicity. Although Cintredekin Besudotox was originally developed to target GBM, when tested in a phase III trial it failed to achieve clinical endpoints and revealed neurotoxicity. Limitations of Cintredekin Besudotox include its short half-life, which demanded frequent or continued administration, and binding to IL4R/IL13R, present in normal brain cells. These shortcomings were overcome by our therapeutic Ad, thus representing a significant advance in the development of targeted therapeutics for GBM.