Delta-24-RGD combined with radiotherapy exerts a potent antitumor effect in diffuse intrinsic pontine glioma and pediatric high grade glioma models
Martinez-Velez N (1,2,3), Marigil M (1,2,3,4), García-Moure M (1,2,3), Gonzalez-Huarriz M (1,2,3), Aristu JJ (1,5), Ramos-García LI (5), Tejada S (1,2,6), Díez-Valle R (1,2,6), Patiño-García A (1,2,3), Becher OJ (7), Gomez-Manzano C (8,9), Fueyo J (8,10), Alonso MM (11,12,13).
(1) The Health Research Institute of Navarra (IDISNA), Pamplona, Navarra, Spain.
(2) Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain.
(3) Department of Pediatrics, Clínica Universidad de Navarra, University of Navarra, CIMA Building, Avd. Pio XII, 55, Pamplona, Spain.
(4) Division of Neurosurgery, Lariboisière University Hospital, 2 Rue Ambroise Paré, 75475, Paris, cedex 10, France.
(5) Department of Radiation Oncology, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain.
(6) Department of Neurosurgery, Clínica Universidad de Navarra, University of Navarra, Pamplona, Spain.
(7) Department of Pediatrics, Northwestern University and Division of Pediatric Hematology-Oncology and Stem Cell Transplant, Ann & Robert H. Lurie Children's Hospital, Chicago, IL, USA.
(8) Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
(9) Department of NeuroOncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
(10) Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
(11) The Health Research Institute of Navarra (IDISNA), Pamplona, Navarra, Spain.
(12) Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain.
(13) Department of Pediatrics, Clínica Universidad de Navarra, University of Navarra, CIMA Building, Avd. Pio XII, 55, Pamplona, Spain.
Magazine: Acta Neuropathologica Communications
Date: Apr 29, 2019Neurosurgery Department Pediatría [SP] Radiation Oncology
Pediatric high grade gliomas (pHGG), including diffuse intrinsic pontine gliomas (DIPGs), are aggressive tumors with a dismal outcome.
Radiotherapy (RT) is part of the standard of care of these tumors; however, radiotherapy only leads to a transient clinical improvement.
Delta-24-RGD is a genetically engineered tumor-selective adenovirus that has shown safety and clinical efficacy in adults with recurrent gliomas. In this work, we evaluated the feasibility, safety and therapeutic efficacy of Delta-24-RGD in combination with radiotherapy in pHGGs and DIPGs models.
Our results showed that the combination of Delta-24-RGD with radiotherapy was feasible and resulted in a synergistic anti-glioma effect in vitro and in vivo in pHGG and DIPG models. Interestingly, Delta-24-RGD treatment led to the downregulation of relevant DNA damage repair proteins, further sensitizing tumors cells to the effect of radiotherapy.
Additionally, Delta-24-RGD/radiotherapy treatment significantly increased the trafficking of immune cells (CD3, CD4+ and CD8+) to the tumor niche compared with single treatments.
In summary, administration of the Delta-24-RGD/radiotherapy combination to pHGG and DIPG models is safe and significantly increases the overall survival of mice bearing these tumors.
Our data offer a rationale for the combination Delta-24-RGD/radiotherapy as a therapeutic option for children with these tumors.
SIGNIFICANCE: Delta-24-RGD/radiotherapy administration is safe and significantly increases the survival of treated mice. These positive data underscore the urge to translate this approach to the clinical treatment of children with pHGG and DIPGs.
CITATION Acta Neuropathol Commun. 2019 Apr 29;7(1):64. doi: 10.1186/s40478-019-0714-6
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