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New Therapeutics Strategies for the Treatment of Pediatric Brain Tumors

Final Report Summary - PEDIAVIR (New Therapeutics Strategies for the Treatment of Pediatric Brain Tumors)

Pediatric high-grade gliomas (HGG) including diffuse intrinsic pontine gliomas (DIPG) are one of the most formidable challenges faced by pediatric oncologist. Children, with HGG have a very poor prognosis and despite the improvement of therapeutic approaches the long-term survival rates range from <10-30% for most supratentorial tumors to <10% for DIPG. In addition, due to either the effects of the tumor or the treatment required to control it, survivors of childhood brain tumors often have severe neurologic, cognitive and psychosocial sequelae. It is clear that the management of high-risk pediatric brain tumor is suboptimal and novel strategies are required that allow not only for more effective treatments but also to defer the severe side effects derived from the current therapeutic choices. Oncolytic adenoviruses therapies have proven to be safe and efficacious in clinical and provide a radically different approach for the treatment of pHGG and DIPGs. Delta-24-RGD is a replication-competent adenovirus that has already shown efficacy in animal models of gliomas. Of clinical significance, compelling results from Phase I/II clinical studies conducted at MDACC (Houston, TX) and in our institution (CUN, Spain) in adult GBM indicate that Delta-24-RGD can cause ongoing tumor destruction and achieve a complete response to therapy. Equally important is Delta-24-RGD superior clinical safety profile of no significant side effects observed at any dose. These results emphasize the urgent need to further develop this approach and the suitability to translate it to DIPGs.

We hypothesize that oncolytic adenovirus alone or in combination with chemotherapy may constitute an alternative therapeutic approach for pHGG and DIPG. This therapy will allow for a reduction in chemotherapy dosage and reduction or avoidance of RT therefore leading to a significant improvement of the prognosis and quality of life of patient with HGG and DIPGs.
Our long-term goal is to improve the survival and quality of life of children with HGG and DIPGs.

The main results obtained by the direct support of this action are:
1) We have accrued through collaborations or developed in our lab several cell lines of pHGG and DIPGs. The generation of cell lines is of paramount importance not only to our project but to the field of pediatric brain tumors. Up to now there was a paucity of pediatric brain tumor cell lines (with the exception of medulloblastomas) that allow studying either the biology of these tumors or different therapeutic agents. In parallel we have develop two different animal models using nude mice; one for supratentorial gliomas and another one for DIPGs using a guide-screw system. These two tools are central to our project and they have allowed us to perform the project. The information regarding the animal models have been compiled in a manuscript and it will be sent for publication in the next month.
2) Regarding the antitumor of Delta-24-RGD in pHGG and DIPG we have shown that the virus is able to infect, replicate and kill pHGG and DIPG cell lines in vitro. In addition, we have observed a potent antitumor effect in vivo in relevant orthotopic models. Moreover, addition of radiotherapy results in a synergistic effect through different mechanism in vivo an in vitro. We have combined the virus with different chemotherapeutics such as temozolomide, rapamycin and inhibitors of IGF1R for the treatment of pHGG and DIPGs with very good results. These data underscore the amenability of the virus to be used in combination with drugs already used in the clinic. We currently summarizing these results and we expect to have a draft for publication in the next couple of months.
3) We have extended our approach to pediatric osteosarcoma. Osteosarcoma is the most common malignant bone tumor in children and adolescents. The presence of metastases and the lack of response to conventional treatment are the major adverse prognostic factors. Our institution has been a pioneer in the treatment of pediatric osteosarcoma and Dr. Ana Patiño had a collection of osteosarcoma cell lines. In collaboration with Dr. Patiño we have developed an orthotopic local osteosarcoma and a lung metastatic osteosarcoma model. Our results showed that Delta-24-RGD exerted a potent antitumor effect against osteosarcoma cell lines that was increased by the addition of cisplatin. Delta-24-RGD osteosarcoma treatment resulted in autophagy in vitro that was further enhanced when combined with cisplatin. Of importance, administration of Δ24-RGD and/or cisplatin, in novel orthotopic and two lung metastatic models in vivo resulted in a significant reduction of tumor burden meanwhile maintaining a safe toxicity profile. Together, our data underscore the potential of Δ24-RGD to become a realistic therapeutic option for primary and metastatic pediatric osteosarcoma. This results have been summarized and published (The oncolytic adenovirus Δ24-RGD in combination with cisplatin exerts a potent anti-osteosarcoma activity. Martinez-Velez N, et al J Bone Miner Res 2014, 29:2287-96)
4) Due to the support of the Marie Curie Actions, among others, we have been able to established valuable international collaborations in the field of pediatric brain tumors and specifically DIPG (diffuse intrinsic pontine gliomas). This collaboration lead by Dr. Monje (Stanford University, USA) and Dr. Keller (Children´s Cancer Therapy Development Institute, Fort Collins, USA) has results in a seminal publication that undercover the preclinical therapeutic effect of the multi-histone deacetylase inhibitor panobinostat both in vitro and in DIPG orthotopic xenograft models. Moreover, combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG. This data have been summarized and published (Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Grasso et al, Nat Med 2015doi:10.1038/nm.3855)

Generally, there have been few significant advances in the treatment of pediatric brain tumor over the last decade, specifically in those with worst prognosis. Novel therapeutic development for CNS tumors is modest, and progress has been meager. Therefore, implementing oncolytic adenovirus for the treatment of high-risk brain tumors alone or in combination with chemotherapy could constitute a breakthrough in the treatment of this disease. Thanks to the Marie Curie we have proposed a clinical trial phase I/II with Delta-24-RGD for the treatment of DIPGs. We are currently waiting for the approval of the relevant regulatory agencies and we hope to be able to open the trial within the next 12 months.
Overall since the management of pediatric brain tumors is infra-optimal any advance in the therapeutic interventions for these malignancies will have a positive action at the local and international level.