Local administration of irinotecan using an implantable drug delivery device stops high-grade glioma tumor recurrence in a glioblastoma tumor model.

The treatment for Glioblastoma is limited due to the presence of the blood brain barrier, which restricts the entry of chemotherapeutic drugs into the brain. Local delivery into the tumor resection margin has the potential to improve efficacy of chemotherapy. We developed a safe and clinically translatable irinotecan implant for local delivery to increase its efficacy while minimizing systemic side effects. Irinotecan-loaded implants were manufactured using hot melt extrusion, gamma sterilized at 25 kGy, and characterized for their irinotecan content, release, and drug diffusion. Their therapeutic efficacy was evaluated in a patient-derived xenograft mouse resection model of glioblastoma. Their safety and translatability were evaluated using histological analysis of brain tissue and serum chemistry analysis. Implants containing 30% and 40% w/w irinotecan were manufactured without plasticizer. The 30% and 40% implants showed moderate local toxicity up to 2- and 6-day post-implantation. Histopathology of the implantation site showed signs of necrosis at days 45 and 14 for the 30% and 40% implants. Hematological analysis and clinical chemistry showed no signs of serious systemic toxicity for either implant. The 30% implants had an 80% survival at day 148, with no sign of tumor recurrence. Gamma sterilization and 12-month storage had no impact on the integrity of the 30% implants. This study demonstrates that the 30% implants are a promising novel treatment for glioblastoma that could be quickly translated into the clinic.

Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy.

Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate of their parental fibroblasts, and TRAIL produced by iNSCs was naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed that Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays demonstrated that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts by approximately 3000-fold compared to treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a novel, easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer.

Auto-loaded TRAIL-exosomes derived from induced neural stem cells for brain cancer therapy.

Transdifferentiation (TD), a somatic cell reprogramming process that eliminates pluripotent intermediates, creates cells that are ideal for personalized anti-cancer therapy. Here, we provide the first evidence that extracellular vesicles (EVs) from TD-derived induced neural stem cells (Exo-iNSCs) are an efficacious treatment strategy for brain cancer. We found that genetically engineered iNSCs generated EVs loaded with the tumoricidal gene product TRAIL at nearly twice the rate as their parental fibroblasts, and the TRAIL produced by iNSCs were naturally loaded into the lumen of EVs and arrayed across their outer membrane (Exo-iNSC-TRAIL). Uptake studies in ex vivo organotypic brain slice cultures showed Exo-iNSC-TRAIL selectively accumulates within tumor foci, and co-culture assays showed that Exo-iNSC-TRAIL killed metastatic and primary brain cancer cells more effectively than free TRAIL. In an orthotopic mouse model of brain cancer, Exo-iNSC-TRAIL reduced breast-to-brain tumor xenografts around 3000-fold greater than treatment with free TRAIL, with all Exo-iNSC-TRAIL treated animals surviving through 90 days post-treatment. In additional in vivo testing against aggressive U87 and invasive GBM8 glioblastoma tumors, Exo-iNSC-TRAIL also induced a statistically significant increase in survival. These studies establish a new easily generated, stable, tumor-targeted EV to efficaciously treat multiple forms of brain cancer.

Combining the constitutive TRAIL-secreting induced neural stem cell therapy with the novel anti-cancer drug TR-107 in glioblastoma.

Tumor-homing neural stem cell (NSC) therapy is emerging as a promising treatment for aggressive cancers of the brain. Despite their success, developing tumor-homing NSC therapy therapies that maintain durable tumor suppression remains a challenge. Herein, we report a synergistic combination regimen where the novel small molecule TR-107 augments NSC-tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy (hiNeuroS-TRAIL) in models of the incurable brain cancer glioblastoma (GBM) in vitro. We report that the combination of hiNeuroS-TRAIL and TR-107 synergistically upregulated caspase markers and restored sensitivity to the intrinsic apoptotic pathway by significantly downregulating inhibitory pathways associated with chemoresistance and radioresistance in the TRAIL-resistant LN229 cell line. This combination also showed robust tumor suppression and enhanced survival of mice bearing human xenografts of both solid and invasive GBMs. These findings elucidate a novel combination regimen and suggest that the combination of these clinically relevant agents may represent a new therapeutic option with increased efficacy for patients with GBM.

Primer Congreso Internacional de Bioinformática: reflexiones y perspectivas / First Internacional Congress of Bioinformatics: perpectives and reflections

La disponibilidad de genomas completos, el volumen de información ubicado actualmente en las bases de datos públicas y los ambiciosos proyectos masivos de estudio sobre la interacción entre proteínas ha generado un cambio de paradigma. El enfoque clásico, que consistía en conocer una determinada función y buscar el gen responsable, se transformó y creó un nuevo escenario donde se dispone de un importante número de genes desconocidos a los que es necesario asignar una función. Este nuevo momento dio lugar al desarrollo de la Bioinformática. La celebración del Primer Congreso Internacional de Bioinformática permitió un amplio intercambio sobre temas relevantes a esta nueva disciplina científica entre los 21 cubanos que actuaron como ponentes y los 11 participantes extranjeros, provenientes de diferentes centros del mundo.Se realizaron propuestas específicas de colaboración nacional e internacional, y varias sugerencias para mejorar los proyectos que actualmente se desarrollan, y para obtener mejores resultados en la formación y superación de los recursos humanos, y, sobre todo, todo ello quedó grabado en el espíritu de los especialistas, en su mayoría jóvenes, que hoy laboran en esta nueva rama de la ciencia contemporánea