Practical Review on Preclinical Human 3D Glioblastoma Models: Advances and Challenges for Clinical Translation

Fifteen years after the establishment of the Stupp protocol as the standard of care to treat glioblastomas, no major clinical advances have been achieved and increasing patient’s overall survival remains a challenge. Nevertheless, crucial molecular and cellular findings revealed the intra-tumoral and inter-tumoral complexities of these incurable brain tumors, and the essential role played by cells of the microenvironment in the lack of treatment efficacy. Taking this knowledge into account, fulfilling gaps between preclinical models and clinical samples is necessary to improve the successful rate of clinical trials. Since the beginning of the characterization of brain tumors initiated by Bailey and Cushing in the 1920s, several glioblastoma models have been developed and improved. In this review, we focused on the most widely used 3D human glioblastoma models, including spheroids, tumorospheres, organotypic slices, explants, tumoroids and glioblastoma-derived from cerebral organoids. We discuss their history, development and especially their usefulness.

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Local intracerebral Inhibition of IRE1 by MKC8866 sensitizes glioblastoma to irradiation/chemotherapy in vivo

10.1101/841296 ◽

2019 ◽

Cited By ~ 1

Author(s):

Pierre Jean Le Reste ◽

Raphael Pineau ◽

Konstantinos Voutetakis ◽

Juhi Samal ◽

Gwénaële Jégou ◽

...

Keyword(s):

Brain Cancer ◽

Treatment Efficacy ◽

Chemotherapy Regimen ◽

Standard Of Care ◽

Tumor Surgery ◽

Relevant Animal Model ◽

The Impact ◽

Radio Chemotherapy ◽

Stupp Protocol

AbstractGlioblastoma multiforme (GBM) is the most severe primary brain cancer. Despite an aggressive treatment comprising surgical resection and radio/chemotherapy patient’s survival post diagnosis remains short. A limitation for success in finding novel improved therapeutic options for such dismal disease partly lies in the lack of a relevant animal model that accurately recapitulates patient disease and standard of care. In the present study, we have developed a novel immunocompetent GBM model that includes tumor surgery and a radio/chemotherapy regimen resembling the Stupp protocol and we have used this model to test the impact of the pharmacological inhibition of the endoplasmic reticulum (ER) stress sensor IRE1, on treatment efficacy.

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Comprehensive characterization of the mutational landscape in localized anal squamous cell carcinoma

10.1101/796367 ◽

2019 ◽

Author(s):

Lucía Trilla-Fuertes ◽

Ismael Ghanem ◽

Joan Maurel ◽

Laura G-Pastrián ◽

Marta Mendiola ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Genetic Variants ◽

Disease Free Survival ◽

Standard Of Care ◽

High Impact ◽

Clinical Samples ◽

Anal Squamous Cell Carcinoma

AbstractPurposeAnal squamous cell carcinoma (ASCC) is a rare neoplasm. Chemo-radiotherapy is the standard of care, with no therapeutic advances achieved over the past three decades. Thus, a deeper molecular characterization of this disease is still necessary.MethodsWe analyzed 46 paraffin-embedded tumor samples from patients diagnosed with primary ASCC by exome sequencing. A bioinformatics approach focused in the identification of high impact genetic variants, which may act as drivers of oncogenesis, was performed. The relation between genetics variant and prognosis was also studied.ResultsThe list of high impact genetic variants was unique for each patient. However, the pathways in which these genes are involved are well-known hallmarks of cancer, such as angiogenesis or immune pathways. Additionally, we determined that genetic variants in BRCA2, ZNF750, FAM208B, ZNF599 and ZC3H13 genes are related with poor disease-free survival in ASCC.ConclusionHigh impact genetic variants in ASCC affect pathways involved in cancer development, and may play a role in the etiology of the disease. Variants in BRCA2, ZNF750, FAM208B, ZNF599 and ZC3H13 genes seem to be related with prognosis in ASCC. Sequencing of ASCC clinical samples appears an encouraging tool for the molecular portrait of this disease.

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Characterization of Brain Tumors in Colombia: A 10-Year Period

10.1055/s-0039-1679725 ◽

2019 ◽

Author(s):

Juan Vega ◽

Oscar Lee ◽

Esther De Vries ◽

Maria Navia ◽

Diego Devia

Keyword(s):

Brain Tumors

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Molecular typing and biofilm characterization of pseudomonas aeruginosa isolated from clinical samples in Lebanon. (c2011)

10.26756/th.2011.44 ◽

2011 ◽

Author(s):

Rola J. Timani

Keyword(s):

Pseudomonas Aeruginosa ◽

Molecular Typing ◽

Clinical Samples

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Targeting IDH Mutations in AML: Wielding the Double-edged Sword of Differentiation

Current Cancer Drug Targets ◽

10.2174/1568009620666200424145622 ◽

2020 ◽

Vol 20 (7) ◽

pp. 490-500 ◽

Cited By ~ 1

Author(s):

Justin S. Becker ◽

Amir T. Fathi

Keyword(s):

Genome Structure ◽

Cellular Metabolism ◽

Standard Of Care ◽

Competitive Inhibitor ◽

Driver Mutations ◽

New Class ◽

Regulatory Enzymes ◽

Idh Mutations ◽

Genomic Characterization

The genomic characterization of acute myeloid leukemia (AML) by DNA sequencing has illuminated subclasses of the disease, with distinct driver mutations, that might be responsive to targeted therapies. Approximately 15-23% of AML genomes harbor mutations in one of two isoforms of isocitrate dehydrogenase (IDH1 or IDH2). These enzymes are constitutive mediators of basic cellular metabolism, but their mutated forms in cancer synthesize an abnormal metabolite, 2- hydroxyglutarate, that in turn acts as a competitive inhibitor of multiple gene regulatory enzymes. As a result, leukemic IDH mutations cause changes in genome structure and gene activity, culminating in an arrest of normal myeloid differentiation. These discoveries have motivated the development of a new class of selective small molecules with the ability to inhibit the mutant IDH enzymes while sparing normal cellular metabolism. These agents have shown promising anti-leukemic activity in animal models and early clinical trials, and are now entering Phase 3 study. This review will focus on the growing preclinical and clinical data evaluating IDH inhibitors for the treatment of IDH-mutated AML. These data suggest that inducing cellular differentiation is central to the mechanism of clinical efficacy for IDH inhibitors, while also mediating toxicity for patients who experience IDH Differentiation Syndrome. Ongoing trials are studying the efficacy of IDH inhibitors in combination with other AML therapies, both to evaluate potential synergistic combinations as well as to identify the appropriate place for IDH inhibitors within existing standard-of-care regimens.

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Focused ultrasound in neuro-oncology: the role of the Focused Ultrasound Foundation in driving adoption and innovation

Journal of Neuro-Oncology ◽

10.1007/s11060-021-03808-5 ◽

2021 ◽

Author(s):

Emily C. Whipple ◽

Camille A. Favero ◽

Neal F. Kassell

Keyword(s):

Drug Delivery ◽

Brain Tumors ◽

Focused Ultrasound ◽

Clinical Evidence ◽

Neurological Injury ◽

High Concentration ◽

Potential Applications ◽

Tumor Agent

Abstract Introduction Intra-arterial (lA) delivery of therapeutic agents across the blood-brain barrier (BBB) is an evolving strategy which enables the distribution of high concentration therapeutics through a targeted vascular territory, while potentially limiting systemic toxicity. Studies have demonstrated lA methods to be safe and efficacious for a variety of therapeutics. However, further characterization of the clinical efficacy of lA therapy for the treatment of brain tumors and refinement of its potential applications are necessary. Methods We have reviewed the preclinical and clinical evidence supporting superselective intraarterial cerebral infusion (SSJACI) with BBB disruption for the treatment of brain tumors. In addition, we review ongoing clinical trials expanding the applicability and investigating the efficacy of lA therapy for the treatment of brain tumors. Results Trends in recent studies have embraced the use of SSIACI and less neurotoxic chemotherapies. The majority of trials continue to use mannitol as the preferred method of hyperosmolar BBB disruption. Recent preclinical and preliminary human investigations into the lA delivery of Bevacizumab have demonstrated its safety and efficacy as an anti-tumor agent both alone and in combination with chemotherapy. Conclusion lA drug delivery may significantly affect the way treatment are delivered to patients with brain tumors, and in particular GBM. With refinement and standardization of the techniques of lA drug delivery, improved drug selection and formulations, and the development of methods to minimize treatment-related neurological injury, lA therapy may offer significant benefits for the treatment of brain tumors.

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Molecular characterization of clinical carbapenem-resistant Enterobacterales from Qatar

European Journal of Clinical Microbiology & Infectious Diseases ◽

10.1007/s10096-021-04185-7 ◽

2021 ◽

Author(s):

Fatma Ben Abid ◽

Clement K. M. Tsui ◽

Yohei Doi ◽

Anand Deshmukh ◽

Christi L. McElheny ◽

...

Keyword(s):

Common Species ◽

Clinical Samples ◽

Whole Genome ◽

E Coli ◽

Carbapenem Resistant ◽

Genes Encoding ◽

Encoding Genes ◽

Sequence Types ◽

Common Sequence

AbstractOne hundred forty-nine carbapenem-resistant Enterobacterales from clinical samples obtained between April 2014 and November 2017 were subjected to whole genome sequencing and multi-locus sequence typing. Klebsiella pneumoniae (81, 54.4%) and Escherichia coli (38, 25.5%) were the most common species. Genes encoding metallo-β-lactamases were detected in 68 (45.8%) isolates, and OXA-48-like enzymes in 60 (40.3%). blaNDM-1 (45; 30.2%) and blaOXA-48 (29; 19.5%) were the most frequent. KPC-encoding genes were identified in 5 (3.6%) isolates. Most common sequence types were E. coli ST410 (8; 21.1%) and ST38 (7; 18.4%), and K. pneumoniae ST147 (13; 16%) and ST231 (7; 8.6%).

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