Personalising glioblastoma medicine: explant organoid applications, challenges and future perspectives.

Glioblastoma (GBM) is a highly aggressive adult brain cancer, characterised by poor prognosis and a dismal five-year survival rate. Despite significant knowledge gains in tumour biology, meaningful advances in patient survival remain elusive. The field of neuro-oncology faces many disease obstacles, one being the paucity of faithful models to advance preclinical research and guide personalised medicine approaches.

CBL0137 and NKG2A blockade: a novel immuno-oncology combination therapy for Myc-overexpressing triple-negative breast cancers.

The MYC proto-oncogene is upregulated in >60% of triple-negative breast cancers (TNBCs), it can directly promote tumor cell proliferation, and its overexpression negatively regulates anti-tumor immune responses. For all these reasons, MYC has long been considered as a compelling therapeutic target. However, pharmacological inhibition of MYC function has proven difficult due to a lack of a drug-binding pocket.

EphA2 regulates vascular permeability and prostate cancer metastasis via modulation of cell junction protein phosphorylation.

Prostate cancer morbidity and mortality demonstrate a need for more effective targeted therapies. One potential target is EphA2, although paradoxically, pro- and anti-oncogenic effects have been shown to be mediated by EphA2. We demonstrate that unique activating and blocking EphA2-targeting monoclonal antibodies display opposing tumor-suppressive and oncogenic properties in vivo.

Integration of transcriptomics, proteomics and loss-of-function screening reveals WEE1 as a target for combination with dasatinib against proneural glioblastoma.

Glioblastoma is characterized by a pronounced resistance to therapy with dismal prognosis. Transcriptomics classify glioblastoma into proneural (PN), mesenchymal (MES) and classical (CL) subtypes that show differential resistance to targeted therapies. The aim of this study was to provide a viable approach for identifying combination therapies in glioblastoma subtypes.

EphA3 CAR T cells are effective against glioblastoma in preclinical models.

Background: Adoptive T-cell therapy targeting antigens expressed in glioblastoma has emerged as a potential therapeutic strategy to prevent or delay recurrence and prolong overall survival in this aggressive disease setting. Ephrin receptor A3 (EphA3), which is highly expressed in glioblastoma; in particular, on the tumor vasculature and brain cancer stem cells, is an ideal target for immune-based therapies.

Methods: We have designed an EphA3-targeted chimeric antigen receptor (CAR) using the single chain variable fragment of a novel monoclonal antibody, and assessed its therapeutic potential against EphA3-expressing patient-derived glioblastoma neurospheres, organoids and xenografted glioblastoma tumors in immunodeficient mice.

ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines.

Glioblastoma cells can restrict the DNA-damaging effects of temozolomide (TMZ) and radiation therapy (RT) using the DNA damage response (DDR) mechanism which activates cell cycle arrest and DNA repair pathways. Ataxia-telangiectasia and Rad3-Related protein (ATR) plays a pivotal role in the recognition of DNA damage induced by chemotherapy and radiation causing downstream DDR activation. Here, we investigated the activity of gartisertib, a potent ATR inhibitor, alone and in combination with TMZ and/or RT in 12 patient-derived glioblastoma cell lines.

Patterning Networks of Grade IV Glioblastoma on Silicon Chip.

Glioblastoma (GBM) is the most aggressive high-grade brain cancer with a median survival time of <15 months. Due to GBMs fast and infiltrative growth patient prognosis is poor with recurrence after treatment common. Investigating GBMs ability to communicate, specifically via Ca signaling, within its functional tumour networks may unlock new therapeutics to reduce the rapid infiltration and growth which currently makes treatment ineffective.

Eliciting calcium transients with UV nanosecond laser stimulation in adult patient-derived glioblastoma brain cancer cells.

Glioblastoma (GBM) is the most common and lethal type of high-grade adult brain cancer. The World Health Organization have classed GBM as an incurable disease because standard treatments have yielded little improvement with life-expectancy being 6-15 months after diagnosis. Different approaches are now crucial to discover new knowledge about GBM communication/function in order to establish alternative therapies for such an aggressive adult brain cancer.

NLGN4X TCR transgenic T cells to treat gliomas.

Background: Neuroligin 4 X-linked (NLGN4X) harbors a human leukocyte antigen (HLA)-A*02-restricted tumor-associated antigen, overexpressed in human gliomas, that was found to induce specific cytotoxic T cell responses following multi-peptide vaccination in patients with newly diagnosed glioblastoma.

Methods: T cell receptor (TCR) discovery was performed using droplet-based single-cell TCR sequencing of NLGN4X-tetramer-sorted T cells postvaccination. The identified TCR was delivered to Jurkat T cells and primary human T cells (NLGN4X-TCR-T).

Preventing recurrence in Sonic Hedgehog Subgroup Medulloblastoma using the OLIG2 inhibitor CT-179.

Recurrence is the primary life-threatening complication for medulloblastoma (MB). In Sonic Hedgehog (SHH)-subgroup MB, OLIG2-expressing tumor stem cells drive recurrence. We investigated the anti-tumor potential of the small-molecule OLIG2 inhibitor CT-179, using SHH-MB patient-derived organoids, patient-derived xenograft (PDX) tumors and mice genetically-engineered to develop SHH-MB.

Proteome profiling of salivary small extracellular vesicles in glioblastoma patients.

Background: Extracellular vesicles (EVs) play a critical role in intercellular communication under physiological and pathological conditions, including cancer. EVs cargo reflects their cell of origin, suggesting their utility as biomarkers. EVs are detected in several biofluids, and their ability to cross the blood-brain barrier has highlighted their potential as prognostic and diagnostic biomarkers in gliomas, including glioblastoma (GBM).

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma.

Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of childhood cancers. Palliative radiotherapy is the only established treatment, with median patient survival of 9-11 months. ONC201 is a DRD2 antagonist and ClpP agonist that has shown preclinical and emerging clinical efficacy in DMG.

Development and Validation of a Targeted Treatment for Brain Tumors Using a Multi-Drug Loaded, Relapse-Resistant Polymeric Theranostic.

This study aimed to develop a multifunctional polymer platform that could address the issue of treatment resistance when using conventional chemotherapeutics to treat glioblastoma (GBM). An antibody-conjugated, multi-drug loaded hyperbranched polymer was developed that provided a platform to evaluate the role of targeted nanomedicine treatments in overcoming resistant GBM by addressing the various complications with current clinically administered formulations. The polymer was synthesized via reversible addition fragmentation chain transfer polymerization and included the clinical first-line alkylating agent temozolomide (TMZ) which was incorporated as a polymerizable monomer, poly (ethylene glycol) (PEG) units to impart biocompatibility and enable conjugation with αPEG-αEphA2 bispecific antibody (αEphA2 BsAb) for tumor targeting, and hydrazide moieties for attachment of a secondary drug which allows exploration of synergistic therapies.

A pilot study: Metabolic profiling of plasma and saliva samples from newly diagnosed glioblastoma patients.

Background: Despite aggressive treatment, more than 90% of glioblastoma (GBM) patients experience recurrences. GBM response to therapy is currently assessed by imaging techniques and tissue biopsy. However, difficulties with these methods may cause misinterpretation of treatment outcomes.

Generation and multi-dimensional profiling of a childhood cancer cell line atlas defines new therapeutic opportunities.

Pediatric solid and central nervous system tumors are the leading cause of cancer-related death among children. Identifying new targeted therapies necessitates the use of pediatric cancer models that faithfully recapitulate the patient's disease. However, the generation and characterization of pediatric cancer models has significantly lagged behind adult cancers, underscoring the urgent need to develop pediatric-focused cell line resources.

Clinical Trials in the Brain Tumour Population: Challenges and Strategies for the Future.

Purpose Of Review: This review identifies challenges and barriers to successful development of drugs in neuro-oncology trials at the preclinical, clinical and translational stages that we believe has contributed to poor outcomes for patients over the last 30 years.

Recent Findings: Several key strategies have been proposed by leading groups to address these and improve patient outcomes. Better preclinical testing using more sophisticated and clinically relevant models is needed.

Determining the Research Priorities for Adult Primary Brain Tumours in Australia and New Zealand: A Delphi Study with Consumers, Health Professionals, and Researchers.

The aim of this project was to determine research priorities, barriers, and enablers for adult primary brain tumour research in Australia and New Zealand. Consumers, health professionals, and researchers were invited to participate in a two-phase modified Delphi study. Phase 1 comprised an initial online survey ( = 91) and then focus groups ( = 29) which identified 60 key research topics, 26 barriers, and 32 enablers.

A Multifunctional Porous Silicon Nanocarrier for Glioblastoma Treatment.

Clinical treatment of glioblastoma (GBM) remains a major challenge because of the blood-brain barrier, chemotherapeutic resistance, and aggressive tumor metastasis. The development of advanced nanoplatforms that can efficiently deliver drugs and gene therapies across the BBB to the brain tumors is urgently needed. The protein "downregulated in renal cell carcinoma" (DRR) is one of the key drivers of GBM invasion.

Engineering Novel Lentiviral Vectors for Labelling Tumour Cells and Oncogenic Proteins.

Lentiviral vectors are unique and highly efficient genetic tools to incorporate genetic materials into the genome of a variety of cells whilst conserving biosafety. Their rapid acceptance made it necessary to improve existing protocols, including molecular engineering and cloning, production of purified lentiviral particles, and efficient infection of target cells. In addition to traditional protocols, which can be time-consuming, several biotechnology companies are providing scientists with commercially available lentiviral constructs and particles.

LUMOS - Low and Intermediate Grade Glioma Umbrella Study of Molecular Guided TherapieS at relapse: Protocol for a pilot study.

Introduction: Grades 2 and 3 gliomas (G2/3 gliomas), when combined, are the second largest group of malignant brain tumours in adults. The outcomes for G2/3 gliomas at progression approach the dismal outcomes for glioblastoma (GBM), yet there is a paucity of trials for Australian patients with relapsed G2/3 gliomas compared with patients with GBM. LUMOS will be a pilot umbrella study for patients with relapsed G2/3 gliomas that aims to match patients to targeted therapies based on molecular screening with contemporaneous tumour tissue.

A novel patient stratification strategy to enhance the therapeutic efficacy of dasatinib in glioblastoma.

Background: Glioblastoma is the most common primary malignancy of the central nervous system with a dismal prognosis. Genomic signatures classify isocitrate dehydrogenase 1 (IDH)-wildtype glioblastoma into three subtypes: proneural, mesenchymal, and classical. Dasatinib, an inhibitor of proto-oncogene kinase Src (SRC), is one of many therapeutics which, despite promising preclinical results, have failed to improve overall survival in glioblastoma patients in clinical trials.