Development of Orthotopic Patient-Derived Xenograft Models of Pediatric Intracranial Tumors.

The development of clinically relevant and reliable models of central nervous system tumors has been instrumental in advancing the field of Neuro-Oncology. The orthotopic intracranial injection is widely used to study the growth, invasion, and spread of tumors in a controlled environment. Orthotopic models are performed to examine tumor cells isolated from a specific region in a patient in the same site or location in an animal model.

Preclinical evaluation of protein synthesis inhibitor omacetaxine in pediatric brainstem gliomas.

Background: Diffuse intrinsic pontine gliomas (DIPGs) pose a significant challenge as a highly aggressive and currently incurable form of pediatric brain cancer, necessitating the development of novel therapeutic strategies. Omacetaxine, an FDA-approved protein synthesis inhibitor for treating certain hematological malignancies, was investigated for its potential antitumor effects against preclinical DIPG models.

Methods: We employed primary DIPG cultures to study omacetaxine's cytotoxicity and its impact on colony formation.

From Pediatric to Adult Brain Cancer: Exploring Histone H3 Mutations in Australian Brain Cancer Patients.

Genetic histone variants have been implicated in cancer development and progression. Mutations affecting the histone 3 (H3) family, H3.1 (encoded by and ) and H3.

Microtubule-Targeting Combined with HDAC Inhibition Is a Novel Therapeutic Strategy for Diffuse Intrinsic Pontine Gliomas.

Diffuse intrinsic pontine gliomas (DIPG) are an incurable childhood brain cancer for which novel treatments are needed. DIPGs are characterized by a mutation in the H3 histone (H3K27M), resulting in loss of H3K27 methylation and global gene dysregulation. TRX-E-009-1 is a novel anticancer agent with preclinical activity demonstrated against a range of cancers.

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.

loss of tumorigenicity in a patient-derived orthotopic xenograft mouse model of ependymoma.

Introduction: Ependymomas (EPN) are the third most common malignant brain cancer in children. Treatment strategies for pediatric EPN have remained unchanged over recent decades, with 10-year survival rates stagnating at just 67% for children aged 0-14 years. Moreover, a proportion of patients who survive treatment often suffer long-term neurological side effects as a result of therapy.

Challenges and opportunities to penetrate the blood-brain barrier for brain cancer therapy.

Despite significant advances in research, the prognosis for both primary and secondary brain cancers remains poor. The blood-brain barrier (BBB) is a complex and unique semi-permeable membrane that serves as a protective structure to maintain homeostasis within the brain. However, it presents a significant challenge for the delivery of therapeutics into the brain and tumor.

FOXR2 Is an Epigenetically Regulated Pan-Cancer Oncogene That Activates ETS Transcriptional Circuits.

Unlabelled: Forkhead box R2 (FOXR2) is a forkhead transcription factor located on the X chromosome whose expression is normally restricted to the testis. In this study, we performed a pan-cancer analysis of FOXR2 activation across more than 10,000 adult and pediatric cancer samples and found FOXR2 to be aberrantly upregulated in 70% of all cancer types and 8% of all individual tumors. The majority of tumors (78%) aberrantly expressed FOXR2 through a previously undescribed epigenetic mechanism that involves hypomethylation of a novel promoter, which was functionally validated as necessary for FOXR2 expression and proliferation in FOXR2-expressing cancer cells.

Therapeutic Targets in Diffuse Midline Gliomas-An Emerging Landscape.

Diffuse midline gliomas (DMGs) are invariably fatal pediatric brain tumours that are inherently resistant to conventional therapy. In recent years our understanding of the underlying molecular mechanisms of DMG tumorigenicity has resulted in the identification of novel targets and the development of a range of potential therapies, with multiple agents now being progressed to clinical translation to test their therapeutic efficacy. Here, we provide an overview of the current therapies aimed at epigenetic and mutational drivers, cellular pathway aberrations and tumor microenvironment mechanisms in DMGs in order to aid therapy development and facilitate a holistic approach to patient treatment.

In vitro and in vivo drug screens of tumor cells identify novel therapies for high-risk child cancer.

Biomarkers which better match anticancer drugs with cancer driver genes hold the promise of improved clinical responses and cure rates. We developed a precision medicine platform of rapid high-throughput drug screening (HTS) and patient-derived xenografting (PDX) of primary tumor tissue, and evaluated its potential for treatment identification among 56 consecutively enrolled high-risk pediatric cancer patients, compared with conventional molecular genomics and transcriptomics. Drug hits were seen in the majority of HTS and PDX screens, which identified therapeutic options for 10 patients for whom no targetable molecular lesions could be found.

Parents' experiences of postmortem tumor donation for high-grade gliomas: benefits and suggested improvements.

Background: Pediatric high-grade glioma is a devastating diagnosis. There has been no improvement in outcomes for several decades, with few children surviving 2 years postdiagnosis. Research progress has been hampered by a lack of tumor samples, which can be used to develop and test novel therapies.

The important role of routine cytopathology in pediatric precision oncology.

Background: The development of high-throughput drug screening (HTS) using primary cultures provides a promising, clinically translatable approach to tailoring treatment strategies for patients with cancer. However, this has been challenging for solid tumors because of often limited amounts of tissue available. In most cases, in vitro expansion is required before HTS, which may lead to overgrowth and contamination by non-neoplastic cells.

Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG.

Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. CBL0137 is an anti-cancer compound developed from quinacrine that targets facilitates chromatin transcription (FACT), a chromatin remodeling complex involved in transcription, replication, and DNA repair. We show that CBL0137 displays profound cytotoxic activity against a panel of patient-derived DIPG cultures by restoring tumor suppressor TP53 and Rb activity.

Doxorubicin-Loaded Gold Nanoarchitectures as a Therapeutic Strategy against Diffuse Intrinsic Pontine Glioma.

Diffuse Intrinsic Pontine Gliomas (DIPGs) are highly aggressive paediatric brain tumours. Currently, irradiation is the only standard treatment, but is palliative in nature and most patients die within 12 months of diagnosis. Novel therapeutic approaches are urgently needed for the treatment of this devastating disease.

Dual targeting of polyamine synthesis and uptake in diffuse intrinsic pontine gliomas.

Diffuse intrinsic pontine glioma (DIPG) is an incurable malignant childhood brain tumor, with no active systemic therapies and a 5-year survival of less than 1%. Polyamines are small organic polycations that are essential for DNA replication, translation and cell proliferation. Ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme in polyamine synthesis, is irreversibly inhibited by difluoromethylornithine (DFMO).

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population.

Targeting reduced mitochondrial DNA quantity as a therapeutic approach in pediatric high-grade gliomas.

Background: Despite increased understanding of the genetic events underlying pediatric high-grade gliomas (pHGGs), therapeutic progress is static, with poor understanding of nongenomic drivers. We therefore investigated the role of alterations in mitochondrial function and developed an effective combination therapy against pHGGs.

Methods: Mitochondrial DNA (mtDNA) copy number was measured in a cohort of 60 pHGGs.

Germline deletion of in familial acute lymphoblastic leukemia.

Recent studies have identified germline mutations in , , , and in kindreds with familial acute lymphoblastic leukemia (ALL), but the genetic basis of ALL in many kindreds is unknown despite mutational analysis of the exome. Here, we report a germline deletion of identified by linkage and structural variant analysis of whole-genome sequencing data segregating in a kindred with thrombocytopenia, B-progenitor acute lymphoblastic leukemia, and diffuse large B-cell lymphoma. The 75-nt deletion removed the exon 7 splice acceptor, resulting in exon skipping and protein truncation.

Predictors of Success of Phase II Pediatric Oncology Clinical Trials.

Background: There are limited data to predict which novel childhood cancer therapies are likely to be successful. To help rectify this, we sought to identify the factors that impact the success of phase II clinical trials for pediatric malignancies.

Materials And Methods: We examined the impact of 24 preclinical and trial design variables for their influence on 132 phase II pediatric oncology clinical trials.

Correction to: International experience in the development of patient-derived xenograft models of diffuse intrinsic pontine glioma.

There are two errors and one omission in the original article. Author Gottardo's correct name is Nicholas G. Gottardo, author Hulleman's correct affiliation is no.