KinoViz: A User-Friendly Web Application for High-Throughput Kinome Profiling Analysis and Visualization in Cancer Research.

Kinases, at the signaling level, dynamically mediate uncontrolled cellular growth, survival and other cancer supporting processes. This, paired with the inherent druggability of kinases, points to the importance of measuring kinase activity, and that of inhibitors against them, directly, and to analyze this accurately. High-throughput kinome profiling technologies, such as the PamStation12, allow researchers to kinetically capture kinase activity, against a multitude of peptide targets simultaneously.

Identifying and exploiting combinatorial synthetic lethality by characterizing adaptive kinome rewiring of EGFRvIII-driven glioblastoma.

GBM is an aggressive primary malignant brain tumor that has a poor prognosis. Molecular characterization of GBM has shown that EGFR mutations are present in over 50% of tumors. However, EGFR inhibitors have not shown clinical efficacy in contrast to other EGFR-driven neoplasms due to the unique EGFR biology found in GBM.

Xenoline-polarized macrophages as an alternative in vitro model of tumor-associated macrophages in glioblastoma.

Tumor-associated macrophages (TAMs) are the most abundant non-cancerous cell type in glioblastoma (GBM) and heavily influence GBM biology, contributing to tumor progression, therapeutic resistance, immune evasion, and neovascularization. Current in vitro models that utilize IL-4/IL-13 stimulation fail to capture the transcriptional and functional heterogeneity of TAMs observed in vivo. In this study, we utilize a serum-free indirect co-culture model with patient-derived xenolines to polarize primary human macrophages and characterize their molecular and functional phenotypes.

Acquired resistance in cancer: towards targeted therapeutic strategies.

Development of acquired therapeutic resistance limits the efficacy of cancer treatments and accounts for therapeutic failure in most patients. How resistance arises, varies across cancer types and differs depending on therapeutic modalities is incompletely understood. Novel strategies that address and overcome the various and complex resistance mechanisms necessitate a deep understanding of the underlying dynamics.

Xenoline-polarized macrophages as a physiologically relevant in vitro model of tumor-associated macrophages in glioblastoma.

Tumor-associated macrophages (TAMs) are the most abundant non-cancerous cell type in glioblastoma (GBM) and heavily influence GBM biology, contributing to tumor progression, therapeutic resistance, immune evasion, and neovascularization. Current models that utilize IL-4/IL-13 stimulation fail to capture the transcriptional and functional heterogeneity of TAMs observed in vivo. In this study, we utilize a serum-free indirect co-culture model with patient-derived xenolines to polarize primary human macrophages and characterize their molecular and functional phenotypes.

IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity.

Identification of isocitrate dehydrogenase (IDH) mutations has uncovered the crucial role of metabolism in gliomagenesis. Oncolytic herpes virus (oHSV) initiates direct tumor debulking by tumor lysis and activates anti-tumor immunity, however, little is known about the role of glioma metabolism in determining oHSV efficacy. Here we identify that oHSV rewires central carbon metabolism increasing glucose utilization towards oxidative phosphorylation and shuttling glutamine towards reductive carboxylation in IDH wildtype glioma.

Requirements and Study Design for the Next Proton FLASH Clinical Trials: an International Multidisciplinary Delphi Consensus.

Purpose: The FLASH effect, defined as normal tissue sparing while maintaining tumor control with ultra-high dose-rate irradiation, has been demonstrated preclinically in different tumors and tissues. Although the biological mechanisms are unclear, there is a need for clinical trials investigating the value of proton FLASH irradiation (pFLASH). The purpose of this study was to establish an expert consensus regarding prerequisites, study design, and endpoints for the next clinical trials exploring the clinical potentials of pFLASH.

A High-Throughput Neurosphere-Based Colony Formation Assay to Test Drug and Radiation Sensitivity of Different Patient-Derived Glioblastoma Lines.

The gold standard assay for radiation response is the clonogenic assay, a normalized colony formation assay (CFA) that can capture a broad range of radiation-induced cell death mechanisms. Traditionally, this assay relies on two-dimensional (2D) cell culture conditions with colonies counted by fixing and staining protocols. While some groups have converted these to three-dimensional (3D) conditions, these models still utilize 2D-like media compositions containing serum that are incompatible with stem-like cell models such as brain tumor initiating cells (BTICs) that form self-aggregating spheroids in neural stem cell media.

Altering fractionation during radiation overcomes radio-resistance in patient-derived glioblastoma cells assessed using a novel longitudinal radiation cytotoxicity assay.

Purpose: Current radiotherapy (RT) in glioblastoma (GBM) is delivered as constant dose fractions (CDF), which do not account for intratumoral-heterogeneity and radio-selection in GBM. These factors contribute to differential treatment response complicating the therapeutic efficacy of this principle. Our study aims to investigate an alternative dosing strategy to overcome radio-resistance using a novel longitudinal radiation cytotoxicity assay.

Exploring Gut Microbiota Alterations with Trimethoprim-Sulfamethoxazole and Dexamethasone in a Humanized Microbiome Mouse Model.

Along with the standard therapies for glioblastoma, patients are commonly prescribed trimethoprim-sulfamethoxazole (TMP-SMX) and dexamethasone for preventing infections and reducing cerebral edema, respectively. Because the gut microbiota impacts the efficacy of cancer therapies, it is important to understand how these medications impact the gut microbiota of patients. Using mice that have been colonized with human microbiota, this study sought to examine how TMP-SMX and dexamethasone affect the gut microbiome.

Explorative Discovery of Gene Signatures and Clinotypes in Glioblastoma Cancer Through GeneTerrain Knowledge Map Representation.

This study introduces the GeneTerrain Knowledge Map Representation (GTKM), a novel method for visualizing gene expression data in cancer research. GTKM leverages protein-protein interactions to graphically display differentially expressed genes (DEGs) on a 2-dimensional contour plot, offering a more nuanced understanding of gene interactions and expression patterns compared to traditional heatmap methods. The research demonstrates GTKM's utility through four case studies on glioblastoma (GBM) datasets, focusing on survival analysis, subtype identification, IDH1 mutation analysis, and drug sensitivities of different tumor cell lines.

Patient-Derived Models of Cancer in the NCI PDMC Consortium: Selection, Pitfalls, and Practical Recommendations.

For over a century, early researchers sought to study biological organisms in a laboratory setting, leading to the generation of both in vitro and in vivo model systems. Patient-derived models of cancer (PDMCs) have more recently come to the forefront of preclinical cancer models and are even finding their way into clinical practice as part of functional precision medicine programs. The PDMC Consortium, supported by the Division of Cancer Biology in the National Cancer Institute of the National Institutes of Health, seeks to understand the biological principles that govern the various PDMC behaviors, particularly in response to perturbagens, such as cancer therapeutics.

Correction: Chen et al. Targeted Extracellular Vesicles Delivered Verrucarin A to Treat Glioblastoma. 2022, , 130.

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Carmofur prevents cell cycle progression by reducing E2F8 transcription in temozolomide-resistant glioblastoma cells.

Sphingolipid metabolism is dysregulated in many cancers, allowing cells to evade apoptosis through increased sphingosine-1-phosphate (S1P) and decreased ceramides. Ceramidases hydrolyze ceramides to sphingosine, which is phosphorylated by sphingosine kinases to generate S1P. The S1P allows cells to evade apoptosis by shifting the equilibrium away from ceramides, which favor cell death.

Tumor Treating Fields Alter the Kinomic Landscape in Glioblastoma Revealing Therapeutic Vulnerabilities.

Treatment for the deadly brain tumor glioblastoma (GBM) has been improved through the non-invasive addition of alternating electric fields, called tumor treating fields (TTFields). Improving both progression-free and overall survival, TTFields are currently approved for treatment of recurrent GBMs as a monotherapy and in the adjuvant setting alongside TMZ for newly diagnosed GBMs. These TTFields are known to inhibit mitosis, but the full molecular impact of TTFields remains undetermined.

Understanding the Effect of Prescription Isodose in Single-Fraction Stereotactic Radiosurgery on Plan Quality and Clinical Outcomes for Solid Brain Metastases.

Background And Objectives: There is wide variation in treatment planning strategy for central nervous system (CNS) stereotactic radiosurgery. We sought to understand what relationships exist between intratumor maximum dose and local control (LC) or CNS toxicity, and dosimetric effects of constraining hotspots on plan quality of multiple metastases volumetric modulated arc therapy radiosurgery plans.

Methods: We captured brain metastases from 2015 to 2017 treated with single-isocenter volumetric modulated arc therapy radiosurgery.

Using 3D-bioprinted models to study pediatric neural crest-derived tumors.

The use of three-dimensional (3D) bioprinting has remained at the forefront of tissue engineering and has recently been employed for generating bioprinted solid tumors to be used as cancer models to test therapeutics. In pediatrics, neural crest-derived tumors are the most common type of extracranial solid tumors. There are only a few tumor-specific therapies that directly target these tumors, and the lack of new therapies remains detrimental to improving the outcomes for these patients.

Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling.

Therapeutic resistance to immune checkpoint blockers (ICBs) in melanoma patients is a pressing issue, of which tumor loss of IFN-γ signaling genes is a major underlying mechanism. However, strategies of overcoming this resistance mechanism have been largely elusive. Moreover, given the indispensable role of tumor-infiltrating T cells (TILs) in ICBs, little is known about how tumor-intrinsic loss of IFN-γ signaling (IFNγR1) impacts TILs.

An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases.

Key molecular regulators of acquired radiation resistance in recurrent glioblastoma (GBM) are largely unknown, with a dearth of accurate preclinical models. To address this, we generated 8 GBM patient-derived xenograft (PDX) models of acquired radiation therapy-selected (RTS) resistance compared with same-patient, treatment-naive (radiation-sensitive, unselected; RTU) PDXs. These likely unique models mimic the longitudinal evolution of patient recurrent tumors following serial radiation therapy.

Serine-Threonine Kinase Receptor Associate Protein (STRAP) confers an aggressive phenotype in neuroblastoma via regulation of Focal Adhesion Kinase (FAK).

Background: Serine-threonine kinase receptor associated protein (STRAP), a scaffolding protein, is upregulated in many solid tumors. As such, we hypothesized that STRAP may be overexpressed in neuroblastoma tumors and may play a role in neuroblastoma tumor progression.

Methods: We examined two publicly available neuroblastoma patient databases, GSE49710 (n = 498) and GSE49711 (n = 498), to investigate STRAP expression in human specimens.

Understanding Drug Sensitivity and Tackling Resistance in Cancer.

Decades of research into the molecular mechanisms of cancer and the development of novel therapeutics have yielded a number of remarkable successes. However, our ability to broadly assign effective, rationally targeted therapies in a personalized manner remains elusive for many patients, and drug resistance persists as a major problem. This is in part due to the well-documented heterogeneity of cancer, including the diversity of tumor cell lineages and cell states, the spectrum of somatic mutations, the complexity of microenvironments, and immune-suppressive features and immune repertoires, which collectively require numerous different therapeutic approaches.

Inhibition of DNA-PK may improve response to neoadjuvant chemoradiotherapy in rectal cancer.

Treatment of locally advanced rectal cancer includes chemoradiation and surgery, but patient response to treatment is variable. Patients who have a complete response have improved outcomes; therefore, there is a critical need to identify mechanisms of resistance to circumvent them. DNA-PK is involved in the repair of DNA double-strand breaks caused by radiation, which we found to be increased in rectal cancer after treatment.

Targeting High-Risk Neuroblastoma Patient-Derived Xenografts with Oncolytic Virotherapy.

Cancer is the leading cause of death by disease in children, and over 15% of pediatric cancer-related mortalities are due to neuroblastoma. Current treatment options for neuroblastoma remain suboptimal as they often have significant toxicities, are associated with long-term side effects, and result in disease relapse in over half of children with high-risk disease. There is a dire need for new therapies, and oncolytic viruses may represent an effective solution.