Use of CTEP portfolio compounds to counteract phenotype conversion in GBM

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Principal Investigator: Frank  Pajonk
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $102,267
Funding agency: National Cancer Institute

SUMMARY/ABSTRACT
Despite a tremendous effort in basic science, clinical trials, drug development, and technical advances in
surgery and radiation oncology, glioblastoma remains incurable and improvements in overall survival have
been marginal. While radiotherapy is still one of the most effective treatment options for glioblastoma, it cannot
control the disease over time. This suggests that novel combination therapies are desperately needed to
improve radiation treatment outcome for patients suffering from this disease. The studies outlined in this
proposal are based on a hypothesis that is backed by our extensive preliminary data and rigorous published
data in the literature. The overall hypothesis is that biomarker-based drug selection predicts synergistic lethality
of combination therapies in GICs and glioblastoma bulk tumor cell populations, prevents radiation-induced
GBM phenotype conversion and allows for individualized optimization of radiotherapy. The three aims of this
study will address this aspect of glioma biology using an innovative tool to track GICs and their progeny, while
leveraging the unique resources and expertise available at UCLA and the NIH/NCI CTEP portfolio of drugs.
Aim 1 will identify compounds in the NCI CTEP portfolio that interfere with radiation-induced phenotype
conversion in glioblastoma and develop biomarker profiles predictive of synergistic lethality in combination with
radiation. Studies in Aim 2 will optimize combination therapies in vivo. Finally, Aim 3, will use patient avatar
studies to validate biomarker-based drug selection in PDX models of glioblastoma.

Terms: <3-D><3-Dimensional><3D><Affect><Assay><BBB crossing><Basic Research><Basic Science><Bioassay><Biological Assay><Biological Markers><Biology><Brain Cancer><Breast Cancer><CTEP><Cancer Therapy Evaluation Program><Cancers><Cell Body><Cell Differentiation><Cell Differentiation process><Cells><Cholesterol><Clinical><Clinical Trials><Clonal Evolution><Combination Drug Therapy><Combined Modality Therapy><Data><Disease><Disorder><Dose><Drug Interactions><Drug Kinetics><Drugs><Electromagnetic Energy><Electromagnetic Radiation><Electromagnetic Waves><Endogenous Nitrate Vasodilator><Endothelium-Derived Nitric Oxide><Fatty Acids><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Generations><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Hypoxia><Hypoxic><In Vitro><Level of Evidence><Literature><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Medication><Metabolic><Modality><Modeling><Mononitrogen Monoxide><Multimodal Therapy><Multimodal Treatment><NIH><National Institutes of Health><Neural Stem Cell><Neuroglial Neoplasm><Neuroglial Tumor><Nitric Oxide><Nitrogen Monoxide><Nitrogen Protoxide><Oxygen Deficiency><PDX model><Pathway interactions><Patient derived xenograft><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pharmaceutical Preparations><Pharmacokinetics><Phenotype><Polychemotherapy><Population><Process><Progenitor Cells><Publishing><Radiation><Radiation Dose><Radiation Dose Unit><Radiation Oncology><Radiation therapy><Radioresistance><Radiotherapeutics><Radiotherapy><Recurrence><Recurrent><Reporting><Research Resources><Research Specimen><Resources><Scheme><Specimen><Surgical Oncology><Temodal><Temodar><Testing><Time><Total Radiation><Toxic effect><Toxicities><Transcript Expression Analyses><Transcript Expression Analysis><Transgenic Mice><Treatment Failure><Tumor Cell><United States National Institutes of Health><analyze gene expression><bio-markers><biologic marker><biomarker><biomarker identification><biomarker validation><blood-brain barrier crossing><bloodbrain barrier crossing><cancer cell><cancer progenitor><cancer progenitor cells><cancer stem cell><cellular differentiation><chemotherapeutic agent><cholesterol biosynthesis><combination chemotherapy><combination pharmacotherapy><combination therapy><combined modality treatment><combined treatment><disease control><disorder control><drug development><drug/agent><effective therapy><effective treatment><endothelial cell derived relaxing factor><gene expression analysis><gene expression assay><glial-derived tumor><glioblastoma multiforme><iPS><iPSC><iPSCs><identification of biomarkers><identification of new biomarkers><imaging system><improved><in vivo><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><inhibitor><innovate><innovation><innovative><malignancy><malignant breast tumor><malignant progenitor><malignant stem cell><marker identification><marker validation><methazolastone><mevalonate><mouse model><multi-modal therapy><multi-modal treatment><murine model><neoplasm/cancer><neoplastic cell><nerve stem cell><nestin><nestin protein><neural precursor><neural precursor cell><neural progenitor><neural progenitor cells><neurogenesis><neuroglia neoplasm><neuroglia tumor><neuron progenitors><neuronal progenitor><neuronal progenitor cells><neuronal stem cells><neuroprogenitor><novel><oncologic surgery><pathway><patient derived xenograft model><patient oriented outcomes><prevent><preventing><radiation resistance><radiation resistant><radiation treatment><radio resistance><radioresistant><resistance to therapy><resistant to radiation><resistant to therapy><responders and non-responders><responders from non-responders><responders or non-responders><responders versus non-responders><responders vs non-responders><responders/nonresponders><self-renew><self-renewal><spongioblastoma multiforme><standard of care><stem cells><synergism><targeted agent><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><temozolomide><therapeutic outcome><therapeutic resistance><therapy failure><therapy outcome><therapy resistant><three dimensional><tool><trait><transcriptional profiling><treatment resistance><treatment with radiation><tumor><tumor initiation>