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Principal Investigator: Daniela Annenelie Bota
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2024
Award: $399,338
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Glioblastoma (GBM) is the most aggressive primary brain tumor with a two years survival rate of less than 50%
following surgical resection, radiation, and chemotherapy. Recurrence is nearly universal after the first-line
treatment, and there is currently no therapy proven to prolong survival after tumor recurrence. Thus, there is an
urgent need for more effective GBM therapies. The overarching goal of this project is to further develop and
validate new chemotherapeutic agents for the treatment of GBM. GBM's resistance to radiation and
chemotherapy heavily correlates with extensive hypoxia-induced, mitochondria-dependent phenotypic changes
such as glycolytic respiration, decreased the ability to undergo apoptosis and extensive invasiveness.
Mitochondrial LonP1 is an ATP-stimulated protease, directly up-regulated by HIF-1α. LonP1 is overexpressed in
human malignant gliomas and its elevated expression levels are associated with high glioma tumor grade and
poor patient survival. Therefore, regulation of mitochondrial function by inhibiting LonP1 protease could represent
a novel approach for GBM and potentially other fast-growing malignancies which heavily depend on hypoxic
adaptation. The proposed project is based on our published and preliminary results obtained from in vitro (cell-
based) studies with LonP1 inhibition using siRNA and the inhibitor compounds CC4 and BT317 and in vivo
LonP1-overexpression xenograft models studies. BT317 is a small molecule compound, able to cross the blood-
brain barrier and to achieve promising concentrations in the brain. BT317 is highly effective in inducing cell death
in multiple glioma lines and patient-derived glioblastoma stem cell cultures, with an IC50 value of 60-100 µM
(temozolomide – the main FDA approved therapy and has minimal toxicity in normal lines. identifying BT317 as
a potentially new therapy for this universally fatal disease. In this project, we propose to: (1) examine the effect
of mitochondrial LonP1 knockout in distinct patient-derived primary glioma stem-like cells (GSC), glioblastoma
cell lines and xenograft models, (2) identify microenvironment cues and LonP1-induced mitochondrial changes
that drive GSC invasiveness, and (3) examine the drug-target inhibition and molecular mechanisms for anti-
cancer efficacy of the LonP1 inhibitor, BT317. The studies outlined here are the first to explore a very promising
avenue – mitochondrial Lon protease inhibition – as a treatment for GBM.
Terms: <21+ years old><Abscission><Adult><Adult Human><Animal Model><Animal Models and Related Studies><Apoptosis><Apoptosis Pathway><Automobile Driving><Autoregulation><BALB C Mouse><BALB/c><BBB crossing><Binding><Biochemical><Bioenergetics><Biogenesis><Biological><Biology><Brain><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Tumors><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancers><Cas nuclease technology><Cell Body><Cell Culture Techniques><Cell Cycle><Cell Death Induction><Cell Division Cycle><Cell Line><Cell Survival><Cell Viability><CellLine><Cells><Cervical><Chaperone><Chemotherapy and Radiation><Chemotherapy and/or radiation><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Colon or Rectum><Colorectal><Cues><DNA Replication><DNA Synthesis><DNA Therapy><DNA biosynthesis><Development><Disease><Disorder><Drug Targeting><Encephalon><Equilibrium><Esteroproteases><Excision><Extirpation><FDA approved><Gene Transfer Clinical><General Prognostic Factor><Generalized Growth><Genetic Intervention><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Growth><Heat shock proteins><Homeostasis><Human><Hypoxia><Hypoxic><Immunodeficient Mouse><In Vitro><Inbred BALB C Mice><Knock-out><Knockout><Lead><Libraries><Link><Lon Protease><Malignant Glial Neoplasm><Malignant Glial Tumor><Malignant Glioma><Malignant Melanoma><Malignant Neoplasms><Malignant Neuroglial Neoplasm><Malignant Neuroglial Tumor><Malignant Tumor><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Measures><Melanoma><Mesenchymal><Metabolic><Metabolic Protein Degradation><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mitochondria><Mitochondrial DNA><Mitochondrial Proteins><Modeling><Modern Man><Molecular><Molecular Chaperones><Molecular Interaction><Neoplasm Metastasis><Neuroglial Neoplasm><Neuroglial Tumor><Non-Polyadenylated RNA><Normal Cell><Operative Procedures><Operative Surgical Procedures><Oral><Origin of Life><Oxygen Deficiency><Pathway interactions><Patients><Pb element><Peptidases><Peptide Hydrolases><Phenotype><Physiological Homeostasis><Primary Brain Neoplasms><Primary Brain Tumors><Process><Progenitor Cells><Prognosis><Prognostic Factor><Prognostic/Survival Factor><Programmed Cell Death><Protease Gene><Protease La><Proteases><Protein Turnover><Proteinases><Proteins><Proteolytic Enzymes><Publishing><RNA><RNA Gene Products><Radiation therapy><Radiotherapeutics><Radiotherapy><Recurrence><Recurrent><Recurrent Neoplasm><Recurrent tumor><Regulation><Regulatory Protein Degradation><Removal><Resistance><Respiration><Ribonucleic Acid><Role><Secondary Neoplasm><Secondary Tumor><Short interfering RNA><Small Interfering RNA><Strains Cell Lines><Structure-Activity Relationship><Study models><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Survival Rate><System><Temodal><Temodar><Testing><Therapeutic><Tissue Growth><Toxic effect><Toxicities><Up-Regulation><Upregulation><Xenograft Model><adulthood><anti-cancer><balance><balance function><biologic><blood-brain barrier crossing><bloodbrain barrier crossing><cancer metastasis><cell culture><cell cultures><chemical structure function><chemo/radiation therapy><chemotherapeutic agent><chemotherapy><chemotherapy and radiotherapy><clinical applicability><clinical application><colorectum><cultured cell line><cytotoxic><developmental><driving><endopeptidase La><epithelial to mesenchymal transition><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic therapy><glial-derived tumor><glioblastoma multiforme><glioma cell line><heavy metal Pb><heavy metal lead><in vivo><in vivo Model><inhibitor><interest><knock-down><knockdown><malignancy><meter><methazolastone><mitochondrial><mitochondrial DNA mutation><mitochondrial dysfunction><mitochondrial metabolism><model of animal><mtDNA><mtDNA mutation><neoplasm recurrence><neoplasm/cancer><neuroglia neoplasm><neuroglia tumor><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><nutrient deprivation><nutritional deprivation><ontogeny><overexpress><overexpression><pathway><pharmacologic><progenitor-like cell><protein degradation><radiation or chemotherapy><radiation treatment><resection><resistance to therapy><resistant><resistant to therapy><respiratory mechanism><response><siRNA><small molecule><social role><spongioblastoma multiforme><stable cell line><standard of care><stem cells><stem-like cell><stress protein><structure function relationship><surgery><synergism><temozolomide><therapeutic resistance><therapy resistant><treatment resistance><treatment with radiation><tumor><tumor cell metastasis><tumor growth><tumor initiation><tumors in the brain><xenograft transplant model><xenotransplant model>