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Principal Investigator: Sandeep Burma
Organization: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
Fiscal Year: 2024
Award: $536,215
Funding agency: National Cancer Institute
Pediatric glioma is characterized by activation of the MAPK pathway, either through a tandem duplication of
the BRAFA locus, or through point mutations (most frequently the V600E mutation). Approximately 1400 new
cases of BRAF-activated childhood brain tumors are diagnosed annually in the US. Recent phase I/II trials have
confirmed the efficacy of MEK inhibitors ((MEKi) for teatment of these cancers. However, for tumors driven by
the BRAF(V600E) mutant patients may progress on selumetinib treatment (i.e. become resistant), or rapidly
progress if drug dose is reduced or treatment stopped (at 2 years as in the recent phase II trial). Thus, while
MEKi is effective in causing tumor regression, it is not curative. Clinical results suggest that selumetinib is equally
as effective as conventional chemo-radiation therapy, but without toxicities associated with intensive chemo-
radiation treatment. Hence, MEK inhibitors usher in a new era in treatment for these patients.
Our studies were some of the only PDX preclinical data that lead to testing of selumetinib (MEK inhibitor) in
the Pediatric Brain Tumor Consortium trial (PBTC029), with efficacy confirmed in the subsequent phase II trial
(NCT01089101). Here we propose preclinical studies that could lead to the next generation of clinical trials
building on the results from current MEKi trials. The studies proposed in this application will use a unique panel
of BRAF(V600E) pediatric brain tumor PDX models to focus on two critical issues: 1) to develop MAPK inhibitor
combinations that selectively enhance tumor cell kill in combination with radiation therapy (RT), and 2) to develop
therapeutic approaches to prevent development of drug resistance. The central hypothesis is that sensitivity
to MAPKi is a consequence of dual MAPK/TORC1 inhibition, and low-dose intermittent rapamycin can prevent
emergence of resistance to MEKi, and also to radiation therapy. These studies will also explore mechanisms of
resistance to MAPK inhibitor combinations and radiation treatment (RT), alone or in combination, and
characterize the mechanism/s by which rapamycin prevents emergence of resistance.
Our overall goal is to identify optimal MAPK/TORC1 inhibitor drug combinations that retard or prevent
emergence of drug or RT resistance, determine the mechanism/s by which rapamycin retards/prevents
emergence of MAPKi and RT resistance, and determine whether such combinations can maintain tumor control
at lower doses of RT. Potentially, the proposed studies will identify novel regimens that will be more efficacious
than selumetinib and ultimately result in the ability to reduce the RT dose in patients, thus improving long-term
outcomes and quality of life.
Terms: <0-11 years old><Address><Astrocytic Glioma><Astrocytic Neoplasm><Astrocytic Tumor><Astrocytoma><Astroglioma><B-raf-1><BRAF><BRAF gene><Bourneville Disease><Bourneville Phakomatosis><Bourneville syndrome><Bourneville-Brissaud disease><Bourneville-Pringle syndrome><Brain Neoplasia><Brain Neoplasms><Brain Tumors><CNS Tumor><CNS neoplasm><Cancers><Cause of Death><Cell Communication and Signaling><Cell Death><Cell Signaling><Central Nervous System Neoplasms><Central Nervous System Tumors><Child><Child Youth><Childhood><Childhood Brain Neoplasm><Childhood Brain Tumor><Childhood CNS Neoplasm><Childhood CNS Tumor><Childhood Central Nervous System Neoplasm><Childhood Central Nervous System Tumor><Childhood Glioblastoma><Childhood Glioma><Childhood Neoplasm><Childhood Pilocytic Astrocytoma><Childhood Tumor><Children (0-21)><Children's Oncology Group><Clinical><Clinical Trials><Combined Modality Therapy><Complex><Cytotoxic agent><Cytotoxic drug><DNA Damage><DNA Injury><Data><Data Bases><Databases><Diffuse astrocytoma><Disease><Disease Progression><Disorder><Dose><Drug Combinations><Drug Therapy><Drug resistance><Drugs><Epiloia><Ganglioglioma><Genetic Alteration><Genetic Change><Genetic defect><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioblastoma><Glioma><Goals><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Intracellular Communication and Signaling><Investigators><Juvenile Pilocytic Astrocytomas><Laboratories><Low Dose Radiation><Lytotoxicity><MAP Kinase Kinase 1><MAP kinase><MAP2K1><MAP2K1 gene><MAPK Inhibitors><MAPK Signaling Pathway><MAPK Signaling Pathway Pathway><MAPK/ERK Kinase 1><MAPKK1><MEK-1><MEK1><MEKs><MKK1><Malignant Neoplasms><Malignant Tumor><Mediating><Medication><Mitogen-Activated Protein Kinase Inhibitor><Mitogen-Activated Protein Kinase Kinase-1><Mitogen-Activated Protein Kinases><Modeling><Multimodal Therapy><Multimodal Treatment><Mutation><NF-1><NF-1 Protein><NF-1 encoded protein><NF1><NF1 GRP><NF1 Protein><NF1 gene><NF1-GAP-Related Protein><Neurofibromatosis 1 Genes><Neurofibromatosis Type 1 Gene Product><Neurofibromatosis Type 1 Protein><Neurofibromin><Neurofibromin 1><Neuroglial Neoplasm><Neuroglial Tumor><Outcome><PDX model><PRKMK1><Pathway interactions><Patient derived xenograft><Patients><Pediatric Brain Tumor Consortium><Pediatric Glioblastoma><Pediatric Glioblastoma multiforme><Pediatric Glioma><Pediatric Neoplasm><Pediatric Oncology Group><Pediatric Pilocytic Astrocytoma><Pediatric Tumor><Pediatric high-grade glioma><Pharmaceutical Preparations><Pharmacology><Pharmacotherapy><Phase><Phase 1/2 trial><Phase I/II Trial><Phosphorylation><Point Mutation><Pringle disease><Protein Phosphorylation><QOL><Quality of life><RAFB1><Radiation Physics><Radiation therapy><Radioresistance><Radiotherapeutics><Radiotherapy><Rapamune><Rapamycin><Regimen><Relapse><Reporting><Research><Research Personnel><Researchers><Resistance><Resistance development><Resistant development><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sirolimus><TSC2><TSC2 gene><TSC4><TSC4 Gene><Testing><Therapeutic><Toxic effect><Toxicities><Translating><Translational Research><Translational Science><Tuberin><Tuberous Sclerosis><Tumor Cell><adenoma sebaceum><biological signal transduction><cancer progression><cell killing><cerebral sclerosis><chemo-/radio-therapy><chemo-radio-therapy><chemo-radiotherapy><chemoradiation><chemoradiation therapy><chemoradiation treatment><chemoradiotherapy><child patients><combination therapy><combined modality treatment><combined treatment><cytotoxicity><data base><develop drug resistance><developing resistance><driver lesion><driver mutation><drug resistance development><drug resistant><drug treatment><drug/agent><epiploia><genome mutation><glial-derived tumor><glioblastoma multiforme><hereditary multiple system hamartomatosis><improved><inhibitor><inhibitor drug><inhibitor therapeutic><inhibitor therapy><kids><malignancy><mouse model><multi-modal therapy><multi-modal treatment><multidisciplinary><murine model><mutant><necrocytosis><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><neurinomatosis centralis><neurofibromatosis type 1 gene><neurofibromatosis type 1 protein/gene><neuroglia neoplasm><neuroglia tumor><neuromatosis universalis><neurospongioblastosis diffusa><next generation><nf 1 Genes><novel><pathway><patient derived xenograft model><pediatric><pediatric CNS neoplasm><pediatric CNS tumor><pediatric brain neoplasm><pediatric brain tumor><pediatric central nervous system neoplasm><pediatric central nervous system tumor><pediatric low grade glioma><pediatric patients><phacomatosis><phase 2 trial><phase II trial><pre-clinical><pre-clinical study><preclinical><preclinical study><prevent><preventing><radiation resistance><radiation treatment><radio resistance><radio-chemo-therapy><radio-chemotherapy><radiochemotherapy><resistance mechanism><resistance to Drug><resistant><resistant mechanism><resistant to Drug><response><sclerosis tuberosa><spongioblastoma multiforme><spongioblastosis circumscripta><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><translation research><translational investigation><treatment with radiation><tuberose sclerosis><tuberous sclerosis complex><tumor><tumor diagnosis><tumor progression><tumors in children><tumors in the brain><tumors in the central nervous system><v-raf Murine Sarcoma Viral Oncogene Homolog B1><youngster>