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Principal Investigator: Leomar Y Ballester
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $260,634
Funding agency: National Cancer Institute
Project Summary/Abstract
Primary and metastatic central nervous system tumors (CNS) are associated with a high degree of morbidity
and mortality. There is a need for new and more effective strategies for diagnosing, treating and monitoring
patients with primary and metastatic CNS tumors. Methodologies that address the need for molecular
information that is required for the use of precision medicine and targeted therapies, in patients with CNS
tumors, are limited. A liquid biopsy assay will facilitate early molecular characterization and monitoring of
patients with CNS tumors and will revolutionize patient management. Studies have shown that blood is not a
suitable fluid for the detection of tumor-derived biomarkers in patients with CNS malignancies. In contrast,
cerebrospinal fluid (CSF), due to its proximity to the brain parenchyma, is a source of informative biomarkers
(e.g., circulating tumor DNA (ctDNA) and metabolites). We hypothesize that it is possible to perform pre-
operative molecular characterization and monitoring of patients with CNS tumors by analyzing ctDNA and
metabolites in the CSF. Moreover, our prediction is that the levels of these biomarkers will correlate with tumor
burden. We anticipate that quantification of these biomarkers in the CSF will facilitate monitoring patients with
CNS cancer for tumor recurrence and response to therapies. Our preliminary experiments show that we can
isolate ctDNA from small volumes of CSF and detect mutations by next generation sequencing (NGS) and
droplet digital PCR (ddPCR), at a mutant allele frequency of 0.25% and 0.1%, respectively. We have also
identified tumor-specific metabolic signatures in the CSF, and our data shows higher levels of D-2-
hydroglyglutarate in the CSF of patients with CNS tumors harboring an IDH1/IDH2 mutation. We propose to
pursue two specific aims to develop a CSF-liquid biopsy assay: (1) Validation of a next generation sequencing
(NGS) assay to quantify tumor DNA in CSF; (2) To perform metabolomic analysis of ~125 tumor-derived
metabolites in CSF. This multi-platform approach will allow comparisons of sensitivity and specificity among
various methodologies and cross correlation of results between platforms. Volumetric analysis of CNS lesions
in MRI will allow us to evaluate the potential of each biomarker for quantifying CNS tumor burden. We
anticipate that these studies will culminate in the clinical implementation of a liquid biopsy assay to facilitate
diagnosis and the use of targeted therapies in adult of pediatric patients with primary or metastatic CNS
tumors.
Terms: <21+ years old><Address><Adult><Adult Human><Affect><Allele Frequency><Assay><Bioassay><Biological Assay><Biological Markers><Biopsy><Blood><Blood Reticuloendothelial System><Body Tissues><Brain Neoplasia><Brain Neoplasms><Brain Tumors><CNS Tumor><CNS neoplasm><Cancers><Central Nervous System Neoplasms><Central Nervous System Tumors><Cerebrospinal Fluid><Clinical><Collection><Data><Detection><Development><Diagnosis><Gene Frequency><Genes><Genetic Alteration><Genetic Change><Genetic defect><Glial Cell Tumors><Glial Neoplasm><Glial Tumor><Glioma><Intermediary Metabolism><Lesion><Liquid substance><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measurement><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methodology><Methods><Molecular><Monitor><Morbidity><Morbidity - disease rate><Mutate><Mutation><Mutation Detection><NGS Method><NGS system><NMR Imaging><NMR Tomography><Neoplasm Metastasis><Neoplasms><Neuroglial Neoplasm><Neuroglial Tumor><Nuclear Magnetic Resonance Imaging><Nucleic Acids><Oncogenic><Patient Monitoring><Patients><Primary Neoplasm><Primary Tumor><Production><Public Health><Recurrent Neoplasm><Recurrent tumor><Research><Sampling><Secondary Neoplasm><Secondary Tumor><Sensitivity and Specificity><Source><Tissue Sample><Tissues><Tumor Burden><Tumor Load><Tumor Tissue><Tumor Volume><Tumor-Derived><Validation><Zeugmatography><adulthood><allelic frequency><assay development><bio-markers><biologic marker><biomarker><brain parenchyma><brain surgery><cancer cell><cancer metastasis><cancer type><cerebral spinal fluid><child patients><clinical implementation><clinical practice><depository><developmental><digital><effective therapy><effective treatment><experiment><experimental research><experimental study><experiments><fluid><genome mutation><glial-derived tumor><innovate><innovation><innovative><liquid><liquid biopsy><malignancy><metabolism measurement><metabolomics><metabonomics><mortality><mutant><neoplasia><neoplasm recurrence><neoplasm/cancer><neoplastic growth><neuroglia neoplasm><neuroglia tumor><new approaches><next gen sequencing><next generation sequencing><nextgen sequencing><novel><novel approaches><novel strategies><novel strategy><pediatric patients><precision medicine><precision-based medicine><repository><response to therapy><response to treatment><spinal fluid><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapy response><treatment response><treatment responsiveness><tumor><tumor DNA><tumor cell DNA><tumor cell metastasis><tumor-specific DNA><tumors in the brain><tumors in the central nervous system><validations>