Glioblastoma and Methionine Addiction

Abstract

Glioblastoma is a fatal brain tumor with a bleak prognosis. The use of chemotherapy, primarily the alkylating agent temozolomide, coupled with radiation and surgical resection, has provided some benefit. Despite this multipronged approach, average patient survival rarely extends beyond 18 months. Challenges to glioblastoma treatment include the identification of functional pharmacologic targets as well as identifying drugs that can cross the blood-brain barrier. To address these challenges, current research efforts are examining metabolic differences between normal and tumor cells that could be targeted. Among the metabolic differences examined to date, the apparent addiction to exogenous methionine by glioblastoma tumors is a critical factor that is not well understood and may serve as an effective therapeutic target. Others have proposed this property could be exploited by methionine dietary restriction or other approaches to reduce methionine availability. However, methionine links the tumor microenvironment with cell metabolism, epigenetic regulation, and even mitosis. Therefore methionine depletion could result in complex and potentially undesirable responses, such as aneuploidy and the aberrant expression of genes that drive tumor progression. If methionine manipulation is to be a therapeutic strategy for glioblastoma patients, it is essential that we enhance our understanding of the role of methionine in the tumor microenvironment.

Reversion of methionine addiction of osteosarcoma cells to methionine independence results in loss of malignancy, modulation of the epithelial-mesenchymal phenotype and alteration of histone-H3 lysine-methylation

“…Thus, cancer cells must have much larger-than-normal amounts of methionine in order to survive and proliferate, which is described as methionine addiction. Other teams are now using the term “methionine addiction of cancer” ( 11 , 17 , 18 ). We have previously shown that osteosarcoma cells, including 143B, Saos-2, MNNG-HOS, and U-2OS, are methionine-addicted, and 143B is the most methionine addicted among these osteosarcoma cell lines ( 19 ).…”

Recurrence Patterns after Radiotherapy for Glioblastoma with [(11)C]methionine Positron Emission Tomography-Guided Irradiation for Target Volume Optimization

“…The value of FDG PET for central nervous system tumors in radiotherapy planning is severely limited, as the high glucose metabolism in the brain reduces the accuracy of tumor delineation. In contrast to FDG, radiolabeled amino acids such as [11C-methyl]-l-methionine (MET) [14][15][16], O-(2-[18F]-fluoroethyl)-l-tyrosine (FET) [17,18], and 3,4-dihydroxy -6-[ 18F]-Fluoro-l-phenylalanine (FDOPA) [19,20] show low uptake in normal brain tissue, allowing for the visualization of brain tumors with a high tumor background signal. Several studies have provided evidence that amino acids detect the solid mass of gliomas and metabolically active tumors more reliably than conventional imaging modalities [21][22][23][24].…”

“…Amino acid PET imaging, in particular, has emerged as a valuable tool for diagnostic and grading purposes, as well as for guiding surgical and radiotherapy planning and distinguishing between tumor recurrences. Among the array of tracers utilized for amino acid PET imaging, l-[Methyl-11C]-Methionine (MET) [10][11][12][13][14][15], 6-fluoro-(18F)-l-3,4dihydroxyphenylalanine (FDOPA), and [18F] fluoroethyl-tyrosine (FET) stand out as the most extensively employed.…”

11C-Acetate PET/CT for Reactive Astrogliosis Outperforms 11C-Methionine PET/CT in Glioma Classification and Survival Prediction

“…The increased transport of methionine suggests a mechanism in response to defects in intracellular methionine synthesis. 12 As an imaging method that demonstrates the exogenous methionine requirement of the glioma cells, 11 C-MET PET/CT has several advantages, such as a high tumor-tocortical background ratio, clear visualization of tumor boundaries, the ability to evaluate early treatment responses, and the potential for prognostication. 9,10 In contrast to tumor-directed amino acid radiotracers, 11 C-acetate (ACE) targets reactive astrogliosis in the tumor microenvironment (TME) and has been associated with reactive astrocytes under inflammatory conditions in the CNS.…”

“…Methionine enters tumor cells via the l -type amino acid transporter 1. The increased transport of methionine suggests a mechanism in response to defects in intracellular methionine synthesis 12 . As an imaging method that demonstrates the exogenous methionine requirement of the glioma cells, 11 C-MET PET/CT has several advantages, such as a high tumor-to-cortical background ratio, clear visualization of tumor boundaries, the ability to evaluate early treatment responses, and the potential for prognostication 9,10 …”