Sabrina M Ronen

University of California, San Francisco | UCSF · Department of Radiology and Biomedical Imaging

Purpose We constructed a ¹³C/³¹P surface coil at 3 T for studying cancer metabolism and bioenergetics. In a single scan session, hyperpolarized ¹³C-pyruvate MRS and ³¹P MRS was carried out for a healthy rat brain. Methods All experiments were carried out at 3 Tesla. The multinuclear surface coil was designed as two coplanar loops each tuned to eit...

Purpose: Telomere maintenance is a hallmark of cancer. Most tumors maintain telomere length via reactivation of telomerase reverse transcriptase (TERT) expression. Identifying clinically translatable imaging biomarkers of TERT can enable non-invasive assessment of tumor proliferation and response to therapy. Methods: We used RNA interference, do...

Metabolic reprogramming is a fundamental hallmark of cancer, which can be exploited for non-invasive tumor imaging. Deuterium magnetic resonance spectroscopy (2H-MRS) recently emerged as a novel, clinically applicable method of non-invasively monitoring flux from 2H-labelled substrates to metabolic products. However, to date, preclinical studies ha...

Background: TERT promoter mutations are observed in 80% of wild-type IDH glioblastoma (GBM). Moreover, the upstream TERT transcription factor GABPB1 was recently identified as a cancer-specific therapeutic target for tumors harboring a TERT promoter mutation. In that context, non-invasive imaging biomarkers are needed for the detection of TERT mod...

Background The alternative lengthening of telomeres (ALT) pathway is essential for tumor proliferation in astrocytomas. The goal of this study was to identify metabolic alterations linked to the ALT pathway that can be exploited for non-invasive magnetic resonance spectroscopy (MRS)-based imaging of astrocytomas in vivo. Methods Genetic and pharma...

Glioma patient management relies heavily on magnetic resonance imaging (MRI). However, MRI is often inadequate for assessment of tumor burden and pseudoprogression. Non-invasive methods that report on molecular pathways such as telomere maintenance that drive tumor proliferation are needed. Among brain tumors, low-grade astrocytomas (LGAs) use the...

Telomere maintenance is essential for tumor immortality and sustained tumor proliferation. Most tumors, including high-grade glioblastomas and low-grade oligodendrogliomas achieve telomere maintenance via reactivation of the expression of telomerase reverse transcriptase (TERT), which is silenced in normal somatic cells. Due to this essential role,...

BACKGROUND TERT promoter mutations that result in TERT expression are observed in over 80% of GBM. Moreover, the upstream transcription factor GABPB1 was recently identified as an ideal therapeutic target for tumors with TERT promoter mutations. In that context, non-invasive reliable biomarkers that can help detect TERT expression are needed. The a...

Metabolic reprogramming is a fundamental hallmark of cancer, which can be exploited for non-invasive tumor imaging. Deuterium magnetic resonance spectroscopy (2H-MRS) recently emerged as a novel, translational method of interrogating flux from 2H-labeled substrates to metabolic products. However, to date, preclinical studies have been performed in...

Gliomas are the most prevalent type of brain tumor in the central nervous system. Mutations in the cytosolic enzyme isocitrate dehydrogenase 1 (IDH1) are a common feature of primary low-grade gliomas, catalyzing the conversion of α-ketoglutarate (αKG) to the oncometabolite 2-hydroxyglutarate (2HG), and mutant IDH1 is a therapeutic target for these...

Telomerase reverse transcriptase (TERT) expression is indispensable for tumor immortality. Non-invasive methods of imaging TERT can, therefore, report on tumor proliferation and response to therapy. Here, we show that TERT expression is associated with elevated levels of the redox metabolite NADH in multiple cancers, including glioblastoma, oligode...

Glucose metabolism via the pentose phosphate pathway (PPP) is typically unregulated in tumors, including gliomas. We previously showed that hyperpolarized δ-[1-13C]gluconolactone metabolism via the PPP to 6-phospho-[1-13C]gluconate (6PG) differentiates tumor from contralateral normal brain in preclinical glioma models. Here, we examined the ability...

Background Telomerase reverse transcriptase (TERT) is essential for tumor proliferation, including in low-grade oligodendrogliomas (LGOGs). Since TERT is silenced in normal cells, it is also a therapeutic target. Therefore, non-invasive methods of imaging TERT are needed. Here, we examined the link between TERT expression and metabolism in LGOGs, w...

Introduction The pentose phosphate pathway (PPP) is essential for NADPH generation and redox homeostasis in cancer, including glioblastomas. However, the precise contribution to redox and tumor proliferation of the second PPP enzyme 6-phosphogluconolactonase (PGLS), which converts 6-phospho-δ-gluconolactone to 6-phosphogluconate (6PG), remains uncl...

Telomerase reverse transcriptase (TERT) is essential for tumor immortality and uncontrolled proliferation, including in low-grade oligodendrogliomas (LGOGs). Since it is silenced in somatic cells, TERT is also a therapeutic target. Non-invasive imaging of TERT can differentiate tumor from normal brain or lesions such as gliosis and allow assessment...

The Warburg effect, characterized by elevated glucose uptake and flux to lactate, is a metabolic hallmark of cancer. Recent studies have identified deuterium 2H-magnetic resonance spectroscopy (MRS) using 6,6’-2H-glucose as a novel method of imaging the Warburg effect in high-grade primary glioblastomas (GBMs). However, its utility for imaging low-...

Telomere shortening constitutes a natural barrier to uncontrolled proliferation and all tumors must find a mechanism of maintaining telomere length. Most human tumors, including high-grade primary glioblastomas (GBMs) and low-grade oligodendrogliomas (LGOGs) achieve telomere maintenance via reactivation of the expression of telomerase reverse trans...

Telomerase reverse transcriptase (TERT) expression is essential for tumor proliferation and is an attractive therapeutic target for gliomas. TERT expression has previously been shown to enhance glucose flux via the pentose phosphate pathway (PPP) in low grade gliomas expressing TERT. Hyperpolarized δ-[1-13C]gluconolactone has been used to detect fl...

Approximately 80% of low-grade glioma (LGGs) harbor mutant isocitrate dehydrogenase 1/2 (IDH1/2) driver mutations leading to accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Thus, inhibition of mutant IDH is considered a potential therapeutic target. Several mutant IDH inhibitors are currently in clinical trials, including AG-881 and B...

Telomere maintenance is a universal hallmark of cancer. Most tumors including low-grade oligodendrogliomas use telomerase reverse transcriptase (TERT) expression for telomere maintenance while astrocytomas use the alternative lengthening of telomeres (ALT) pathway. Although TERT and ALT are hallmarks of tumor proliferation and attractive therapeuti...

BACKGROUND TERT promoter mutations that result in TERT expression are observed in over 80% of GBM and upstream inhibition of TERT expression by targeting GABPB1L is currently under investigation. In that context, non-invasive reliable biomarkers that can help detect TERT expression are needed. The aim of this research was to assess the value of mag...

Telomeres are nucleoprotein structures at chromosomal ends that shorten with cell division and constitute a natural barrier to proliferation. In order to proliferate indefinitely, all tumors require a telomere maintenance mechanism (TMM). Telomerase reverse transcriptase (TERT) expression is the TMM in most tumors, including low-grade oligodendrogl...

Although lower grade gliomas are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene and are less aggressive than primary glioblastoma, they nonetheless generally recur. IDH1-mutant patients are increasingly being treated with temozolomide, but early detection of response remains a challenge and there is a need for complementary imagi...

Synopsis Telomerase reverse transcriptase (TERT) expression is essential for tumor proliferation and is also an attractive therapeutic target for gliomas. Imaging TERT can help monitor tumor development and response to therapy. TERT expression has previously been shown to enhance glucose flux via the pentose phosphate pathway in low grade glioma ce...

Background IDH-mutant lower-grade gliomas (LGG) evolve under selective pressure of therapy, but well-characterized patient-derived cells (PDC) modeling evolutionary stages are lacking. IDH-mutant LGG may develop therapeutic resistance associated with chemotherapy-driven hypermutation and malignant progression. The aim of this study was to establish...

Mutations in isocitrate dehydrogenase 1 (IDH1mut) are reported in 70-90% of low-grade gliomas and secondary glioblastomas. IDH1mut catalyzes the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite which drives tumorigenesis. Inhibition of IDH1mut is therefore an emerging therapeutic approach, and inhibitors such as A...

Glutathione (GSH) is often upregulated in cancer, where it serves to mitigate oxidative stress. γ-glutamyl-transferase (GGT) is a key enzyme in GSH homeostasis, and compared to normal brain its expression is elevated in tumors, including in primary glioblastoma. GGT is therefore an attractive imaging target for detection of glioblastoma. The goal o...

Our understanding of the molecular basis of glioma initiation and maintenance has increased tremendously in recent years. This information needs to be incorporated into clinical patient management in order to make personalized neuro-oncology a reality. One promising approach is metabolic imaging, which can translate metabolic information that refle...

γ-glutamyl-transferase (GGT) is a key enzyme in the γ-glutamyl cycle, which regulates glutathione homeostasis. The enzyme is localized on the outer cell membrane and cleaves glutathione to glutamate and cysteinylglycine. As such, it facilitates uptake of the amino acids essential for intracellular synthesis of glutathione (GSH), which is the major...

Low-grade gliomas, driven by mutations in the cytosolic isocitrate dehydrogenase 1 (IDH1) gene, are less aggressive than primary glioblastoma, but nonetheless always recur and ultimately lead to patient death. The treatment of IDH1 mutant patients with Temozolomide (TMZ) improves survival, but there remains a need for complementary imaging methods...

The pentose phosphate pathway (PPP) generates NADPH and ribose 5-phosphate, which are involved in the scavenging of reactive oxygen species and the synthesis of nucleotides. As such, the PPP is typically upregulated in cancer cells to address the metabolic needs of rapid cell proliferation. Imaging PPP upregulation could therefore be useful in tumo...

Telomerase reverse transcriptase (TERT) expression is a hallmark of cancer, including in primary glioblastomas and low-grade oligodendrogliomas. Since TERT is essential for glioma proliferation and is an attractive therapeutic target, metabolic imaging of TERT status can inform on tumor progression and response to therapy. To that end, the goal of...

Mutations in isocitrate dehydrogenase 1/2 (IDHmut) are reported in 70–90% of low-grade gliomas and secondary glioblastomas. IDHmut catalyzes the reduction of a-ketoglutarate (a-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite that drives tumorigenesis. Inhibition of IDHmut is therefore a rapidly emerging therapeutic approach and IDHmut inhibitor...

We developed methods for the preparation of hyperpolarized (HP) sterile [2-13C]pyruvate to test its feasibility in first-ever human NMR studies following FDA-IND & IRB approval. Spectral results using this MR stable-isotope imaging approach demonstrated the feasibility of investigating human cerebral energy metabolism by measuring the dynamic conve...

70–90% of low-grade gliomas and secondary glioblastomas are characterized by mutations in isocitrate dehydrogenase 1 (IDHmut). IDHmut produces the oncometabolite 2-hydroxyglutarate (2HG), which drives tumorigenesis in these tumors. The phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway represents an attractive therapeutic...

Low-grade gliomas, driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene, are less aggressive than primary glioblastoma (GBM), but nonetheless always recur and ultimately lead to patient death. To improve patient survival, one therapeutic strategy is treatment with the alkylating chemotherapeutic agent Temozolomide (TMZ), previously res...

Dysregulation in NAD⁺/NADH levels is associated with increased cell division and elevated levels of reactive oxygen species in rapidly proliferating cancer cells. Conversion of the ketone body acetoacetate (AcAc) to β-hydroxybutyrate (β-HB) by the mitochondrial enzyme β-hydroxybutyrate dehydrogenase (BDH) depends upon NADH availability. The β-HB-to...

This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) ¹³C magnetic resonance imaging’s (MRI’s) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolari...

Vorinostat is a histone deacetylase (HDAC) inhibitor that inhibits cell proliferation and induces apoptosis in solid tumors, and is in clinical trials for the treatment of glioblastoma (GBM). The goal of this study was to assess whether hyperpolarized ¹³C MRS and magnetic resonance spectroscopic imaging (MRSI) can detect HDAC inhibition in GBM mode...

The alkylating agent temozolomide (TMZ), previously reserved for treatment of glioblastoma, is now being considered for the treatment of low-grade glioma that are driven by mutations in the isocitrate dehydrogenase 1 (IDH1) gene. Though the treatment of IDH1 mutant patients with TMZ improves survival, there is a need for metabolic imaging to help i...

Hotspot promoter mutations reactivate expression of telomerase reverse transcriptase (TERT) in mutant IDH1 oligodendrogliomas. TERT expression allows glioma cells to avoid telomere dysfunction-induced senescence, thereby enabling limitless proliferation. Since TERT expression is essential for glioma proliferation and TERT inhibitors are attractive...

70–90% of low-grade gliomas and secondary glioblastomas are characterized by mutations in isocitrate dehydrogenase (IDH1mut). Mutant IDH produces the oncometabolite 2-hydroxyglutarate (2HG), which drives tumorigenesis. Inhibitors of phosphoinositide-3-kinase (PI3K) pathway are currently under clinical investigation for IDH1mut gliomas with positive...

Introduction: Cancer cells up-regulate phospholipid biosynthesis in order to meet the demands of uncontrolled cell proliferation. Unusually, mutant isocitrate dehydrogenase 1 (IDHmut) gliomas down-regulate levels of the phospholipid precursors phosphocholine and phosphoethanolamine relative to wild-type IDH1 (IDHwt) gliomas. The goal of this study...

A robust and selective late-stage deuteration methodology was applied to 13C-enriched amino and alpha hydroxy acids to increase spin-lattice relaxation constant T1 for hyperpolarized 13C magnetic resonance imaging. For the five substrates with 13C-labeling on the C1-position ([1-13C]alanine, [1-13C]serine, [1-13C]lactate, [1-13C]glycine, and [1-13C...

Background Magnetic resonance spectroscopy (MRS) studies have identified elevated levels of the phospholipid precursor phosphocholine (PC) and phosphoethanolamine (PE) as metabolic hallmarks of cancer. Unusually, however, PC and PE levels are reduced in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas that produce the oncometabolite 2-hydroxyglut...

Tumor metabolism is reprogrammed to meet the demands of proliferating cancer cells. In particular, cancer cells upregulate synthesis of the membrane phospholipids phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdE) in order to allow for rapid membrane turnover. Nonetheless, we show here that, in mutant isocitrate dehydrogenase 1 (IDHmu...

Acetate has recently been identified as a major alternative source of nutrients for glioblastoma and brain metastases. After cellular uptake, acetate is converted to acetyl-CoA, a key metabolic intermediate that fuels the TCA cycle and is an essential building block for the biosynthesis of fatty acids. Interestingly, the potential role of acetate i...

Mutations in isocitrate dehydrogenase (IDH1) drive tumorigenesis in 70–90% of low-grade gliomas and secondary glioblastomas. The mutant IDH1 enzyme produces the oncometabolite 2-hydroxyglutarate (2HG), which, in addition to driving tumorigenesis, also induces significant metabolic reprogramming. Dual phosphoinositide-3-kinase (PI3K)/mammalian targe...

Today, there is no reliable noninvasive imaging method available to monitor glioblastoma (GBM) response to therapy and predict survival prior to tumor shrinkage. Dissolution Dynamic Nuclear Polarization (DNP) combined with hyperpolarized 13C Magnetic Resonance Spectroscopic Imaging (MRSI) is a novel imaging method that allows probing real-time tumo...

Mutations in isocitrate dehydrogenase 1 (IDH1) drive tumorigenesis in low-grade gliomas and result in production of the oncometabolite 2-hydroxyglutarate (2-HG). 2-HG extensively reprograms cell metabolism, often in a manner atypical relative to wild-type IDH1 gliomas. In particular, compared to normal tissue, wild-type IDH1 gliomas are characteriz...

Low-grade gliomas can undergo hypermutation (HM) and malignant progression after treatment with temozolomide (TMZ). We and others have demonstrated that TMZ-associated HM is characterized by predominant C>T/G>A nucleotide transitions and mutation of mismatch repair (MMR) and PI3K pathway genes. Well-characterized models of HM glioma are needed to b...

IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite d-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal an...

Autophagy traditionally sustains metabolism in stressed cells by promoting intracellular catabolism and nutrient recycling. Here, we demonstrate that in response to stresses requiring increased glycolytic demand, the core autophagy machinery also facilitates glucose uptake and glycolytic flux by promoting cell surface expression of the glucose tran...

Introduction: Missense R132H mutations in the active site of isocitrate dehydrogenase 1 (IDH1) biologically and diagnostically distinguish low-grade gliomas and secondary glioblastomas from primary glioblastomas. IDH1 mutations lead to the formation of the oncometabolite 2-hydroxyglutarate (2-HG) from the reduction of α-ketoglutarate (α-KG), which...

Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment....

Clinical trials revealed limited response duration of glioblastomas to VEGF-neutralizing antibody bevacizumab. Thriving in the devascularized microenvironment occurring after antiangiogenic therapy requires tumor cell adaptation to decreased glucose, with 50% less glucose identified in bevacizumab-treated xenografts. Compared with bevacizumab-respo...

Mutations in the isocitrate dehydrogenase 1 (IDH1) gene are common in lower-grade (WHO grade II or III) glioma and result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, altered gene expression and gliomagenesis. IDH1 mutations are believed to occur at an early stage during gliomagenesis and also co-segrega...

Aberrant choline metabolism with up-regulated levels of phosphocholine (PC) and phosphoethanolamine (PE) has been recognized as a hallmark of cancer. PC and PE are crucial precursors in the synthesis of the membrane phospholipids, phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn). Interestingly, low-grade gliomas carrying the isoci...

Inflammation is now recognized as an important hallmark of cancer, and immunotherapies offer a promising therapeutic approach. In particular, myeloid-derived suppressor cells (MDSCs) are highly prevalent inflammatory cells that play a key role in tumor development and are considered as potential therapeutic targets in the treatment of glioblastoma....

Missense mutations in the active site of isocitrate dehydrogenase 1 (IDH1) biologically and diagnostically distinguish low-grade gliomas and secondary glioblastomas from primary glioblastomas. IDH1 mutations lead to the formation of the oncometabolite 2-hydroxyglutarate (2-HG) from the reduction of α-ketoglutarate (α-KG), which in turn facilitates...

Mutations in the isocitrate dehydrogenase gene IDH1 are common in lower-grade glioma where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation and gliomagenesis. IDH1 mutations also co-segregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation...

Myeloid-derived suppressor cells (MDSCs) are highly prevalent inflammatory cells that play a key role in tumor development and are considered therapeutic targets. MDSCs promote tumor growth by blocking T-cell-mediated anti-tumoral immune response through depletion of arginine that is essential for T-cell proliferation. To deplete arginine, MDSCs ex...

Missense mutations in the active site of isocitrate dehydrogenase 1 (IDH1) biologically and diagnostically distinguish low-grade gliomas and secondary glioblastomas from primary glioblastomas. IDH1 mutations lead to the formation of the oncometabolite 2-hydroxyglutarate (2-HG) from the reduction of α-ketoglutarate (α-KG), which in turn facilitates...

Metabolic imaging of brain tumors using 13C Magnetic Resonance Spectroscopy (MRS) of hyperpolarized [1-13C] pyruvate is a promising neuroimaging strategy which, after a decade of preclinical success in glioblastoma (GBM) models, is now entering clinical trials in multiple centers. Typically, the presence of GBM has been associated with elevated hyp...

Metabolic reprogramming is an important hallmark of cancer. Alterations in many metabolic pathways support the requirement for cellular building blocks that are essential for cancer cell proliferation. This metabolic reprogramming can be imaged using magnetic resonance spectroscopy (MRS). H MRS can inform on alterations in the steady-state levels o...

Purpose: To develop a compressed sensing (CS) acceleration method with a high spectral bandwidth exploiting the spatial-spectral sparsity of MR spectroscopic imaging (MRSI). Methods: Accelerations were achieved using blip gradients during the readout to perform nonoverlapped and stochastically delayed random walks in kx -ky -t space, combined wi...

Mutations in isocitrate dehydrogenase 1 (IDH1) are characteristic of low-grade gliomas. We recently showed that mutant IDH1 cells reprogram cellular metabolism by down-regulating pyruvate dehydrogenase (PDH) activity. Reduced pyruvate metabolism via PDH could lead to increased pyruvate conversion to lactate. The goal of this study was therefore to...

Mutations in the metabolic enzyme isocitrate dehydrogenase (IDH) have recently been identified as drivers in the development of several tumor types. Most notably, cytosolic IDH1 is mutated in 70-90% of low-grade gliomas and upgraded glioblastomas, and mitochondrial IDH2 is mutated in ~20% of acute myeloid leukemia cases. Wild-type IDH catalyzes the...

Current standard of care for glioblastoma (GBM) is surgical resection, radiation, and treatment with Temozolomide (TMZ). However, resistance to current therapies and recurrence are common. To improve survival, agents that target the phosphoinositide-3-kinase (PI3K) signaling pathway, which is activated in ~88% of GBM, are currently in clinical tria...

Purpose: To develop a lump-element double-tuned common-mode-differential-mode (CMDM) radiofrequency (RF) surface coil with independent frequency tuning capacity for MRS and MRI applications. Methods: The presented design has two modes that can operate with different current paths, allowing independent frequency adjustment. The coil prototype was...

Somatic mutations in the isocitrate dehydrogenase 1 (IDH1) gene occur in 70-90% of low-grade gliomas. The mutation leads to the production of 2-hydroxyglutarate (2-HG), a novel “oncometabolite” that alters the epigenetic profile of DNA and inhibits cellular differentiation. Recent studies indicate that metabolic changes in IDH1 mutant cells extend...