About

Dr. Timothy Cloughesy is a Professor of Neurology and Molecular and Medical Pharmacology at the University of California, Los Angeles. He is a member of the UCLA Brain Research Institute and the Jonsson Comprehensive Cancer Center, as well as the Director of the UCLA Neuro-Oncology Program, the UCLA Brain Tumor Center, and the Henry Singleton Brain Cancer Research Program. Dr. Cloughesy received his B.A. degree with honors from the University of California, Santa Barbara, and his M.D. from Tulane University. He completed his neurology residency and fellowships in clinical neurophysiology at UCLA. He is board certified in neurology and clinical neurophysiology and holds the UCNS Neuro-Oncology Certification. His research encompasses therapeutic, imaging, translational, and basic investigations in brain cancer. He has extensive experience with clinical trials involving small molecule inhibitors, antibodies, antibody drug conjugates, chemotherapies, vaccines, viral gene transfer, and immune checkpoint therapies. Dr. Cloughesy has played leadership roles in first-in-human studies, pharmacokinetics/pharmacodynamics studies, and traditional Phase I through Phase III trials. His focus on clinical trials in brain cancer includes novel clinical trial design, biomarker incorporation, and development of new biomarkers. He provided principal leadership for the accelerated approval and the conversion to full approval of bevacizumab for recurrent glioblastoma. He developed a brain cancer bioinformatics database that integrates clinical outcomes, imaging, and molecular analysis to support translational research. Dr. Cloughesy has authored or co-authored over 380 peer-reviewed articles on brain cancer and has a Google Scholar H index of 110. He currently receives funding from NIH, NBTS, IVY Foundation, and other private foundations, including a recent Brain Cancer SPORE at UCLA where he serves as co-principal investigator. Additionally, he is the global principal investigator for GBM AGILE, a master protocol utilizing an adaptive Bayesian approach for late-stage glioblastoma development.

Research topics

• Medicine
• Internal medicine
• Computer Science
• Cancer research
• Oncology
• Artificial Intelligence
• Nuclear medicine
• Data Mining
• Machine Learning
• Pathology
• Radiology
• Medical physics
• Surgery
• Gastroenterology
• Psychology
• Intensive care medicine
• Chemistry
• Physics
• Dermatology
• Engineering
• Data science
• Genetics
• Biology
• Pharmacology

Selected publications

• Evaluation of Regorafenib in Newly Diagnosed and Recurrent Glioblastoma: GBM AGILE Phase II/III Bayesian Randomized Platform Trial

  Journal of Clinical Oncology · 2026-04-14

  articleOpen access

  PURPOSE: GBM AGILE (ClinicalTrials.gov identifier: NCT03970447) is a phase II/III Bayesian adaptive platform registration trial testing multiple arms against a common control; the primary end point is overall survival (OS). Regorafenib, a multikinase inhibitor, showed OS benefit in recurrent (RD) glioblastoma in the phase II REGOMA trial and entered GBM AGILE as the first investigational arm. METHODS: Patient subtypes included in the regorafenib arm of GBM AGILE were newly diagnosed unmethylated (NDU) and RD glioblastoma. Prospective defined sets of subtypes, or arm signatures, were NDU, RD, and all (NDU + RD). As the first investigational arm in GBM AGILE, regorafenib was equally randomized to the control arm. Treatment in the control arm is temozolomide + radiotherapy (in newly diagnosed) or lomustine (in RD). Efficacy was assessed by OS hazard ratio (HR), arm/control, and demonstrated when the Bayesian probability of benefit (HR <1.00) was ≥98%. Analysis was performed monthly for limited efficacy, which occurs when the Bayesian predictive power is <25% for all signatures, and determines stopping enrollment. Follow-up continued for 12 months after accrual stopped. RESULTS: When the predictive power was <25% in all predefined signatures for regorafenib, accrual stopped for limited efficacy. The final analysis did not demonstrate OS improvement in the regorafenib arm in RD nor NDU glioblastoma. Median HRs were 1.05 (NDU), 1.07 (RD), and 1.07 (all) with final probabilities of benefit (HR <1.00) of 0.421 (NDU), 0.312 (RD), and 0.296 (all). Regorafenib was associated with increased toxicity relative to control. CONCLUSION: GBM AGILE did not show superiority of regorafenib over control in RD (lomustine) or NDU (temozolomide + radiotherapy) glioblastoma, yet caused increased toxicities. Regorafenib has been removed from National Comprehensive Cancer Network guidelines as a treatment option for RD.

  PublisherDOI

• EPCO-63. LIPID METABOLIC HETEROGENEITY ACROSS GLIOMA CELLULAR STATES REVEALS ENVIRONMENTAL DEPENDENCIES

  Neuro-Oncology · 2025-11-01

  articleOpen access

  Abstract Gliomas are lethal malignancies composed of heterogeneous and dynamic subpopulations of cellular states that resemble both normal neurodevelopmental cell types and adaptive responses to stress within the tumor microenvironment (TME). While cellular plasticity enables gliomas to survive environmental pressures, the mechanisms driving glioma state dynamics remain unclear. To explore how glioma state heterogeneity functionally and metabolically interacts with the brain TME, we conducted a multi-omic analysis across 392 glioma specimens, including patient tumors, orthotopic xenografts and gliomasphere cultures using bulk RNA/whole-exome sequencing and lipidomic profiling. Single-cell transcriptome sequencing of a diverse panel of glioma tumors (n = 21) integrated with bulk tumor transcriptome profiling revealed a spectrum of cellular identities associated with distinct lipidomic profiles. Comparison of matched patient and derived models showed that the non-native environments, such as gliomasphere culture, restricted glioma state diversity and enriched for states characterized by elevated de novo fatty acid synthesis. Across environmental contexts, glioma state plasticity was coupled to lipid metabolic plasticity, enabling tumors to concordantly remodel their state composition and lipid profiles in response to environmental constraints. Of note, certain tumors exhibited limited state and metabolic plasticity – specifically those enriched for states within oligodendroglial and neuronal lineages. These gliomas demonstrated reduced de novo lipid synthesis capacity, and a concordant increased reliance on exogenous lipid scavenging within the brain microenvironment for survival. Together, these results link glioma heterogeneity and plasticity to lipid metabolic reprogramming, and highlight how distinct cellular state profiles result in environment-dependent metabolic liabilities.

  PublisherOA PDFDOI

• P17.15.A ASSOCIATION OF PROTON PUMP INHIBITOR USE WITH OUTCOME OF PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

  Neuro-Oncology · 2025-10-01

  articleOpen access

  Abstract BACKGROUND Proton pump inhibitors (PPI) are often prescribed to prevent steroid-induced gastritis and peptic ulcer disease in patients with glioblastoma. Yet, these drugs may enhance the activity of aldehyde dehydrogenase 1 A1 (ALDH1A1) which has been linked to protection from oxidative stress, radiotherapy and chemotherapy. MATERIAL AND METHODS We analyzed data from 2981 patients enrolled into 5 randomized clinical trials for newly diagnosed glioblastoma to explore an association of the use of potent ALDH1A1-activating PPI (PA-PPI) and other anti-acid drugs with outcome. We assessed drug use at baseline and at defined landmarks: start of temozolomide maintenance cycles 1 (landmark 1) and 4 (landmark 2), and end of cycle 6 (landmark 3). RESULTS On univariate analysis, we noted inferior progression-free and overall survival for patients treated with PA-PPI at all 4 time points. The multivariate analysis accounting for age, sex, performance status, steroid use, extent of resection, and O6-methylguanine DNA methyltransferase promoter methylation (MGMT) status confirmed a difference for progression-free survival at landmarks 1, 2 and 3, and for overall survival at landmarks 1 and 2. No such effect was seen for the use of other anti-acid drugs. The negative association of PA-PPI use with outcome was observed independently of MGMT promoter methylation and of steroid use. CONCLUSION We conclude that PA-PPI use should be discouraged in patients with glioblastoma since alternative agents are available and since a detrimental effect cannot be excluded. Translational research studies should explore whether PPI-induced activity of ALDH mediates the potential adverse effects of PPI in glioblastoma.

  PublisherOA PDFDOI

• STEM-23. GBM NEURODEVELOPMENTAL LINEAGE PLASTICITY DRIVES RAPID ADAPTATION TO ONCOGENE TARGETED THERAPY

  Neuro-Oncology · 2025-11-01

  articleOpen access

  Abstract Phenotypic plasticity plays a pivotal role in cancer, enabling tumor cells to adapt to environmental pressures and evade therapeutic interventions by transitioning between distinct cellular states. However, the contribution of phenotypic plasticity to adaptive drug resistance in glioblastoma (GBM), one of the most lethal of all cancers, remains poorly understood. In this study, we identify that GBM tumor-initiating cells resembling normal radial glia (RG), which occupy the apex of normal neurodevelopment, are driven by aberrant epidermal growth factor receptor (EGFR) signaling. Using a suite of patient-derived GBM models, we demonstrate through global proteomics and single-cell RNA sequencing that pharmacological inhibition of EGFR triggers a lineage transition toward neuronal and oligodendrocyte progenitor (OPC)-like states. This shift is accompanied by activation of oncogenic RAS-MAPK signaling – despite robust and durable inhibition of EGFR activation – and is further modulated by brain microenvironmental cues, including synaptic and calcium-mediated signaling programs. Dual inhibition of EGFR and RAS-MAPK with novel, tumor-selective small molecules blocks these phenotypic transitions and enhances GBM cell death in EGFR-mutated GBM models. To determine the subpopulation dynamics of RAS-MAPK signaling within GBM neurodevelopmental lineages, we develop DENALI (Dual-Expression Nuclear reporter of ERK Activity and Lineage Identity) – a novel, high-complexity barcoded lentiviral vector and integrative fluorescence reporter system. Using DENALI, we investigate the clonal mechanisms driving lineage plasticity in GBM following oncogenic EGFR inhibition and couple adaptive RAS signaling programs to the emergence of neuronal and OPC-like states under EGFRi therapy. Together, our findings establish neurodevelopmental lineage plasticity as a key driver of adaptive resistance in GBM and support dual-inhibition strategies to improve therapeutic outcomes in patients with GBM tumors.

  PublisherOA PDFDOI

• Proton Pump Inhibitor Use and Survival in Patients With Newly Diagnosed Glioblastoma

  JAMA Network Open · 2025-11-25 · 1 citations

  articleOpen access

  Importance: Proton pump inhibitors (PPI) are often prescribed to prevent steroid-induced gastritis and peptic ulcer disease in patients with glioblastoma. Yet, these drugs may enhance the activity of aldehyde dehydrogenase 1 A1 (ALDH1A1), which has been linked to protection from oxidative stress, radiotherapy, and chemotherapy. Objective: To explore the associations of the use of potent ALDH1A1-activating PPIs (PA-PPIs) and other antacid drugs with outcomes in patients with newly diagnosed glioblastoma. Design, Setting, and Participants: This meta-analysis was a secondary analysis of individual prospectively captured patient data using a dataset of 5 randomized clinical trials conducted between 2008 and 2020. Participants included patients with a new diagnosis of glioblastoma. Data analysis was completed in November 2024. Exposure: We assessed drug use at baseline and defined 3 landmarks: start of temozolomide maintenance cycles 1 (landmark 1) and 4 (landmark 2), and end of cycle 6 (landmark 3). Main Outcomes and Measures: The primary outcome measures were progression-free survival (PFS) and overall survival (OS) from baseline and from the start of each corresponding landmark time. Results: The study population included 2981 patients (1858 [62.3%] male; median [range] age, 58 [18-85] years). On univariate analysis, patients treated with PA-PPI had worse PFS and OS at all 4 time points. The multivariate analysis accounting for age, sex, performance status, steroid use, extent of resection, and MGMT status confirmed a difference for PFS at landmarks 1 (hazard ratio [HR], 1.14 [95% CI, 1.01-1.28]), 2 (HR, 1.26 [95% CI, 1.09-1.44]), and 3 (HR, 1.31 [95% CI, 1.10-1.56]), and for OS at landmarks 1 (HR, 1.34 [95% CI, 1.08-1.66]) and 2 (HR, 1.14 [95% CI, 1.01-1.29]). No such association was seen for the use of other antacid drugs. The negative association of PA-PPI use with PFS and OS was observed independently of MGMT promoter methylation and steroid use. Conclusions and Relevance: In this meta-analysis of patients with newly diagnosed glioblastoma, PPI use was associated with inferior survival outcomes. These findings suggest that PA-PPI use should be discouraged in patients with glioblastoma, since alternative agents are available and a detrimental effect cannot be excluded. Translational research studies should explore whether PPI-induced activity of ALDH mediates the potential adverse effects of PPI in glioblastoma. .

  PublisherOA PDFDOI

• Supplemental Figure S2 from Depth of Radiographic Response and Time to Tumor Regrowth Predicts Overall Survival Following Anti-VEGF Therapy in Recurrent Glioblastoma

  2025-11-25

  articleOpen accessSenior author

  &lt;p&gt;Supplemental Figure S2&lt;/p&gt;

  PublisherOA PDFDOI

• TIP-10. Update on GBM AGILE: A global, phase 2/3 adaptive platform trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma

  Neuro-Oncology · 2025-11-01 · 1 citations

  articleOpen access

  Abstract BACKGROUND GBM AGILE (Glioblastoma Adaptive, Global, Innovative Learning Environment) is a multi-arm, international, seamless Phase 2/3 response adaptive randomization (RAR) platform trial designed to efficiently identify investigational therapies that improve overall survival and confirm efficacious therapies and biomarker signatures to support registration. GBM AGILE is a collaboration among academic investigators, patient organizations, and industry to support new drug applications for newly diagnosed and recurrent glioblastoma. METHODS The primary objective of GBM AGILE is to identify therapies that improve overall survival in patients with newly diagnosed or recurrent glioblastoma. Operating under a Master Protocol, GBM AGILE allows multiple drugs from different companies to be evaluated simultaneously and/or over time against a common control. Investigational therapies are added as information about promising drugs is identified, while other therapies are removed as they complete evaluation. RAR is used within subtypes of the disease to assign participants to investigational arms based on their performance. GBM AGILE has screened over 2300 patients and enrollment continues to be robust. In addition to the efficient evaluation of investigational arms, a goal of GBM AGILE is to expand knowledge of glioblastoma to support advancements in treatment using the data collected within the trial (learning environment). Over 7 million data points are currently available for inclusion in the development of a longitudinal model. Such a model may be able to inform randomization by providing earlier and continuous information regarding patient and arm performance. In addition, serial magnetic resonance imaging scans and biospecimens from baseline through patient progression are being collected for further analysis. An initial 500 baseline tissue samples are being characterized by genome sequencing and transcriptome analysis. NCT number: NCT03970447.

  PublisherOA PDFDOI

• IMG-68. Corticosteroid-induced contrast-enhancing volume shrinkage and apparent diffusion coefficient reduction in glioblastoma MRI

  Neuro-Oncology · 2025-11-01

  articleOpen access

  Abstract BACKGROUND Corticosteroids, which are commonly used in the clinical management of glioblastoma, are known to impact the radiographic interpretation of glioblastoma. In particular, corticosteroids can induce an apparent reduction in contrast-enhancing tumor volume and intensity (i.e., a “pseudoresponse”), as well as a reduction of the apparent coefficient diffusion (ADC) from diffusion imaging. This study aimed to estimate the influence of corticosteroids on these measurements in treatment naïve glioblastoma before surgery. METHODS 57 pairs of MRI scans from 54 patients with pre-surgical treatment-naïve glioblastoma were retrospectively grouped as increased (n=29), stable (n=25), or decreased (n=3) corticosteroid dose between scans (median interval: 15 days). All cases with steroid increase (n=29) and the majority of cases stable (n=21) with stable steroids were off steroids at the first timepoint. Tumor size and ADC changes between timepoints were compared between lesions with increased and stable corticosteroids. Volumetric changes ascribable to increased corticosteroid dose was modeled, adjusting for the time between scans. RESULTS Increased corticosteroid dose showed an observed volumetric shrinkage of the contrast-enhancing tumor (median shrinkage: 23.7%) and reduction in estimated growth rates, significantly different (p&amp;lt;0.0001) from the control group receiving a stable dose (median growth: 36.0%; with 2.08% growth rate). When adjusting for the interval growth between scans, while comparing the two groups, the estimated corticosteroid-induced volumetric shrinkage was 44.0% (p&amp;lt;0.0001, 95%C.I. 25.7–62.2%). Increased corticosteroid dose also caused an ADC drop in the contrast-enhancing tumor (median ADC reduction: 180, IQR=39–281×10-6 mm2/s, p=0.0005). CONCLUSION Corticosteroid administration induce a significant “pseudoresponse” in glioblastoma. Providing benchmark quantitation of this phenomenon is crucial for the future development of adjusted response criteria accounting for corticosteroid use. Additionally, a quantitative estimate of corticosteroid-induced ADC reduction can lead to corticosteroid-adjusted ADC measurements, potentially improving diffusion imaging applications for differential diagnosis, molecular profiling, and prognosis stratification.

  PublisherOA PDFDOI

• EXTH-02. GliomaPDOX – A direct brain-to-brain glioma xenograft library for drug discovery and development

  Neuro-Oncology · 2025-11-01

  articleOpen access

  Abstract Cancer drug discovery and development rely on preclinical models that accurately reflect the molecular and functional characteristics of human tumors, while accounting for in vivo factors that influence drug efficacy, such as pharmacokinetics, metabolism and toxicity. Malignant gliomas are highly aggressive brain tumors that develop within the brain parenchyma, where their heterogeneous cellular composition engage in complex interactions with highly specialized brain cells, and a blood brain barrier that restricts drug penetration. When removed from this native environment, such as in culture or heterotopic in vivo environments (e.g., flank), gliomas either lose their molecular diversity or fail to grow altogether. Therefore, there is a critical need for physiologically relevant models that capture both the intra and inter-tumor diversity of glioma, as well as the organismal context required for drug development. Here, we present GliomaPDOX – a direct brain to brain glioma orthotopic xenograft biobank, consisting of more than 200 unique models that faithfully recapitulate the key molecular, histopathological, and proliferative features of their parental tumors. By incorporating a non-invasive, secreted reporter system to monitor tumor burden in real time—including drug-induced changes in intracranial tumor growth—we demonstrate the utility of GliomaPDOX for therapeutic evaluation. Together, this robust platform provides a physiologically relevant system to accelerate drug discovery and development for glioma.

  PublisherOA PDFDOI

• Vorasidenib in IDH1-mutant or IDH2-mutant low-grade glioma (INDIGO): secondary and exploratory endpoints from a randomised, double-blind, placebo-controlled, phase 3 trial

  The Lancet Oncology · 2025-10-29 · 13 citations

  article1st authorCorresponding
  PublisherDOI

Recent grants

• UCLA SPORE in Brain Cancer

  NIH · $35.6M · 2017–2027

• NIH Grant U01CA105695

  NIH · $720k · 2008

• UCLA SPORE in Brain Cancer

  NIH · $4.4M · 2017–2022

• NIH Grant M01RR000865

  NIH · $41.8M · 2011

• Role of decorin and diffusion MRI in anti-VEGF efficacy for recurrent glioblastoma

  NIH · $3.0M · 2022–2027

Frequent coauthors

• Patrick Y. Wen

  2691 shared

• Lisa M. DeAngelis

  Memorial Sloan Kettering Cancer Center

  1533 shared

• Minesh P. Mehta

  1284 shared

• Michael D. Prados

  University of California, San Francisco

  1204 shared

• David A. Reardon

  Dana-Farber Cancer Institute

  1140 shared

• J. Raizer

  Columbia University

  987 shared

• John G. Kuhn

  University of California, Los Angeles

  941 shared

• Lauren E. Abrey

  Roche (Switzerland)

  913 shared