About

Thomas Graeber is faculty in the Department of Molecular and Medical Pharmacology at UCLA and a member of the Crump Institute for Molecular Imaging. His background includes physics, cancer biology, signal transduction, metabolism, computational biology, proteomics, and metabolomics. His work builds experimental and computational approaches to studying cancer signaling and metabolism from a systems perspective. His research focuses on understanding cancer signaling and metabolism through the development of genome-, proteome-, and metabolome-wide assays, and applying these to measure and model aberrant functions in cancer cells. He collaborates with clinical scientists, working directly with patient samples to translate discoveries into clinical applications. His research involves collecting high-dimensional data using mass spectrometry-based phosphoproteomic and metabolomic profiling, and developing computational approaches to overlay this data with known signaling and metabolic network structures. A key emphasis is on how cellular signaling and metabolism are rewired when cancers develop resistance to targeted therapies, such as mutant BRAF kinase inhibitors used in melanoma. His work has highlighted the importance of feedback loops in maintaining cancer signaling and metabolic homeostasis, and he explores therapeutic strategies to disrupt these loops to induce cancer cell death. His goal is to identify minimal sets of components that reflect cellular states and serve as targets for diagnostics, imaging, and personalized treatment. His interdisciplinary approach merges biology, chemistry, mathematics, and bioinformatics.

Research topics

• Biology
• Cell biology
• Biochemistry
• Medicine
• Cancer research
• Pathology
• Internal medicine
• Genetics
• Immunology

Selected publications

• Synthetic lethality between RB-loss and E2F3 inhibition in small cell cancers targeted by pyrimidine synthesis blockade

  Proceedings of the National Academy of Sciences · 2026-03-20

  articleOpen access

  Small cell carcinoma is a highly lethal cancer variant often found with neuroendocrine (NE) features, as exemplified by small cell lung cancer and small cell NE prostate cancer (SCPC). A genome-wide CRISPR dependency screen using SCPC models generated through human prostate cell transformation identifies a requirement for the transcription factor E2F3. E2F3 dependency is linked to RB inactivation, a near universal occurrence across small cell cancers. The requirement for E2F3 is shared by RB-deficient cells originating from the prostate, lung, and adnexa. In RB-deficient cancer cells, E2F3 inhibition restrains cell cycle progression, proliferation, and tumor growth in vivo. Inhibition of de novo pyrimidine synthesis limits E2F3 expression and suppresses small cell carcinoma proliferation in culture. Directly or indirectly targeting E2F3 to leverage a pan-cancer synthetic lethality resulting from RB inactivation represents a potential treatment strategy.

  PublisherDOI

• The liver regulates ectopic calcification in Abcc6-deficient models of pseudoxanthoma elasticum

  Journal of Clinical Investigation · 2026-03-10

  articleOpen access

  Pseudoxanthoma Elasticum (PXE) is a rare disease caused by loss of function of the ATP-binding cassette C (ABC) member 6 (Abcc6) gene and characterized by ectopic calcification of multiple tissues, but the physiological reasons underlying ectopic calcification in PXE remain unclear. In a murine model of Abcc6-deficient PXE in which animals developed robust cardiac calcification after heart injury, we show the critical importance of the liver in mediating ectopic cardiac calcification. Tissue-specific deletion of Abcc6 in the liver, but not in the heart, was sufficient to cause post-injury cardiac calcification. Metabolomics and gene expression analysis demonstrated deficiencies in nucleotide metabolism, cellular energetics, and defects in cellular respiration underlying ectopic calcification in PXE. Functional abnormalities in cellular respiration in the injured heart were similar in animals with global or liver-specific Abcc6 deficiency, showing that hepatic Abcc6 expression regulated cellular respiration in the injured heart. We show that ectopic calcification in PXE was primarily dystrophic and that treatment with clodronate or etidronate, which prevent the growth of calcium hydroxyapatite mineralization, was sufficient to rescue the phenotype of ectopic cardiac calcification in Abcc6-deficient states. Taken together, these observations highlight the role of the liver in regulating target tissue metabolic and mitochondrial function in causing ectopic calcification in Abcc6-deficient states.

  PublisherOA PDFDOI

• Abstract 2162: GliomaPDOX - A direct brain-to-brain glioma xenograft library for drug discovery and development.

  Cancer Research · 2026-04-03

  article

  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. Citation Format: Elizabeth G. Fernandez, Christopher Tse, Jennifer Salinas, Nicholas Bayley, Lisa H. Ta, Laura Gosa, Henan Zhu, Michael Vigman, Francesco Sanvito, Benjamin M. Ellingson, Linda M. Liau, Timothy Cloughsey, Thomas G. Graeber, Nathanson David. GliomaPDOX - A direct brain-to-brain glioma xenograft library for drug discovery and development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2162.

  PublisherDOI

• Author Correction: BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR–ABL1 kinase inhibition

  Nature · 2026-02-18

  articleOpen access
  PublisherOA PDFDOI

• Discovery and Optimization of Orally Bioavailable Heterobifunctional Degraders of KAT2A/B for the Treatment of Cancer

  Journal of Medicinal Chemistry · 2026-02-09

  article

  Using our proprietary AI/ML platform AURIGIN that maps tumor cells against normal developmental pathways, we identify targets that have been hijacked by cancerous cells to maintain a highly plastic proliferative cell state. We identified the histone acetyltransferase KAT2A as a key driver of tumor cell plasticity in a subset of acute myeloid leukemias (AML) and neuroendocrine carcinomas such as small cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Herein, we describe our development of heterobifunctional degraders of KAT2A/B, resulting in compound 7, a picomolar degrader that is capable of inhibiting proliferation of AML (MOLM-13) and SCLC (NCI–H1048) cell lines in vitro and demonstrates robust degradation of KAT2A in NCI–H1048 engrafted mice when administered IP. Building on the success of compound 7, we subsequently developed orally bioavailable degraders of KAT2A/B, exemplified by compound 24, that achieved an oral bioavailability of 47% in mice.

  PublisherDOI

• Abstract 3808: Bidirectional glutamine transport prevents mitochondrial stress in B-cell transformation

  Cancer Research · 2025-04-21

  article

  Comparing cell surface proteome changes during B-cell transformation, we found strong induction of SLC7A5, which simultaneously mediates leucine uptake and glutamine export. However, the significance of glutamine export is unknown.Slc7a5 deletion in transformed B cells (BCR-ABL1), but not primary resting B-cells, resulted in accumulated intracellular glutamine, reduced cell proliferation and viability, and prolonged survival of transplant recipients. Interestingly, glutamine deprivation, and pharmacological glutamine sequestration, partially rescued cell fitness, suggesting abnormal accumulation of glutamine impedes malignant transformation.Mechanistically, Slc7a5 deletion and glutamine accumulation resulted in integrated mitochondrial stress response, which signals through mTORC1 to activate ATF4 expression. Treatment with rapamycin significantly rescued growth disadvantage of Slc7a5-deficient cells, whereas treatment with p70 S6K1 inhibitor (PF-470671) had no rescue effect. These results suggested that activated mTORC1 in Slc7a5-deficient cells induced ATF4-mediated stress response rather than global protein synthesis. Chemogenomic screen with a selective SLC7A5 inhibitor in human B-cell leukemia revealed that deletion of genes involved in integrated stress response, including ATF4, led to synthetic lethality. By contrast, deletion of genes involved in mitochondrial tRNA aminoacylation and protein translation had rescue effects. Consistently, alleviation of mitochondrial stress by inhibiting protein synthesis with CHX completely rescued cell defects. In addition, metabolomic analysis and isotope tracing of (15N)2-glutamine revealed that Slc7a5-deficient cells directed glutamine metabolism towards purine synthesis, at the expense of glutathione and NAD+ synthesis. This is consistent with previous findings that mTORC1-ATF4 axis directly induced purine synthesis. Despite the critical role of glutaminolysis in cancer metabolism, our study show that SLC7A5-mediated glutamine export is critical in preventing mitochondrial stress and that abnormal accumulation of glutamine could be detrimental. Citation Format: Ruifeng Sun, Gauri Deb, Kohei Kume, Yanzhi Feng, Johanna Scott, Thomas Graeber, Markus Müschen. Bidirectional glutamine transport prevents mitochondrial stress in B-cell transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3808.

  PublisherDOI
• RETRACTED

  Single-Cell Heterogeneity of EGFR Pathway Is Linked to Unique Signatures of Drug Response and Malignancy in Patient Derived Glioblastoma Stem Cells

  Cancer Research and Treatment · 2025-01-07 · 2 citations

  article

  In glioblastoma, the therapeutically intractable and resistant phenotypes can be derived from glioma stem cells, which often have different underlying mechanisms from non-stem glioma cells. Aberrant signaling across the EGFR-PTEN-AKT-mTOR pathways have been shown as common drivers of glioblastoma. Revealing the inter and intra-cellular heterogeneity within glioma stem cell populations in relations to signaling patterns through these pathways may be key to precision diagnostic and therapeutic targeting of these cells.

  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

• 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

• Complexity and Time

  Journal of the European Economic Association · 2025-02-22 · 5 citations

  article

  Abstract A large literature shows that people’s valuation of delayed financial rewards violates exponential discounting, exhibiting a hyperbolic pattern: high short-run impatience that strongly decreases in the length of the delay. We test the hypothesis that the hyperbolic pattern in measured discount rates over money reflects mistakes driven by the complexity of evaluating delayed payoffs. We document that hyperbolicity (i) is strongly associated with choice inconsistency and cognitive uncertainty, (ii) increases in overt complexity manipulations, and (iii) arises nearly identically in computationally similar tasks that involve no actual payoff delays. Our results suggest that even if people had exponential discount functions, complexity-driven mistakes would cause them to make hyperbolic choices. We examine which experimental techniques to estimate present bias are (not) confounded by information-processing constraints.

  PublisherDOI

Recent grants

• Mammalian models for integrated metabolic and molecular profiling of malignant glioma

  NIH · $2.7M · 2018–2023

• NIH Grant P01CA168585

  NIH · $16.9M · 2019

• Targeting Genomic Instability in Lethal Neuroendocrine Prostate Cancer

  NIH · $2.6M · 2018–2023

• NIH Grant R21CA169993

  NIH · $356k · 2014

Frequent coauthors

• Antoni Ribas

  Parker Institute for Cancer Immunotherapy

  169 shared

• Owen N. Witte

  113 shared

• Evangelia Komisopoulou

  University of California, Los Angeles

  105 shared

• Lídia Robert

  88 shared

• Richard C. Koya

  79 shared

• Jiaoti Huang

  Duke University

  79 shared

• Jennifer Tsoi

  University of California, Los Angeles

  77 shared

• Stephen Mok

  The University of Texas MD Anderson Cancer Center

  73 shared

Education

• Ph.D., Physics

  Stanford University

  1996

• B.S., Physics

  University of California Los Angeles

  1990

Awards & honors

• Melanoma Research Alliance Established Investigator
• American Cancer Society Research Scholar