About

Dr. David Nathanson is an Associate Professor of Molecular and Medical Pharmacology at UCLA. He received his Ph.D. from UCLA under Dr. Paul Mischel, where he discovered a 'hide and seek' resistance mechanism involving oncogenes on extrachromosomal DNA that can be dynamically eliminated in response to environmental pressures such as drugs, to maintain tumor growth. His post-doctoral work focused on tumor metabolism, drug development, and molecular imaging with Drs. Caius Radu and Johannes Czernin at UCLA, leading to the development of new therapeutic approaches, companion molecular biomarkers, and clinical drug candidates targeting DNA metabolism in cancer. His current laboratory investigates the dynamic interplay between specific molecular alterations and critical functional processes like metabolism and apoptosis in glioblastoma, aiming to develop new drugs and therapeutic strategies to exploit vulnerabilities for improved patient outcomes.

Research topics

• Medicine
• Internal medicine
• Genetics
• Endocrinology
• Oncology
• Environmental health
• Pediatrics
• Demography
• Biology

Selected publications

• Selected Pathological Criteria That Predict Low Rates of Axillary Lymph Node Metastases Regardless of Patient Age: A Single Institution Study

  The Breast Journal · 2026-01-01

  articleOpen access1st authorCorresponding

  BACKGROUND AND AIMS: Omission of sentinel node biopsy is increasingly offered to selected older women with cN0 low-risk breast cancer (BC). We hypothesized that some younger women might exhibit a low enough incidence of lymph node metastases to possibly justify excluding axillary surgery. METHODS: We statistically analyzed, using parametric and nonparametric tests as appropriate, multiple demographic and clinicopathologic variables in cT1-2 N0 M0 BC patients of all ages undergoing axillary LN excisional surgery from a long-term, prospectively maintained database. RESULTS: Patients with (816) and without (3617) LN metastases were compared. Although older patients were significantly (p < 0.0001) less likely to have LN metastases compared to younger patients, 3/61 (4.92%) of those < 50 years old with grade 1 tumors ≤ 1 cm in size (T1a and b) and no lymphovascular invasion had LN metastases compared to 30/504 (5.95%) ≥ 50. Patients aged 50 or older with Grade 2/3, < 1 cm, LVI-negative tumors had only 53/774 (6.85%) LN positive, compared to 19/131 (14.5%) in women < 50 with the same pathology. CONCLUSIONS: Women with grade 1, ≤ 1 cm invasive BCs, and no LVI had < 6% incidence of LN metastases regardless of age. Instead of excluding younger women from axillary node surgery de-escalation strategies, this study suggests that any woman with a tumor size ≤ 1 cm, Grade 1, and no LVI could be evaluated in prospective studies whose objective is to safely avoid axillary LN surgery.

  PublisherDOI

• P02.31.B INDUCTION OF A CHRONIC INTERFERON STIMULATED TUMOR-ASSOCIATED MYELOID CELL PHENOTYPE IS DIRECTLY ORCHESTRATED BY ABERRANT TUMOR-INTRINSIC EGFR-ACTIVATION IN GLIOBLASTOMA

  Neuro-Oncology · 2025-10-01

  articleOpen access

  Abstract BACKGROUND Glioblastoma (GB) is a lethal primary brain tumor frequently driven by amplification and aberrant activation of the epidermal growth factor receptor (EGFR). Tumor-associated myeloid cells (TAMs) comprise the majority of tumor infiltrating leukocytes (TILs) and secrete inflammatory molecules that promote tumor growth including IL-6, IL-1β, and EGF, a canonical EGFR ligand. These TAMs orchestrate a suppressive tumor immune microenvironment (TIME) with poor T cell infiltration. However, whether EGFR activation plays a direct role in mediating TAM recruitment and phenotype is poorly understood. MATERIAL AND METHODS We leveraged the MADR-mEGFRvIII murine GB model which expresses constitutively active mEGFRvIII under a tetracycline-off promoter. Orthotopic MADR-mEGFRvIII-bearing mice were treated with doxycycline (dox) for one week followed by flow cytometric TIME profiling. Tumor conditioned media (CM) and orthotopic tumor lysates were assessed via ELISA and cytokine array. Lymphocytes (CD4, CD8, NK) were depleted via antibody administration. Magnetically isolated CD45+ TILs from MADR-mEGFRvIII and newly diagnosed (nd) GB patient tumors with known EGFR status underwent bulk or single-cell RNA sequencing. RESULTS Immunophenotyping of TILs from MADR-mEGFRvIII tumors revealed EGFR activation is associated with significantly enhanced F4/80+ myeloid cell infiltration. Assessment of MADR-mEGFRvIII tumor CM identified EGFR-dependent secretion of myeloid chemoattractants CCL2 and CXCL10 in vitro, which was corroborated in tumor lysates from mice. Further, sequencing of TILs revealed EGFR activation is significantly associated with interferon (IFN)-stimulated gene (ISG) expression in both brain-resident microglia and monocytic macrophages. Lymphocyte depletion prior to tumor implantation did not affect the EGFR-driven induction of ISGs in TILs, suggesting type I IFN is responsible for the observed TAM phenotype. Pan-IFNα and IFNβ ELISAs confirmed type I IFN was not present in tumor CM, indicating IFN is secreted by other constituents in the TIME. Importantly, ndGB patient TILs were assessed to determine if EGFR activation is associated with TAM ISG expression in human GB. Indeed, significant differential expression of numerous ISGs including IRF7, IFI44, and MX1 was observed in TAMs from EGFR activated tumors compared to wild type further supporting the concept that EGFR orchestrates the induction of a chronic TAM IFN response in GB. CONCLUSION Our results indicate tumor-intrinsic EGFR activation promotes TAM recruitment via CCL2 and CXCL10 secretion and potentiates robust induction of type I IFN signaling within the TIME, ultimately resulting in a TAM phenotype characterized by ISG expression. Therapeutically targeting this EGFR-driven tumor-TAM crosstalk may be a viable strategy to reduce immunosuppression arising from chronic IFN signaling.

  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

• TMOD-35. Introducing MADR: A next-generation EGFR-driven glioblastoma model that recapitulates human immunotherapy resistance

  Neuro-Oncology · 2025-11-01

  articleOpen access

  Abstract Early pre-clinical studies suggested that immune checkpoint blockade (ICB) would be a viable treatment for glioblastoma (GB). However, ICB and other immunotherapies have largely failed to provide meaningful survival benefits in patients. This stark disconnect underscores a desperate need for improved models that better recapitulate human disease. Here, we characterize and compare a novel syngeneic and orthotopic pre-clinical GB model, MADR-mEGFRvIII, with the existing CT-2A, GL261, and SB28 models. We demonstrate that this new model closely resembles the histopathologic, molecular, immunologic, and functional features of primary human GB. Unlike existing models, MADR-mEGFRvIII was developed through targeted deletions in Pten and Cdkn2a and ectopic expression of a murine form of the oncogenic EgfrvIII. We demonstrate that mice bearing MADR-mEGFRvIII tumors fail to respond to dual anti-PD-1 and anti-CTLA-4 ICB, with treated mice showing a similar 30-day median overall survival time as the IgG control group. Using scRNA-sequencing and flow cytometry, we compare the composition of the tumor immune microenvironment (TIME) across all models. We reveal that MADR-mEGFRvIII tumors have significantly fewer infiltrating lymphocytes. Notably, MADR-mEGFRvIII tumors were highly enriched in microglia, as opposed to bone marrow-derived macrophages seen in other models, accounting for over 70% of all immune cells. Leveraging the hgp100-antigen specific Pmel-1 T cell model system, we show that MADR-mEGFRvIII cells more readily avoid mounting T cell pressure in vitro despite high levels of secreted IFN-γ, resulting in less cytotoxicity compared to other models. Therefore, we interrogated tumor-intrinsic responses to IFN-γ treatment, which identified a comparatively stronger transcriptional response in MADR-mEGFRvIII cells. Overall, the MADR-mEGFRvIII model shares many characteristics of primary human GB, suggesting this model is highly suitable for pre-clinical GB research. We hope to leverage this model to gain meaningful insight into the immunological determinants that govern immunotherapy resistance and help guide new therapeutic strategies to treat GB.

  PublisherOA PDFDOI

• DDDR-57. A brain-penetrant EGFR inhibitor overcomes EGFR variant heterogeneity in glioblastoma

  Neuro-Oncology · 2025-11-01

  articleOpen accessSenior author

  Abstract The epidermal growth factor receptor (EGFR) is one of the most frequently altered genes in glioblastoma (GBM), yet therapeutic efforts have been limited by the heterogeneity of EGFR variants and poor blood–brain barrier permeability. We describe KTM-101, a reversible, highly selective EGFR inhibitor engineered for CNS delivery and broad activity against both amplified wild-type and extracellular domain EGFR mutants common to GBM. KTM-101 exhibited exceptionally high brain-to-plasma ratio across species (3.9-13) and effectively suppressed EGFR phosphorylation, downstream signaling, and tumor growth across diverse EGFR-altered patient-derived gliomasphere and orthotopic xenograft (PDOX) models at well tolerated exposures. Preliminary clinical evidence from a first-in-human phase I trial (NCT05222802) supports activity in a patient with recurrent, EGFR-altered GBM. In a large-scale, preclinical phase II-like trial across 30 distinct PDOX models, KTM-101 achieved an objective response rate (ORR) of 43% and extended median survival by 93% in EGFR-altered responsive models, with the greatest efficacy observed in newly diagnosed GBM. These findings position KTM-101 as a new brain-penetrant EGFR inhibitor with the potential to overcome longstanding challenges in treating EGFR-driven GBM and to enable precision-targeted therapy for this aggressive cancer.

  PublisherOA PDFDOI

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

  Neuro-Oncology · 2025-11-01

  articleOpen accessSenior author

  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

• CNSC-84. GLIOBLASTOMA HIJACKS NEURONAL MECHANISMS TO EVADE APOPTOSIS

  Neuro-Oncology · 2025-11-01

  articleOpen accessSenior author

  Abstract Infiltration and integration of cancer cells into normal brain structures is a hallmark of glioblastoma (GBM) and contributes to both the high recurrence rates and the limited efficacy of current therapies. Recent studies have shown that glioma cells can functionally integrate into neuronal circuits, enabling neuronal activity to directly promote tumor cell proliferation. However, the underlying molecular mechanisms responsible for neuron-glioma circuits driving therapeutic resistance remain unclear. Here, we uncover that glioma-neuronal integration can alter the ability of GBM to evade cell death. Specifically, we find that the brain microenvironment modulates the intrinsic apoptotic machinery of GBM cells through direct cell-cell contact and alters their calcium signaling dynamics. We hypothesize that neuron-induced calcium modulation mediates the expression or activity of key apoptosis proteins, ultimately suppressing intrinsic cell death pathways. Collectively, by defining the molecular underpinnings of this neuron-mediated resistance to apoptosis could reveal novel, microenvironment-specific vulnerabilities that inform the next generation of GBM therapies.

  PublisherOA PDFDOI

• Correction: Associations amongst genes, molecules, cells, and organs in breast cancer metastasis

  Clinical & Experimental Metastasis · 2025-09-19

  article1st authorCorresponding
  PublisherDOI

• A clinical drug candidate that triggers non-apoptotic cancer cell death

  Research Square · 2025-02-11

  preprintOpen accessSenior author
  PublisherOA PDFDOI

• DDDR-40. TARGETING BCL-XL WITH MIRZOTAMAB CLETUZOCLAX (ABBV-155) AND STANDARD OF CARE THERAPIES OVERCOMES APOPTOTIC RESISTANCE IN GLIOBLASTOMA

  Neuro-Oncology · 2024-11-01 · 1 citations

  articleOpen accessSenior author

  Abstract Conventional GBM therapies (e.g., temozolomide (TMZ), irradiation (IR)) transiently halt tumor growth of glioblastoma (GBM) but fail to induce apoptosis, inevitably leading to disease progression and poor patient survival. Targeting apoptotic blocks with BH3 mimetics can be an efficacious strategy to trigger apoptosis; however, these therapies can prevent high exposures in patients due to on-target, off-tumor toxicity in normal tissues. Mirzotamab Cletuzoclax (ABBV-155) is a first-in-class antibody-drug conjugate (ADC) that is specific for the highly expressed cell surface protein B7-H3 (CD276) and delivers a selective and potent BCL-XL inhibitor warhead. Here we identified that both TMZ and IR leave p53 WT GBM tumors exclusively dependent on the apoptotic block, BCL-XL, for survival. ABBV-155 negated the BCL-XL apoptotic block in both cell culture and orthotopic xenograft GBM models. Consequently, ABBV-155 combined with TMZ or IR initiates apoptosis and is synergistically lethal in GBM cells. Moreover, these combinations decrease tumor burden and extend survival in patient derived orthotopic xenografts. Taken together, these results demonstrate that the combination of DNA damaging therapy and ABBV-155 can have a synergistic anti-tumor impact in p53 WT GBM.

  PublisherOA PDFDOI

Recent grants

• UCLA SPORE in Brain Cancer

  NIH · $35.6M · 2017–2027

Frequent coauthors

• Marlys H. Witte

  65 shared

• Jonathan S. Zager

  Moffitt Cancer Center

  64 shared

• Najjia N. Mahmoud

  Hospital of the University of Pennsylvania

  64 shared

• Richard J. Straker

  64 shared

• Aida Bao‐Caamano

  Instituto de Investigación Sanitaria de Santiago

  64 shared

• Mara Hieken

  Henry Ford Hospital

  64 shared

• Colleen M. Costelloe

  The University of Texas MD Anderson Cancer Center

  64 shared

• Tadashi Nakano

  64 shared

Labs

• Nathanson Lab at UCLAPI

  Previous lab members include Lynn Baufeld, Laura Gosa, Wilson Mai, Lisa Ta.

Education

• MBBCH, Medicine

  University of the Witwatersrand

  1966

Awards & honors

• Ruth Kirschstein National Research Service Award by the NIH
• STOP Cancer Award
• Sanofi Innovation Award
• Johnny Mercer Foundation Award for brain tumor research