About

Sean Lawler, Ph.D, is an Associate Professor of Pathology and Laboratory Medicine at Brown University. He leads the Brain Cancer Therapy Lab within the Department of Pathology and Laboratory Medicine and serves as co-leader of the CNS Cancer Translational Disease Research Group at the Legorreta Cancer Center. Additionally, he is co-Director of the Therapeutic Sciences Graduate Program at Brown University. His research focuses on developing new treatments for brain cancers, which are among the most challenging due to their location and aggressive nature. His major research interests include drug delivery across the blood-brain barrier for brain cancer treatment, harnessing innate immune mechanisms to improve immunotherapies for brain cancer, and understanding the effects of cytomegalovirus on the growth of glioblastoma. Dr. Lawler earned his Ph.D. from Birkbeck University of London in 1992 and his BSc from the University of Edinburgh in 1987.

Research topics

• Biology
• Cancer research
• Immunology
• Cell biology
• Neuroscience
• Virology
• Medicine
• Genetics

Selected publications

• Asthma-mediated control of optic glioma growth via T cell-microglia interactions: A mathematical model

  npj Systems Biology and Applications · 2026-01-16

  articleOpen access

  Optic glioma, a slow-growing tumor, is associated with Neurofibromatosis type 1 (NF1) mutations and increased midkine (MDK) production. A connection between asthma and optic glioma has previously been observed, but the mechanisms are unclear. To elucidate the role of asthma in the regulation of glioma formation, we investigated the role of T cells and the subsequent pathways in the regulation of microglia, a key player in the glioma tumor microenvironment (TME). While asthma is often linked to chronic inflammation, our mathematical analysis and experimental evidence suggest that inflammation can play a key role in suppressing the proliferation of optic glioma cells via immune reprogramming of T cells and the delicate control of signaling networks in microglia. Our mathematical model unveils the complex interactions between tumor and immune cells in optic glioma. Our results indicate that asthma-induced T cell reprogramming inhibits tumor growth by promoting the release of decorin and a subsequent suppression of CCR8 and the intercellular binding kinetics in microglia, followed by blocking of CCL5 production in TME via suppression of NFκB. We developed anti-cancer strategies by leveraging this asthma-induced immune regulation.

  PublisherDOI

• IMMU-21. Antiviral Therapy Reverses CMV-Induced Oncogenic Signaling and Enhances NK Cell Cytotoxicity in Glioblastoma with Associated PD-L1 Upregulation and Immune Modulation

  Neuro-Oncology · 2025-11-01

  articleOpen accessSenior author

  Abstract BACKGROUND Cytomegalovirus (CMV) has been implicated in glioblastoma (GBM) pathogenesis by promoting stemness, angiogenesis and immune evasion. Clinical trials targeting CMV in GBM have shown preliminary promise, however, the molecular mechanisms remain unclear. We hypothesized that CMV enhances oncogenic signaling and immune resistance in GBM, and that antiviral therapy may reverse these effects and increase susceptibility to immune-mediated cytotoxicity MATERIALS AND METHODS Human GBM cell lines (U251, U87, U138, T98G, LN229) and normal astrocytes were infected with a mCherry-human CMV TB40 strain (MOI 0.5). Phenotypic assays including spheroid & colony formation were performed. A 60-plex cytokine panel and Western blotting were used to evaluate cytokine profiles & signaling pathway activation (IL-6/STAT3, Akt, SOX2, Survivin, p-RB). Co-culture experiments with NK-92 MI cells were conducted using CMFDA and EthD dyes to assess cytotoxicity. RESULTS CMV infection upregulated IL-6/STAT3, SOX2, Survivin, p-AKT, and p-RB, promoting GBM cell proliferation, stemness, and apoptosis resistance. Infected cells exhibited a tumor-supportive cytokine profile and, after ganciclovir treatment, reduced VEGF and Angiopoietin-2 levels. CMV-infected astrocytes also showed increased oncogenic signaling and colony formation, suggesting a role in early transformation. Ganciclovir partially reversed these effects, shifting cytokine expression toward an immune-permissive state. While NK cells alone failed to lyse GBM cells, ganciclovir-treated, CMV-infected cells showed significantly enhanced NK-mediated cytotoxicity. PD-L1 expression increased after CMV infection and remained elevated post-treatment, indicating immune modulation and potential for checkpoint blockade. CONCLUSIONS CMV infection reprograms both glioblastoma cells and normal astrocytes toward a more aggressive, immune-evasive phenotype through activation of IL-6/STAT3, p-AKT, SOX2, and angiogenic pathways. Ganciclovir treatment partially reverses these effects, reducing VEGF and Angiopoietin-2 levels, shifting cytokine profiles, and—critically—enhancing NK cell-mediated cytotoxicity. Persistent PD-L1 upregulation following infection suggests a novel immune checkpoint vulnerability, opening the door for synergistic antiviral and immunotherapy approaches. These findings identify CMV not only as a driver of tumor progression but as a tractable therapeutic target in GBM.

  PublisherOA PDFDOI

• Modulating populational variance of methyl-guanine methyl transferase expression through miR-181d degradation: a novel mechanism of temozolomide resistance

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-04-26

  preprintOpen access

  Abstract Intratumoral heterogeneity plays a pivotal role in cancer evolution, providing the substrate for adaptation to selective pressures, including treatment with chemotherapy. Here, we show that micro-RNA regulation of variance in the expression of the DNA repair protein methyl-guanine methyl transferase (MGMT) contributes to this heterogeneity and acquired therapeutic resistance. In cell lines derived from glioblastomas, the most common form of primary brain tumor, treatment with standard-of-care temozolomide chemotherapy triggers a feed-forward loop between polyribonucleotide nucleotidyltransferase 1 (PNPT1) and miR-181d, an MGMT regulating miRNA, expediting miR-181d degradation. This degradation requires the activation of Ataxia Telangiectasia and Rad3-related (ATR) kinase. The degradation of miR-181d in glioblastoma cells increased both the mean and the variance of MGMT expression in the cell population. Subclone reconstituted cell populations with similar populational mean MGMT levels but with differences in the variance of MGMT expression exhibited differential temozolomide sensitivity, with the higher MGMT variance population showing increased resistance. This resistance is suppressed by exogenously transfected miR-181d. These findings suggest a key role for miRNA in regulating intra-tumoral heterogeneity through modulation of key DNA repair enzymes and provide a compelling rationale for miRNA delivery as a platform for glioblastoma therapy. Significance Statement This study demonstrates a mechanistic link between a feed-forward loop mediating microRNA degradation and cell-to-cell variance in gene expression, and the contribution of this mechanism to intratumoral heterogeneity and therapeutic resistance. We show that when glioblastoma, the most common form of adult primary brain tumor, is treated with standard-of-care chemotherapy, temozolomide, a feed-forward loop between miR-181d and PNPT1 is initiated, causing rapid degradation of miR-181d. This degradation increases the cell-to-cell variability in methyl-guanine methyl transferase (MGMT) expression, expanding intra-tumoral heterogeneity and contributing to acquired temozolomide resistance. This process can be suppressed by therapeutic delivery of microRNA, providing compelling considerations for clinical translation.

  PublisherOA PDFDOI

• IMMU-31. Investigating innate immune targeting of pediatric high grade glioma via STING immunostimulation and therapeutic anti-tumor antibodies

  Neuro-Oncology · 2025-11-01

  articleOpen accessSenior author

  Abstract At present, there is a lack of effective treatments for pediatric high-grade glioma (pHGG). While conventional immunotherapies have been effective in treating cancers outside the central nervous system (CNS), they have been largely unsuccessful in CNS malignancies. Research conducted primarily on adult brain tumors has demonstrated the importance of immunoediting and the tumor microenvironment (TME) in both preventing disease progression and facilitating tumor escape. Building on this understanding, our research aims to explore the interactions of pHGG with the innate immune system, with the goal of harnessing anti-tumor activity through immunotherapy. The growing body of knowledge about pHGG highlights important differences compared to adult glioblastoma (GBM), extending beyond genomic mutational profiles. In this study, we investigated the expression of the immunostimulatory STING signaling pathway in pHGG cells, as well as the immunological target GD2 ganglioside. We demonstrate that STING pathway components are expressed in pHGG cells and that treatment with the STING agonist ADU-S100 induces robust downstream signaling, resulting in type I interferon secretion and increased cytotoxic activity of peripheral blood mononuclear cells (PBMCs) in co-culture assays. Furthermore, our research demonstrates strong expression of GD2 in pHGG cell lines. Delivery of the anti-GD2 monoclonal antibody Dinutuximab to these tumors activates the anti-tumor effects of PBMCs. Lastly, we explore tumor modulation of the GD2 target when undergoing immune stress. These findings highlight promising therapeutic approaches for pHGG, emphasizing the potential of targeted immunotherapies and increasing our understanding of tumor response to immune pressure.

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• Abstract 7206: STING agonist ADU-S100 in combination with vemurafenib induces STING upregulation, immune-stimulatory cytokine modulation and enhancing NK-mediated cytotoxicity in BRAF V600E-mutant melanoma

  Cancer Research · 2025-04-21

  articleSenior author

  Abstract Background: Targeting the mitogen-activated protein kinase (MAPK) pathway with BRAF inhibitors, has significantly advanced the treatment of melanoma patients whose tumor harbor a BRAF V600E/K mutation. therapeutic resistance occurs in the majority of patients, highlighting the need for combination strategies to improve treatment outcomes. The activation of the Stimulator of Interferon Genes (STING) pathway has emerged as a promising approach to boost anti-tumor immunity. This study explores the potential efficacy of combining the STING agonist ADU-S100 (ADU) with vemurafenib in human melanoma cell lines harboring the BRAF V600E mutation, focusing on its impact on tumor signaling, cytokine profiles, and NK-cell-mediated cytotoxicity. Methods: Human melanoma cell lines with BRAF V600E mutation—SK-MEL-28, SK-MEL-24-SH4, RPMI7951, and SK-MEL-3—were treated with ADU, vemurafenib, or both in combination. Cell viability was assessed, while changes in total STING were measured by Western blot. Cytokine profiles were analyzed using a multiplex Luminex panel. NK cell-mediated cytotoxicity was assessed through co-culture experiments. Results: Cell viability assays demonstrated treatment with ADU alone did not significantly reduce cell viability. Western blot analysis revealed minimal baseline STING levels in the SH4 cell line, with a marked increase following ADU, vemurafenib, or their combination. The most pronounced upregulation of STING occurred when ADU & vemurafenib were used together. In SK-MEL-28, the combination treatment was the only condition to result in substantial STING upregulation and a corresponding reduction in pERK. Cytokine analysis showed that the combination treatment significantly increased the levels of beta-2 microglobulin (B2M) across all three cell lines, suggesting modulation of immune checkpoint inhibitor resistance. Additionally, the combination treatment led to a marked reduction in CXCL-8, a key mediator of melanoma progression and metastasis, and decreased VEGF levels across all three cell lines. The CXCL5/CXCL13 axis, known to influence responses to targeted immunotherapies, was most favorably modulated under the combination condition. Co-culture with NK cells revealed an increase in tumor cell death in all three cell lines following combination treatment. Conclusion: The combination of STING agonist ADU-S100 and vemurafenib effectively enhances immune-stimulatory cytokine profiles in BRAF V600E-mutant melanoma. Notably, this approach may be used to promote NK cell-mediated cytotoxicity and modulation of key cytokines associated with immune resistance. This strategy shows promise for overcoming resistance and improving outcomes, warranting further clinical investigation. Citation Format: Vida Tajiknia, Matthew Hadfield, Andrea Schmidt, Connor purcell, Claire Lin, wafik El Deiry, Sean Lawler. STING agonist ADU-S100 in combination with vemurafenib induces STING upregulation, immune-stimulatory cytokine modulation and enhancing NK-mediated cytotoxicity in BRAF V600E-mutant melanoma [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 7206.

  PublisherDOI

• 943 Understanding STING signaling in glioblastoma; identifying a role for STING in tumor cells

  Regular and Young Investigator Award Abstracts · 2025-11-01

  articleOpen accessSenior author

  Background Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis.Only 5% of patients survive beyond five years.This dire survival rate underscores the need for improved strategies.GBM remains refractory to immunotherapy, potentially due to its immunosuppressive tumor microenvironment (TME).STING (Stimulator of Interferon Genes), which is essential for secretion of immune activating cytokines in response to some pathogens, may be a target for TME modulation in GBM.Our Lab previously showed that a small molecule STING agonist (ADU-S100), can turn on the pathway and improve survival in mouse GBM models.It is thought that STING agonists target the pathway in the stromal cells of the TME, and that the pathway is disabled in tumor cells, as a potential immunoevasion mechanism.However, our studies have shown that STING pathway components are expressed in many GBM cells.The goal of this study was to understand whether STING signaling can play a role in tumor cells and to better define that role.Methods We used western blotting, RT-qPCR, RNAseq and ELISA to examine responses to STING modulation in a panel of patient-derived GBM cell lines.Results We confirmed that STING signaling pathway components are present in GBM cell lines.Treatment with the STING agonists ADU-S100 led to activation of STING signaling as measured by Western blotting for phosphorylation of STING and downstream proteins TBK1 and NF-kB.However, secretion of cytokines was largely lacking in GBM cells, despite STING phosphorylation, indicating pathway failure.Furthermore, RNA sequencing after treatment with ADU-S100 revealed very few alterations, suggesting that the defect in STING signaling is at the transcriptional level in GBM cells, which could represent an immune evasion mechanism.Interestingly, treatment with a STING inhibitor, led to a decrease in GBM cell viability, suggesting that STING plays other roles in the biology of tumor cells.Conclusions GBM cells rewire STING signaling likely as an immune evasion mechanism.Our data shows that GBM cells can respond to STING agonists, suggesting additional functions of STING signaling which may facilitate tumor growth.These are currently under investigation.

  PublisherOA PDFDOI

• Abstract 6939: MAPKAP kinase 2 regulates inflammatory responses in glioblastoma

  Cancer Research · 2025-04-21

  article

  Abstract IDH-wildtype glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, with 5-year survival rates of only 6% and a median survival of 14-22 months, depending on the MGMT promoter methylation status. Despite advances in treatment, GBM remains highly resistant due to its complex molecular landscape, characterized by rapid proliferation, angiogenesis, immune invasion, and metabolic dysregulation. In this study, we investigate the role of MAPK-activated protein kinase 2 (MK2), a critical kinase in the MAPK signaling pathway, as a potential therapeutic target in GBM. MK2 regulates key cellular processes including inflammation, stress response, DNA damage repair, and cell migration, all of which contribute to GBM progression. Notably, MK2 is highly enriched in microglia and peripherally derived macrophages. Our results demonstrate that MK2 is significantly upregulated in GBM tissues compared to normal brain tissue, and its expression correlates with poor survival outcomes. In vitro, MK2 inhibition significantly suppresses glioma cell proliferation, induces G1 cell cycle arrest, and promotes apoptosis, suggesting its potential to limit tumor growth and metastasis. To assess the in vivo antitumor effects of MK2 inhibition, we orthotopically implanted GL261 and CT-2A gliomas in MK2 knockout (KO) and wild-type C57BL/6 mice. MK2 genomic knockout is well tolerated in immunocompetent C57BL/6 mice. GL261 tumor cells with intact MK2 signaling effectively implant in hosts with global MK2 deficiency and shows more aggressive tumor growth than in hosts with wild-type MK2. In contrast, there was no effect on tumor growth in the CT-2A model, suggesting that tumor immunogenicity may influence the role of MK2 signaling in GBM. Mechanistically, host MK2 deficiency leads to increased circulating Gr1+CD11b+ myeloid-derived suppressor cells (MDSCs) and elevated PD-L1 expression on these cells, indicating a tumor-promoting inflammatory response and an altered immune profile within the myeloid compartment. These findings suggest an important role of MK2 in immune responses to GBM tumors that restricts growth. Ongoing studies are investigating the immunoregulatory function of MK2 using conditional knockout models targeting MK2 specifically in myeloid cells, as well as selective silencing of MK2 in tumor cells through CRISPR/Cas9 in vivo. Together, our results highlight MK2 as a possible therapeutic target in GBM, and underscores the importance of tumor-selective MK2 inhibitors and targeted therapies. These approaches could serve as adjunctive treatments to overcome therapy resistance and improve patient outcomes in this devastating malignancy. Citation Format: Eleni Panagioti, Yi Wen Kong, Xueyang Yu, Sean E. Lawler, Michael B. Yaffe, Charles H. Cook. MAPKAP kinase 2 regulates inflammatory responses in glioblastoma [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 6939.

  PublisherDOI

• ARHGAP12 and ARHGAP29 exert distinct regulatory effects on switching between two cell morphological states through GSK-3 activity

  Cell Reports · 2025-03-01 · 1 citations

  articleOpen access

  Cancer cells undergo morphological changes and phenotype switching to promote invasion into healthy tissues. Manipulating the transitional morphological states in cancer cells to prevent tumor dissemination may enhance survival and improve treatment response. We describe two members of the RhoGTPase activating protein (ARHGAP) family, ARHGAP12 and ARHGAP29, as regulators of transitional morphological states in glioma via Src kinase signaling events, leading to morphological changes that correspond to phenotype switching. Moreover, we establish a link between glycogen synthase kinase 3 (GSK-3) inhibition and β-catenin translocation in altering transcription of ARHGAP12 and ARHGAP29. Silencing ARHGAP12 causes loss of N-cadherin and adoption of mesenchymal morphology, a characteristic feature of aggressive cellular behavior. In patients with glioblastoma (GBM), we identify a link between ARHGAP12 and ARHGAP29 co-expression and recurrence after treatment. Consequently, we propose that further investigation of how ARHGAPs regulate transitional morphological events to drive cancer dissemination is warranted.

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• Acquired resistance to molecularly targeted therapies for cancer

  Cancer Drug Resistance · 2025-06-04 · 11 citations

  reviewOpen access

  Acquired resistance to molecularly targeted therapies remains a formidable challenge in the treatment of cancer, despite significant advancements over the last several decades. We critically evaluate the evolving landscape of resistance mechanisms to targeted cancer therapies, with a focus on the genetic, molecular, and environmental contributors across a variety of malignancies. Intrinsic mechanisms such as mutations, drug and drug target modifications, and, notably, the activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/Akt pathways are mechanisms different malignancies use to combat therapeutic effectiveness. Furthermore, extrinsic alterations to the tumor microenvironment contribute to therapeutic resistance. We highlight similarities and differences in mechanisms across a wide spectrum of cancers including hematologic malignancies, non-small cell lung cancer, gastrointestinal, breast, and prostate cancers, pancreatic, ovarian, endometrial, and intracranial gliomas. Emerging strategies to overcome resistance, including multi-targeted approaches, combination therapies, and exploitation of synthetic lethality, are all critically discussed. We advocate for a nuanced understanding of resistance mechanisms as a cornerstone for developing future therapeutic strategies, emphasizing the necessity for integrated approaches that encompass genomic insights and precision medicine to outpace the dynamic and complex nature of cancer evolution and therapy resistance.

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• Abstract 4709: Enhancing chemotherapy efficacy in pancreatic cancer synergistic effects of ONC206 and ONC212 with 5-FU through inhibition of p-ERK

  Cancer Research · 2025-04-21

  article

  Abstract Background: Pancreatic cancer is a lethal malignancy projected to become the second leading cause of cancer deaths by 2030, with a 5-year survival rate of just 12%. Resistance to chemotherapy, particularly 5-fluorouracil (5-FU), remains a major challenge in treating pancreatic ductal adenocarcinoma (PDAC). ONC206 and ONC212, imipridone-class agents targeting DRD2/ClpP and GPR132/ClpP, show promise in disrupting tumor growth and inducing apoptosis. Phosphorylated ERK (p-ERK), a key driver of PDAC aggressiveness via the MAPK pathway, is a critical therapeutic target. We hypothesize that combining ONC206 or ONC212 with 5-FU could enhance efficacy by synergistically inhibiting p-ERK, supporting their potential in PDAC treatment. Materials & Methods: The synergy of ONC206 or ONC212 with 5-FU was tested in PDAC cell lines (PANC1, CFPAC-1, HPAF-II, CAPAN-2, ASPAC1) using CellTiter-Glo for cell viability at 72 hours. Western blotting assessed p-ERK, ATF4, and other key proteins for pathway inhibition. Results: Synergy between 5-FU and ONC212, or 5-FU and ONC206, was observed across all cell lines, with IC50 values for ONC206 ranging from 300-500 nM and for ONC212 from 70-100 nM. At the 48-hour time point in the HPAF-ll cell line, 100 nM ONC212 significantly inhibited p-ERK levels compared to 300 nM ONC206. Both treatments as monotherapies resulted in reduced p-ERK levels compared to control. When combined with 25 µM 5-FU, ONC212 caused a more pronounced reduction in p-ERK. In the PANC-1 cell line, the strongest reduction in p-ERK was observed with the combination of ONC212 and 5-FU at 48 hours. In the ASPAC1 cell line, p-ERK inhibition occurred only in conditions containing ONC212, with a more significant effect when combined with 5-FU. Conclusions: Our data demonstrate that combining 5-FU with ONC206 or ONC212 results in the inhibition of p-ERK, a critical node in the PDAC growth pathway. This synergy between 5-FU and the imipridone compounds ONC206 and ONC212 is a universal phenomenon in the tested human PDAC cell lines. Notably, ONC212 is more potent than ONC206, allowing for lower dosages, and in cases where ONC206 does not effectively inhibit p-ERK, ONC212 can be a more effective option Further studies are needed to elucidate the exact mechanism of this synergy, but these findings provide a promising foundation for developing novel combination therapies to improve PDAC treatment outcomes. Citation Format: Vida Tajiknia, Claire Lin, Maximilian Pinho-Schwermann, Connor Purcell, Sean Lawler, Wafik El-Deiry. Enhancing chemotherapy efficacy in pancreatic cancer synergistic effects of ONC206 and ONC212 with 5-FU through inhibition of p-ERK [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 4709.

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Recent grants

• Fluorinated macrocyclic peptides as BBB penetrating agent for improved GBM treatment

  NIH · $3.0M · 2019–2024

Frequent coauthors

• E. Antonio Chiocca

  476 shared

• Michal O. Nowicki

  Harvard University

  381 shared

• Jakub Godlewski

  210 shared

• Agnieszka Bronisz

  Mossakowski Medical Research Institute, Polish Academy of Sciences

  149 shared

• Josie Hayes

  131 shared

• Michael C. Ostrowski

  Medical University of South Carolina

  124 shared

• Pierpaolo Peruzzi

  Harvard University

  122 shared

• Ichiro Nakano

  118 shared

Education

• Ph.D.

  Birkbeck University of London

  1992

• B.S.

  University of Edinburgh

  1987