Turalio (pexidartinib) / Daiichi Sankyo - LARVOL DELTA

Identification and targeting oxidative phosphorylation/glycolysis to overcome anti-CSF-1R therapy resistance in glioblastoma. (PubMed, Cell Death Dis) - "To solve above problem, we have established a highly stable and refractory mouse G422TN-GBM model, in which temozolomide (TMZ) is the most effective monotherapy but can only slightly extend animal survival...TRAP-seq identified oxidative phosphorylation/glycolysis as anti-CSF1R therapy resistance mechanism, and it's combined with Cancer Therapeutics Response Portal (CTRP) identified piperlongumine (PL) or vorinostat (SAHA) as targeting drugs...In conclusion, targeting oxidative phosphorylation/glycolysis by PL or SAHA prominently improves therapeutic efficacy of PLX3397 + TMZ in GBM, which deserves priority for clinical trials. Our study also reveals that translatome profiling is efficient for uncovering drug-resistant targets."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Efficacy of Targeted Agents and Immune Checkpoint Inhibitors in Patients with Malignant Histiocytosis (ASH 2024) - "TAs included BRAF inhibitor (vemurafenib [1]), MEK inhibitors (binimetinib [1], cobimetinib [2], trametinib [2]) and others (dasatinib [1], pazopanib [1], pexidartinib [1]), while ICIs were exclusively pembrolizumab (5)...TAs included BRAF inhibitor only (vemurafenib [3], dabrafenib [3]), MEK inhibitor only (trametinib [5]), BRAF + MEK inhibitors (2), and others (apatinib, anlotimib, bevacizumab, daratumumab, dasatinib, imatinib, pazopanib, sorafenib, or combinations [9]), while ICIs included pembrolizumab (4), nivolumab (4), tislelizumab (1), and sintilimab (1)...Conclusion TAs and ICIs can be considered in the management of MH. The responses to ICI therapy may be associated with the degree of PDL1 expression"

Checkpoint inhibition • Clinical • IO biomarker • Hematological Malignancies • Oncology • Sarcoma • Solid Tumor • DOCK8 • MAP2K1 • PD-L1 • PTPN11

Interplay Between Therapy-Induced Senescence and Macrophage Polarization in the Tumor Microenvironment of Triple-Negative Breast Cancer (SABCS 2025) - "In contrast, direct exposure of RAW cells to doxorubicin significantly induced senescence and promoted an M2-like, pro-tumorigenic phenotype characterized by elevated CD206 expression. Notably, pretreatment with PLX3397 led to a marked reduction in macrophage numbers in senescent cultures, suggesting impaired TAM survival. These findings reveal a role for senescence in promoting M2-like macrophage polarization and highlight the potential of PLX3397 as a therapeutic strategy to target senescent TAMs and reshape the immune landscape within the TME."

Biomarker • Tumor microenvironment • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CDKN1A • IL6 • MRC1 • TP53

Modulating Tumor-Associated Macrophages to Enhance EpCAM-Directed CAR T Cell Efficacy in Lung Cancer Brain Metastases (SNO 2025) - "TAM/M depletion was achieved via CSF1R inhibition using a PLX 3397 diet... Our findings demonstrate that TAM/M mediate CAR T-cell suppression in brain metastases of lung cancer. CSF1R inhibition reprogrammed TAM/M, enhancing CAR T-cell trafficking, intratumoral persistence, and antitumor efficacy, resulting in prolonged survival. These results support the development of combinatorial strategies incorporating CSF1R blockade to boost CAR T-cell functionality and improve therapeutic outcomes in brain metastases."

CAR T-Cell Therapy • Clinical • Brain Cancer • Lung Cancer • Oncology • Solid Tumor • MRC1

Microglia Depletion Demonstrates a Time-dependent But Sex-independent Decrease in Survival in a Murine Model of Glioblastoma (SNO 2025) - "Microglia depletion with PLX3397 demonstrates a temporal effect on survival in a murine model of GBM. These results demonstrate the potential time-dependent role of microglia in the acute phase of GBM implantation and provide insight into the evolving phenotype across time."

Preclinical • Brain Cancer • Glioblastoma • Solid Tumor

Vessel-Associated Microglia Maintain Vascular Integrity and Prevent Early Hemorrhage in Glioblastoma (SNO 2025) - "To address this, we characterize vessel-associated myeloid cells in murine gliomas with high spatial and temporal resolution, leveraging in vivo two-photon imaging, MRI, and transgenic mouse lines.To investigate the role of microglia in glioma vasculature, we pretreated glioma-bearing mice with CSF1R inhibitors (PLX3397 & PLX5622) to ablate microglia prior to tumor inoculation. Using TMEM119CreER/+:R26tdTomato/+ mice, we confirmed these vessel-associated cells as brain-resident microglia, not infiltrating macrophages.Quantitatively, ~60% of peritumoral microglia were vessel-associated, compared to ~30% in naïve or contralateral hemispheres. These microglia displayed elongated somata and processes aligned with vessels or wrapping around vessels, which is a phenotype also observed following single-vessel photothrombosis, suggesting a response to impaired blood flow and BBB leakage.Our findings uncover a critical neurovascular role for vessel-associated microglia..."

Brain Cancer • Cerebral Hemorrhage • CNS Disorders • Glioblastoma • Glioma • Hematological Disorders • Solid Tumor • Thrombosis

Modulating Tumor-Associated Macrophages to Enhance EpCAM-Directed CAR T Cell Efficacy in Lung Cancer Brain Metastases (SNO 2025) - "TAM/M depletion was achieved via CSF1R inhibition using a PLX 3397 diet... Our findings demonstrate that TAM/M mediate CAR T-cell suppression in brain metastases of lung cancer. CSF1R inhibition reprogrammed TAM/M, enhancing CAR T-cell trafficking, intratumoral persistence, and antitumor efficacy, resulting in prolonged survival. These results support the development of combinatorial strategies incorporating CSF1R blockade to boost CAR T-cell functionality and improve therapeutic outcomes in brain metastases."

CAR T-Cell Therapy • Clinical • Brain Cancer • Lung Cancer • Oncology • Solid Tumor • MRC1

Microglial Inflammatory Response in the Glioblastoma Microenvironment in Preclinical Models. (PubMed, Mol Neurobiol) - "Microglia inhibition or depletion by treating organotypic cultures with minocycline or PLX3397 resulted in reduced levels of all the evaluated cytokines in the medium, confirming the role of microglia in the inflammatory microenvironment of glioblastoma. These findings provide valuable insights into how microglia interact with tumors and healthy cells in the tumor microenvironment, driving neuroinflammation and tumor cell dedifferentiation. This understanding could pave the way for the development of innovative therapies for glioblastoma."

Journal • Preclinical • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • CD133 • IL10 • IL1B • IL6 • NES • TNFA

EFFICACY WITH VIMSELTINIB IN PATIENTS (PTS) WITH TENOSYNOVIAL GIANT CELL TUMOR (TGCT) AND PRIOR COLONY-STIMULATING FACTOR 1 (CSF1) INHIBITOR THERAPY: A PHASE 2 CASE SERIES (CTOS 2025) - P1/2 | "Here, we report efficacy with vimseltinib in pts with prior pexidartinib or vimseltinib treatment. Pts with symptomatic TGCT not amenable to surgery were enrolled in this multicenter, open-label, phase 1/2 trial. These results suggest that pts with TGCT not amenable to surgery can derive clinical benefit from resumption of anti-CSF1R therapy, even after discontinuing the same (vimseltinib) or a different inhibitor. Vimseltinib retreatment was well tolerated with a manageable safety profile, consistent with prior reports."

P2 data • Giant Cell Tumor of Bone • Oncology • Tenosynovial Giant Cell Tumor • CSF1

PEXIDARTINIB RISK EVALUATION AND MITIGATION STRATEGY PROGRAM: 5-YEAR RETROSPECTIVE HEPATIC SAFETY ASSESSMENT (CTOS 2025) - "The results from this retrospective 5-year hepatic safety assessment of the tREMS Program show that careful monitoring of liver enzyme levels, along with early intervention, can mitigate the risk of potential hepatotoxicity associated with pexi treatment in adult pts with TGCT. The frequency, pattern, and timing of serious hepatic AEs was consistent with previous reports, and no new safety signals were observed."

Retrospective data • Giant Cell Tumor of Bone • Oncology • Tenosynovial Giant Cell Tumor

KNOWLEDGE, ATTITUDES, AND BEHAVIOR OF HEALTHCARE PROVIDERS ENROLLED IN THE PEXIDARTINIB RISK MITIGATION AND EVALUATION PROGRAM (CTOS 2025) - "The tREMS Program is considered to be meeting its goal if the point estimates of all KRMs achieve a demonstrated understanding of ≥80%. The results from retrospective assessment of all survey waves indicate that this threshold was consistently exceeded since TURALIO approval. The HCPs demonstrated a solid understanding of all 3 KRMs."

Oncology

THERAPEUTIC OUTCOMES IN NF1-ALTERED GIST TREATED WITH MEK INHIBITION: A SINGLE-CENTER EXPERIENCE (CTOS 2025) - "NF1-altered GIST is characterized by unique clinical and molecular features and demonstrates variable response to MEK inhibitor-based regimens with some patients experiencing prolonged disease control."

Clinical • Gastrointestinal Cancer • Gastrointestinal Stromal Tumor • Oncology • Sarcoma • Solid Tumor • NF1

TREATMENT PATTERNS IN PATIENTS WITH TENOSYNOVIAL GIANT CELL TUMORS: ADDRESSING COMMUNICATION IN A NEW THERAPEUTIC LANDSCAPE (CTOS 2025) - "Twelve patients received systemic therapy with pexidartinib or imatinib, and a majority (83.4%) experienced radiographic and/or symptomatic improvement after starting systemic therapy. Treatment of individuals with TGCT at our institution involved providers across various specialties and coordination with support services. With medical therapy emerging as both safe and effective, we propose a change to the historical referral pattern for patients specifically with recurrent TGCTs or external diagnoses to include an initial evaluation by both orthopedic and medical oncology, ideally at a multidisciplinary tumor board, to optimize patient understanding of all treatment options.TGCT Treatment Characteristics"

Clinical • Giant Cell Tumor of Bone • Oncology • Tenosynovial Giant Cell Tumor

MEDICAL MANAGEMENT OF TENOSYNOVIAL GIANT CELL TUMOR (CTOS 2025) - "Multiple colony-stimulating factor 1 receptor inhibitors (CSF1Ris) have emerged for symptomatic pts, with pexidartinib (pexi) and vimseltinib (vim) approved. Here, we review phase 3 reports for pexi, vim, and pimicotinib (pimi). PubMed was searched for publications associated with TGCT, CSF-1Ri, therapies for treatment of TGCT, and known guidelines, with a focus on phase 3 trials and postmarket analyses... CSF1Ris show efficacy in TGCT. Pts should be monitored for potential side effects that are different for each presented drug. Further research to understand long-term side effects and duration of response will be paramount to optimize therapeutic strategies for pts with TGCT."

Giant Cell Tumor of Bone • Oncology • Tenosynovial Giant Cell Tumor

PEXIDARTINIB FOR THE TREATMENT OF TENOSYNOVIAL GIANT CELL TUMORS: CLINICAL EXPERIENCE FROM FIVE CHINESE PATIENTS (CTOS 2025) - "These real-world observations from five Chinese patients with D-TGCT who were treated with pexi for >4 years showed improvements in TGCT-related symptoms in all patients. Most patients achieved long-term improvements in range of motion and reductions in tumor diameter. Most TRAEs were grade 1-2 in severity and represented the known safety profile of pexi."

Clinical • Giant Cell Tumor of Bone • Oncology • Tenosynovial Giant Cell Tumor

COMPLETE RESPONSE TO FRONT-LINE PEXIDARTINIB IN SYMPTOMATIC TEMPOROMANDIBULAR JOINT TENOSYNOVIAL GIANT CELL TUMOR (CTOS 2025) - "Here we present a unique case of TGCT of the TMJ where surgery would have meant catastrophic morbidity. Pexidartinib therapy represents a feasible, well-tolerated front-line management strategy in cases where surgical morbidity is high, offering symptom relief and the opportunity for tumor resolution."

Clinical • Giant Cell Tumor of Bone • Oncology • Tenosynovial Giant Cell Tumor

Stag2-Cohesin Loss Attenuates Flt3ITD Myeloid Blast Expansion Yet Preserves Mutant HSC (ASH 2023) - "To understand the mechanistic contribution of STAG2-cohesin loss with FLT3ITD, we generated sequential mutagenesis murine models where the order of Stag2 and Flt3ITD mutation is set as either ITD1st Stag22nd (de novo like) or Stag21stITD2nd (sAML like) using tamoxifen-inducible Cre/Flpo recombinase or pIpC-inducible Mx1Cre...STAG2 mutations are more likely to be identified in poor responders to FLT3 inhibition as both reported by us with Pexidartinib treatment, as well as in the setting of Crenolanib treatment where expansion of the STAG2-mutant clone was observed during treatment...Our data highlights an important regulatory role of Stag2-cohesin in Flt3ITD mediated leukemogenesis, while generating a model that mimics the genetic evolution of sAML. This model will not only shed light on the sAML pathogenesis but also with creates a pre-clinical testing platform with potential therapeutic relevance."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • FLT3 • SOCS2 • STAG2 • STAT5 • STAT5AWqe

Modulating Tumor-Associated Macrophages to Enhance EpCAM-Directed CAR T Cell Efficacy in Lung Cancer Brain Metastases (WFNOS 2025) - "TAM/M depletion was achieved via CSF1R inhibition using a PLX 3397 diet... Our findings demonstrate that TAM/M mediate CAR T-cell suppression in brain metastases of lung cancer. CSF1R inhibition reprogrammed TAM/M, enhancing CAR T-cell trafficking, intratumoral persistence, and antitumor efficacy, resulting in prolonged survival. These results support the development of combinatorial strategies incorporating CSF1R blockade to boost CAR T-cell functionality and improve therapeutic outcomes in brain metastases."

CAR T-Cell Therapy • Clinical • Brain Cancer • Lung Cancer • Solid Tumor • MRC1

Microglia Depletion Demonstrates a Time-dependent But Sex-independent Decrease in Survival in a Murine Model of Glioblastoma (WFNOS 2025) - "Microglia depletion with PLX3397 demonstrates a temporal effect on survival in a murine model of GBM. These results demonstrate the potential time-dependent role of microglia in the acute phase of GBM implantation and provide insight into the evolving phenotype across time."

Preclinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Vessel-Associated Microglia Maintain Vascular Integrity and Prevent Early Hemorrhage in Glioblastoma (WFNOS 2025) - "To address this, we characterize vessel-associated myeloid cells in murine gliomas with high spatial and temporal resolution, leveraging in vivo two-photon imaging, MRI, and transgenic mouse lines.To investigate the role of microglia in glioma vasculature, we pretreated glioma-bearing mice with CSF1R inhibitors (PLX3397 & PLX5622) to ablate microglia prior to tumor inoculation. Using TMEM119CreER/+:R26tdTomato/+ mice, we confirmed these vessel-associated cells as brain-resident microglia, not infiltrating macrophages.Quantitatively, ~60% of peritumoral microglia were vessel-associated, compared to ~30% in naïve or contralateral hemispheres. These microglia displayed elongated somata and processes aligned with vessels or wrapping around vessels, which is a phenotype also observed following single-vessel photothrombosis, suggesting a response to impaired blood flow and BBB leakage.Our findings uncover a critical neurovascular role for vessel-associated microglia..."

Brain Cancer • Cerebral Hemorrhage • CNS Disorders • Glioblastoma • Glioma • Hematological Disorders • High Grade Glioma • Solid Tumor • Thrombosis

Modulating Tumor-Associated Macrophages to Enhance EpCAM-Directed CAR T Cell Efficacy in Lung Cancer Brain Metastases (WFNOS 2025) - "TAM/M depletion was achieved via CSF1R inhibition using a PLX 3397 diet... Our findings demonstrate that TAM/M mediate CAR T-cell suppression in brain metastases of lung cancer. CSF1R inhibition reprogrammed TAM/M, enhancing CAR T-cell trafficking, intratumoral persistence, and antitumor efficacy, resulting in prolonged survival. These results support the development of combinatorial strategies incorporating CSF1R blockade to boost CAR T-cell functionality and improve therapeutic outcomes in brain metastases."

CAR T-Cell Therapy • Clinical • Brain Cancer • Lung Cancer • Solid Tumor • MRC1

Microglial depletion promotes perineuronal net accumulation in the hippocampal CA2 region and impairs social memory (Neuroscience 2025) - "Here, we fed mice PLX3397 chow to pharmacologically inhibit colony-stimulating factor 1 receptor to effectively deplete microglia...This data suggests that microglia remodel CA2 PNNs, at least in part, by regulating CSPG accumulation. Ongoing studies are exploring whether microglia influence PNN formation and loss to better understand their role in regulating CA2 PNN abundance."

CNS Disorders • Psychiatry • ACAN

The role of perivascular and meningeal macrophages in modulating basal cerebral arteriole tone (Neuroscience 2025) - "Here, we extend these findings by combining two-photon imaging through a cranial window with global ablation using PLX3397 (660 mg/kg chow for eight days)...Together, these results reveal vessel-specific functions for microglia, PVMs, and meningeal macrophages in cerebrovascular regulation. Ongoing work is focused on confirming the contribution of meningeal macrophages to COX1-dependent hypercapnic vasodilation and further elucidating the COX1-independent mechanisms by which PVMs influence arteriolar and venular tone."

Late-breaking abstract • CNS Disorders

Activation of amygdala CRF neurons drives neuroimmune signaling (Neuroscience 2025) - "After 3 weeks, DREADD activators (deschloroclozapine, DCZ or clozapine N-oxide, CNO) were administered intraperitoneally for 7 days. Chemogenetic activation of CRF neurons in the CeA resulted in decreased mechanical thresholds and increased evoked vocalizations in both sexes and promoted anxiety-like behaviors in females only. Intra-CeA PLX3397 injection blocked the facilitatory effects of the chemogenetic activation CeA-CRF neurons in male, but not in female, rats, suggesting a sex-specific contribution of amygdala microglia to pain behaviors generated by the activation of CRF neurons.These data suggest that hyperactivity of amygdala CRF neurons induces pain like-behaviors that depend on neuroimmune signaling in male but not female rats."

CNS Disorders • Mental Retardation • Mood Disorders • Psychiatry

Microglia Depletion Improves Hippocampal Circuit Function After Mild Traumatic Brain Injury in Male Mice (Neuroscience 2025) - "We demonstrate that microglia depletion using PLX3397 for 7-10 days after mTBI significantly reduces microglia and restores network excitability in area CA1 and the dentate gyrus (DG), thus mitigating cognitive dysfunctions...We show that using the immunomodulator, thalidomide, in slices from injured animals restores excitability, similarly to microglia depletion, by targeting pre-synaptic dysregulation in the hippocampal circuitry. Our findings further suggest that microglia depletion, and more specifically cytokine modulation offer promising therapeutic avenues for improving long term deficits post-TBI by targeting synaptic dysfunction. These new insights contribute to our understanding of the altered microglial-neuronal relationship in TBI and highlight potential targets for future interventions that can specifically address detrimental effects of chronic inflammation after injury."

Preclinical • CNS Disorders • Cognitive Disorders • Vascular Neurology • TNFA