Glioblastoma is a highly aggressive brain tumor whose treatment has improved little over the past decade. We report on the synergistic effect of the FDA-approved anti-GBM drug (temozolomide) and inhibitors (acriflavine, PT2385) of hypoxia-inducible factors (HIFs) embedded into coaxial fiber membranes (NanoMesh). In vitro cytotoxicity has been evaluated for various glioma cell lines, and synergistic drug combinations have been identified. Preliminary animal studies with the three-drug-loaded NanoMesh indicate a significant improvement of median survival of >50 days and long-term (>120 days) survival rate of 40%, indicating the potential of this material platform as a translatable local GBM therapy.

Background/Objectives: Glioblastoma (GBM) remains one of the most aggressive primary brain malignancies, with limited therapeutic progress over the past two decades. Systemic administration of temozolomide (TMZ) is a pillar of clinical management but is constrained by poor brain penetration, short half-life, and systemic toxicity. Localized drug delivery systems represent a compelling approach to address these limitations. We report the development and evaluation of an injectable poly(sebacic acid–ricinoleic acid) poly(anhydride-ester) (pSARA) gel for sustained intratumoral delivery of TMZ. Methods: The pSARA gel was synthesized using a one-pot melt polycondensation technique, and its in vitro release dynamics were assessed using spectrophotometry. In vivo efficacy of the TMZ-loaded pSARA gel was evaluated as a monotherapy and as an adjuvant to radiation or surgical resection using an orthotopic 9L gliosarcoma rat model. Results: The formulation exhibits shear-thinning behavior, enabling syringe-based administration, and undergoes surface erosion in aqueous environments to achieve controlled drug release. In vivo, the TMZ-loaded pSARA significantly prolonged survival compared to controls and outperformed paclitaxel-loaded formulations. Furthermore, combination therapy with radiation or surgical resection demonstrated combined survival benefits, including long-term survivors. Conclusions: These findings highlight the translational potential of pSARA-based local delivery systems as an adjunct or alternative to systemic chemotherapy in GBM treatment.

Despite the clinical importance of the meibomian gland (MG), the mechanisms controlling its proliferation and differentiation remain unclear. Ocular adnexal sebaceous carcinoma (SebCA), an aggressive malignancy that most often arises from the MG, lacks well-defined oncogenic drivers, but high MYC expression has been demonstrated in both tumors and primary human cell lines. This study evaluated the ongoing dependence of MYC in the MG. MYC-modulated murine MGs were evaluated using histopathology, morphometry, immunohistochemistry, and quantitative PCR. Viability, differentiation, and proliferation were evaluated in vitro, clonogenic potential was assessed by quantifying anchorage-dependent colony formation, and MYC expression was determined using enzyme-linked immunosorbent assay and quantitative PCR. MYC-inhibited murine MGs exhibited significantly reduced cytoplasmic volume with diminished proliferation and increased apoptosis with altered lipid droplet formation relative to contralateral control eyelids. SebCA viability and clonogenicity were significantly impaired by MYC inhibition, and proliferation was significantly reduced in all cells following incubation with MYCMI6. MYCMI6 also showed the most prominent suppression of canonical MYC transcriptional targets of the three MYC inhibitors used. MYC concentration was significantly lower in MYCi361- and 10074-G5-treated cells relative to vehicle control, and relative MYC expression was significantly up-regulated in 10074-G5-treated SebCA01 cells. MYC stability, MYC transcriptional activity, and the MYC:MAX heterodimer may represent critical regulators of proliferation and differentiation in the MG, with dysregulation contributing to oncogenic potential.

Objective Both primary optic nerve sheath meningiomas (pONSMs) and secondary optic nerve sheath meningiomas (sONSMs) pose clinical challenges because standard treatments such as surgical debulking and radiation therapy can further damage the optic nerve, producing permanent visual loss. The molecular pathology of primary skull base meningiomas is becoming clearer. However, by comparison, pONSMs and sONSMs have not been studied adequately with contemporary high-throughput molecular genetic techniques, which is the primary aim of this study. This is a crucial issue because these tumors may harbor distinct genetic alterations that render them susceptible to targeted therapy, allowing for vision preservation or even visual improvement.Methods A total of 18 optic nerve sheath meningiomas, of which 11 were pONSMs and 7 were sONSMs, were obtained from 3 different institutions and underwent next-generation sequencing.Results We found that pONSMs and sONSMs harbor gene variants previously identified in other meningiomas but also distinct alterations in genes implicated in cell signaling, transcriptional regulation, and DNA damage repair.Conclusions These findings expand our understanding of a relatively understudied specific meningioma with unique therapeutic challenges.

BACKGROUND:Atypical teratoid rhabdoid tumor (ATRT) is the most common malignant brain tumor in infants. ATRT is associated with inactivation/deletion of SMARCB1, a member of the SWI/SNF chromatin remodeling complex. SMARCB1 loss contributes to tumorigenicity by compromising SWI/SNF activity at specific loci associated with the CoREST repressor complex, which regulates transcription at critical gene promoters and enhancers. We therefore explored the role of the CoREST repressor complex in ATRT. METHODS:We evaluated the effects of the bifunctional LSD1/HDAC1/2 small molecule CoREST inhibitor, corin, on ATRT tumor cell growth, apoptosis, differentiation, gene expression and chromatin accessibility. RESULTS:Corin inhibited the growth of ATRT cells regardless of their epigenetic subgroup. Corin caused increased tumor cell apoptosis and differentiation. ATAC-seq showed increased chromatin accessibility in corin-treated ATRT cells, with changes seen at genes associated with neuronal differentiation and synaptic function. RNA-seq confirmed increased expression of neuronal differentiation genes in ATRT cells treated with corin. Knockdown of RCOR2 phenocopied the effects of corin, and desensitized the cells to the drug, confirming corin specificity to the CoREST complex. Corin suppressed orthotopic ATRT tumor growth, leading to significant extension of lifespan in ATRT mouse models. Corin caused increased histone acetylation (H3K9ac) and methylation (H3K4Me1) in ATRT orthotopic xenografts, consistent with on-target pharmacodynamics. CONCLUSIONS:The CoREST inhibitor, corin, suppressed tumor growth, induced differentiation, and promoted apoptosis in ATRT leading to significantly increased survival of mice bearing ATRT orthotopic xenografts. Our results suggest a potential application of CoREST complex inhibitors in patients with ATRT.

Group 3 medulloblastoma (G3 MB) is an aggressive pediatric brain tumor with limited treatment options, necessitating the development of novel therapeutic strategies. The long noncoding RNA (lncRNA) lnc-HLX-2-7 and its host-coding transcription factor, HLX, are highly expressed in G3 MB and act as oncogenic drivers. However, their role in regulating metabolism in G3 MB remains poorly understood. In this study, we investigate the metabolic functions of lnc-HLX-2-7 in D425-Med and MED211 cells and uncover its role in regulating oxidative phosphorylation (OXPHOS) and ATP production through the TCA cycle. Our findings reveal that lnc-HLX-2-7 is an upstream regulator of HLX, which, in turn, directly controls the expression of OXPHOS-related genes. Specifically, inhibition of lnc-HLX-2-7 and HLX significantly reduces the expression of OXPHOS complexes I (NDUFB8), II (SDHB), and IV (MTCO1) by disrupting direct binding to and activating the promoters of these genes. Targeting oxidative phosphorylation with the small-molecule inhibitor IACS-010759 substantially inhibits G3 MB tumor progression in xenograft models, further supporting the critical role of OXPHOS in tumor progression. Rescue experiments demonstrate that overexpression of HLX in lnc-HLX-2-7-depleted cells restored OXPHOS gene expression and ATP production, confirming HLX as a downstream effector of lnc-HLX-2-7. These results highlight a coordinated lnc-HLX-2-7/HLX axis that regulates metabolism and oncogenesis in G3 MB. In conclusion, our findings establish lnc-HLX-2-7 and its host-coding gene, HLX, as critical regulators of OXPHOS reprogramming and propose these molecules as promising therapeutic targets for this high-risk MB subtype.

Meningiomas are the most common primary central nervous system tumors, with histologic grading predicting prognosis and guiding treatment decisions. Recent updates to the WHO Classification of Tumors of the Central Nervous System have incorporated molecular criteria, including homozygous deletion of CDKN2A in grade 3 meningiomas. CDKN2A encodes the tumor suppressor protein p16INK4a, a key regulator of cell cycle progression, and loss is associated with increased proliferation, recurrence, and poor clinical outcomes. Previous studies have shown that p16INK4a protein levels can serve as a surrogate immunohistochemical marker that correlates with CDKN2A status in higher-grade meningiomas. However, p16 utility in segregating cases for further testing remains unclear. In this study, we aimed to stratify meningiomas to identify cases that may benefit from molecular testing. We investigated whether Ki-67 labeling could serve as a stratification tool to identify meningiomas for which minimal expression of p16 is indicative of underlying CDKN2A inactivation. Using Ki-67 as a surrogate marker for tumor aggressiveness, we identified a threshold of 5% in tumors with low p16 expression as a sensitivity cutoff for predicting CDKN2A inactivation, suggesting that the subset of meningiomas with a higher labeling index could benefit from further molecular validation, whereas the subset with p16hi expression is low yield to profile for CDKN2A status. Our findings support the clinical utility of Ki-67 and p16 expression as cost-effective screening tools to flag potentially aggressive meningiomas, particularly in resource-constrained settings.

INTRODUCTION:Schlafen11 (SLFN11) has emerged as a powerful biomarker of sensitivity to DNA-damaging agents in various cancers. However, not much is known about its role in brain tumors. Conflicting reports show that it is a biomarker for response to cisplatin and a prognostic factor in some brain tumors, such as medulloblastomas, but can even be a negative prognostic factor in others, like glioblastomas. AREAS COVERED:In this review, we discuss what is known about the various roles of SLFN11 in cancer, with special attention to brain tumors. Specifically, we focus on the seemingly dual role of SLFN11 in brain tumors; positive prognostic in some and negative in others. Additionally, we describe some glioma cases with high SLFN11 expression, often showing aggressive presentation, a good response to initial treatment, and subsequent widespread relapse. EXPERT OPINION:In brain tumors such as medulloblastomas and primary central nervous system lymphomas (PCNSL), when total cell killing can be expected by chemotherapy and/or chemoradiotherapy, high SLFN11 expression is a positive prognostic marker. However, SLFN11 can also be highly expressed in mesenchymal tumors, and in cases where total cell killing cannot be achieved, widespread relapse can accompany an initial response.

A meaningful subset of IDH-mutant astrocytoma harbors ATRX missense variants that retain ATRX IHC immunoreactivity yet exhibit functional ALT activation, supporting the biologic relevance of these missense mutations.

Radiation-induced gliomas (RIGs) are rare and aggressive secondary brain tumors arising years after cranial irradiation. Their management remains challenging due to prior radiation exposure, which limits additional radiation, and a lack of effective chemotherapies. Recent studies have revealed distinct molecular profiles in RIGs with unclear clinical implications. This study presents the case of an individual who developed a high-grade glioma three decades after curative craniospinal radiation for medulloblastoma. He was treated with repeat radiation and temozolomide chemotherapy but developed recurrence with disseminated leptomeningeal disease thereafter. Molecular profiling of the tumor revealed a loss-of-function NF1 mutation and a gain-of-function PTPN11 mutation, two convergent alterations in the MAPK pathway. Based on these findings, the patient was treated with a MEK inhibitor, trametinib, and achieved durable disease control for 20 months until progression. This case underscores the importance of genomic profiling in RIGs and potential utility of molecularly targeted approaches in this population.

We present an SWItch/Sucrose NonFermentable (SWI/SNF) complex-deficient carcinoma centered in the lacrimal drainage system and orbit of a 76-year-old male. The patient presented with nasolacrimal duct obstruction, which persisted after dacryocystorhinostomy. Imaging and surgical exploration showed a 3-cm orbital mass centered around the lacrimal sac with involvement of the nasolacrimal duct and orbit. Microscopic examination revealed sheets, nests, and strands of poorly differentiated tumor cells. Some had enlarged hyperchromatic nuclei and eosinophilic cytoplasm, and others had round to oval, somewhat vesicular nuclei with paler cytoplasm. In situ carcinoma was present in the lacrimal sac lining, with invasion into adjacent structures. Immunohistochemical analysis showed loss of INI1 protein in the neoplastic cells, with retained expression in non-neoplastic stroma. While a few SWI/SNF complex-deficient sinonasal carcinomas have been shown to invade into the orbit, this case highlights the need to consider this rare entity in the differential diagnosis of tumors arising in the lacrimal drainage system.

Focused ultrasound (FUS) is an innovative technology that delivers angled acoustic energy to a small target region. Previous FUS technology has demonstrated efficacy in applications such as tumor destruction, nerve modulation, and drug delivery in the brain. We investigated the effects of low-intensity FUS (LIFU) stimulation on the spinal cord and its ability to regulate mean arterial pressure (MAP). We found that LIFU stimulation on exposed rat spinal cord could modulate MAP, causing a decrease when applied at a lower thoracic level and an increase when applied at a lumbosacral level. We also found that shorter stimulation periods (30 s) were more effective in inducing a decrease in MAP than more extended stimulation periods (90 s). The time required to return to baseline for MAP was shown to increase with subsequent periods of FUS stimulation. FUS could enable non-pharmacological, spatially targeted MAP control, especially for impaired patients. Future applications of FUS neuromodulation extend into solutions for clinical blood pressure disorders, such as autonomic dysreflexia or chronic hypertension.

Diffuse midline glioma (DMG) is a highly aggressive brain tumor that predominantly affects children. Conventional treatments such as radiation therapy can control progression for a time, but DMG kills nearly 100 percent of patients. Although murine models have provided critical insights into the biology of DMG and in assessing new therapeutic strategies, they are not suitable for high-throughput screening to identify and profile novel therapies due to technical challenges, ethical considerations and high cost. Zebrafish ( Danio rerio ) is an established vertebrate model for large-scale drug screening, and zebrafish have demonstrated the ability to replicate the key biological and pathlogical aspects of human malignancies. Here, we developed a novel method for transplanting human DMG cells into large numbers of zebrafish embyros to speed the assessment of anti-tumor drug efficacy in vivo and thereby facilitate the development of novel therapeutics for clinical translation. We transplanted red fluorescent protein (RFP)-labeled, patient-derived DMG cell lines into zebrafish blastulas. Remarkably, many DMG cells migrate into the developing brain and are present in the midline of the brain 24 hours after blastula injection. Tumor cell burden was monitored by measuring RFP fluorescence intensity changes over time. Time-course images of transplanted tumor cell volumes were acquired, and the interactions between transplanted DMG cells and microglial cells were further analyzed using Imaris software. We have developed a simple and rapid transplantation protocol to establish a zebrafish xenograft model of DMG. Our method involves transplanting DMG cells into the blastula stage (1000 cell stage) of zebrafish embryos, which does not require complex surgical techniques. This approach allows for the transplantation of hundreds of embryos per hour, significantly increasing the efficiency of creating DMG zebrafish xenografts that are suitable for high-throughput drug and gene discovery screens.

Melanoma brain metastasis (MBM) leads to significant morbidity and mortality. Building on previous findings that WNT5A regulates melanoma metastasis and dormancy in extracranial niches, we hypothesize that WNT5A signaling facilitates melanoma invasion across the blood-brain barrier, while its downregulation drives intracranial metastatic proliferation. To explore this, we conducted functional studies using human melanoma cell lines and an organotypic mouse brain xenograft system. Overexpression or pharmacologic induction of WNT5A increased melanoma migration and invasion toward brain explant conditioned media in transwell assays. Wholemount confocal imaging of brain explant cultures revealed distinct tumor colonization patterns mirroring clinical dormancy and proliferative outgrowth depending on WNT5A level: melanoma overexpressing WNT5A formed single-cell dispersions perivascularly, whereas silencing WNT5A in syngeneic cells produced proliferative clusters. Exogenous recombinant WNT5A also induced G1 cell cycle arrest in FUCCI-transduced melanoma cells, supporting its role in maintaining dormancy. Conversely, the WNT5A antagonist SFRP1 drove melanoma toward increased tumor size and accelerated tumor development. Interestingly, immunohistochemical analysis of postmortem human brain tissue demonstrated robust SFRP1 expression in cerebral endothelium and neurons, indicating a potential source promoting metastatic outgrowth. Integrin profiling revealed elevated expression of adhesion proteins in invasive melanoma compared to WNT5A-silenced syngeneic lines, suggesting an association with enhanced metastatic potential and tumor extravasation. WNT5A overexpression resulted in greater endothelial and extracellular matrix engagement by adhesion assay and live-cell tracking. These interactions were recapitulated in ex vivo xenografts, with WNT5A-high melanoma adhering to endothelial basement laminin. Together, these findings highlight the importance of WNT5A regulation through the metastatic cascade, from endothelial adhesion and establishment of a perivascular dormancy niche to metastatic outgrowth. Further integration of transcriptomics and proteomics on mouse models and clinical MBM samples aim to uncover key modulators of WNT signaling and associated pathways in MBM progression which might be targeted therapeutically.

An 11-y-old male lionhead rabbit (Oryctolagus cuniculus) was presented with progressive hindlimb weakness and right-sided neurologic deficits, and was subsequently euthanized due to poor prognosis. Autopsy revealed a 1.6 × 1.1 × 1.0-cm, well-circumscribed, extra-axial mass compressing the occipital lobe and affecting both telencephalic hemispheres. Histologic and immunohistochemical analyses demonstrating positivity for synaptophysin and neuron-specific enolase, along with a Ki67 proliferative index of ~20%, were highly suggestive of a high-grade pineal parenchymal tumor (PPT). The tumor was densely cellular with marked atypia and frequent binucleation, and lacked pineocytomatous rosettes-features most consistent with a pineal parenchymal tumor of intermediate differentiation in humans. No evidence of metastasis was observed. Pineal tumors are exceptionally rare in domestic animals, with limited documentation in species such as dogs, horses, goats, cattle, and birds. To our knowledge, PPT has not been reported previously in a rabbit, underscoring the diagnostic challenges associated with intracranial neoplasms in this species.

RECQL4 plays an important role in maintaining the integrity of the genome and regulating DNA replication. However, the role of RECQL4 in CNS tumors remains unknown. Sequencing data were reviewed and immunohistochemistry was performed on a variety of glial and nerve sheath tumors. Functional studies were performed in glioma (U251) and malignant peripheral nerve sheath tumors (MPNSTs) (NF90-8, ST88-14) cell lines following RECQL4 knockdown and treatment with ATR-inhibitors. Across 1580 CNS tumors, RECQL4 gene variants were identified in 71 cases (4.5%), with 21 (29.6%) of probable pathogenic significance. RECQL4 expression differed significantly across glioma subgroups (P = 0.012). Low-grade gliomas (diffuse: median H-score 57.5; circumscribed: median 130) showed lower expression than high-grade gliomas (median 145, P < 0.05). Neurofibromas displayed higher RECQL4 expression (median 160) compared with MPNSTs (median 97.5, P < 0.001). Among MPNSTs, NF1-associated cases (n = 24, median 95) expressed significantly less RECQL4 than sporadic cases (n = 8, median 162.5, P < 0.001). RECQL4 knockdown in glioma and MPNST cell lines resulted in increased apoptosis and susceptibility to ATR-inhibitors. Our findings show that RECQL4 expression has divergent patterns across tumor types and that targeting RECQL4 may dampen tumor survival and enhance susceptibility to ATR inhibitor therapy in CNS tumors.

OBJECTIVE:Ciliary body medulloepithelioma (CBME), a pediatric intraocular tumor with potential for locally aggressive behavior and metastasis, may present with a diverse spectrum of clinical and histopathologic features leading to diagnostic and management challenges. Examination of unusual CBME cases highlights challenges and modern diagnostic techniques which facilitate accurate diagnosis and guide management. METHODS:A retrospective clinicopathologic analysis of 6 patients with unusual clinical or pathologic features of CBME was performed. RESULTS:The mean duration of delay in accurate diagnosis was 5.7 years (SD: 8.2, median: 3, range: 0-22). All patients developed cataract, 4 (67%) were diagnosed with glaucoma, and 4 (67%) underwent surgery prior to accurate diagnosis. At initial presentation, only one patient with a known history of genetically confirmed DICER1 syndrome underwent appropriate imaging leading to a timely identification of a ciliary body mass and no delay in diagnosis. Following identification of intraocular mass, 4 (67%) patients underwent enucleation. Two patients (33%) underwent exenteration for extraocular extension of CBME. Initial histopathologic differential diagnosis included CBME, melanoma, adenoma or adenocarcinoma of the pigmented ciliary body epithelium, retinoblastoma, sarcoma, and malignant teratoma. Immunohistochemistry and genetic testing assisted in the diagnosis of CBME. Two patients (33%) had a germline DICER1 variant; this was known prior to CBME diagnosis in one patient and discovered after CBME diagnosis in the second patient. CONCLUSION:This series highlights the unusual clinical and histopathologic features of CBME that contribute to delays in diagnosis. Modern aids including genetic testing, ancillary imaging studies, and immunohistochemistry facilitate a timely accurate diagnosis of CBME and guide management.

Neurofibromatosis type 1 (NF1)-associated high-grade gliomas (HGGs) harboring ATRX mutations exhibit an aggressive clinical phenotype, driven by heightened genomic instability and metabolic reprogramming. Existing therapies, including chemotherapy and radiotherapy, are limited by resistance mechanisms and formation of secondary malignancy, underscoring the need for novel therapeutic strategies. Here, we report the results of a high-throughput screening of 10,000 small molecules aimed at identifying compounds selectively targeting vulnerabilities associated with concurrent ATRX and NF1 loss. Among the screened compounds, K784-6195 (ChemDiv ID) emerged as a promising candidate, exhibiting marked selective cytotoxicity in NF1-associated glioma cell lines with ATRX deficiency (IC50 = 4.84 μM). In comparison, wild-type ATRX sporadic glioma cell lines (U251) exhibited significantly reduced sensitivity to K784-6195 (IC50 = 37.03 μM). However, ATRX knockout U251 glioma cells recapitulating concurrent ATRX and NF1 loss exhibited heightened susceptibility to K784-6195 (IC50 = 20-23 μM) compared to their wild-type counterpart. Metabolomic analysis revealed that K784-6195 treatment impairs metabolic pathways, including the pentose phosphate pathway, glutamine metabolism, and redox homeostasis, leading to oxidative stress and impaired cell survival. These findings highlight K784-6195 as a promising candidate for therapeutic development, offering a targeted approach for the treatment of NF-1 associated HGGs with ATRX deficiency.

Low-grade gliomas and reactive piloid gliosis can present with overlapping features on conventional histology. Given the large implications for patient treatment, there is a need for effective methods to discriminate these morphologically similar but clinically distinct entities. Using routinely available stains, we hypothesize that a limited panel including SOX10, p16, and cyclin D1 may be useful in differentiating mitogen-activated protein (MAP) kinase-activated low-grade gliomas from piloid gliosis. Reviewers blinded to clinical and pathologic data reviewed and quantified immunohistochemical expression patterns across 20 cases of piloid gliosis and 37 cases of MAP kinase-activated low-grade gliomas, including pilocytic astrocytoma and ganglioglioma. The majority of MAP kinase-activated low-grade glioma cases demonstrated extensive immunoreactivity for at least 2 of the 3 immunohistochemical markers, whereas none of the gliosis cases demonstrated significant immunoreactivity for more than one individual immunohistochemical marker. SOX10 and p16 demonstrated the highest individual sensitivity whereas cyclin D1 demonstrated the highest individual specificity to discriminate neoplastic from nonneoplastic cases in this cohort. A composite panel score based on significant immunoreactivity of at least 2 of the 3 markers provided specificity and a positive predictive value of 100% in differentiating MAP kinase-activated low-grade glioma from gliosis, as 0/20 (0%) of gliosis cases were scored positive compared with 24/37 (65%) of MAP kinase-activated low-grade glioma cases. We conclude that while the immunoreactivity of these markers may be suggestive of a low-grade glioma diagnosis, SOX10, p16, and cyclin D1 should be applied in combination to maximize diagnostic value.

Background BCL-6 corepressor (BCOR) loss-of-function alterations are common in clinically aggressive retinoblastoma. The study aim was to determine if BCOR loss promotes the growth and dissemination of retinoblastoma cells, and identify the pathways it regulates in these retinal tumors of childhood.Methods Gain- and loss-of-function strategies were used to modulate BCOR levels in a panel of retinoblastoma cell lines, and the effects on proliferation, clonogenicity, apoptosis, and migration were assessed in vitro and in murine xenograft models.Results BCOR knockdown or knockout in retinoblastoma lines with high protein levels increased tumor growth, invasion, clonogenicity, and chemoresistance in vitro, while increased expression in low BCOR lines slowed growth. Growth of retinoblastoma xenografts was similarly sensitive to BCOR gain or loss. BCOR reduction resulted in upregulation of IGF1 and activation of IGF1 receptor (IGF1R) signaling, and the effects of IGF1R inhibition were dependent on BCOR level. In vitro, reduction of retinoblastoma growth and induction of apoptosis by the IGF1R inhibitors linsitinib and AEW541 were also significantly stronger in cells with low BCOR as compared to controls. Both linsitinib and AEW541 suppressed colony formation in a dose-dependent manner in BCOR knockout or knockdown cells. Finally, high BCOR levels rendered retinoblastoma xenografts insensitive to linsitinib.Conclusions Loss of BCOR function is associated with more aggressive retinoblastoma cell line growth and chemoresistance, at least in part due to increased IGF1R signaling. Inhibiting IGF1R pharmacologically had a marked anti-tumor effect in aggressive retinoblastoma lacking BCOR, suggesting it as a new therapeutic target, although this still needs to be confirmed in clinical samples with BCOR mutations.