Recurrent Brain Tumors Research Articles

The Role of Cancer Stem Cells in Glioblastoma Treatment: New Strategies for Targeted Therapy

Glioblastoma (GBM) is a highly aggressive and recurrent brain tumor for which traditional treatments often yield limited success. According to recent research, cancer stem cells (CSCs) are essential for the development, spread, and resistance to treatment of GBM. This review systematically explores the critical roles of cancer stem cells (CSCs) in glioblastoma (GBM), especially through the regulation of Notch, Wnt, and Hh signaling pathways. The maintenance of CSC properties is primarily dependent on the Notch, Wnt, and Hedgehog (Hh) signaling pathways. This review explores the mechanisms of these pathways in GBM, discusses multi-targeted combination therapies, and highlights emerging strategies and drugs for targeted therapy. The results indicate that targeting Notch, Wnt, and Hh pathways can effectively suppress CSC proliferation and invasiveness in GBM, significantly delaying tumor recurrence. Future research should further explore the clinical potential of these pathway inhibitors and develop more specific targeted therapies to improve GBM treatment outcomes and patient prognosis.

A Self-Cascading Catalytic Therapy and Antigen Capture Scaffold-Mediated T Cells Augments for Postoperative Brain Immunotherapy.

The recruitment of T lymphocytes holds great potential for suppressing the most aggressive glioblastoma (GBM) recurrence with immunotherapy. However, the phenomenon of immune privilege and the generally low immunogenicity of vaccines often reduce the presence of lymphocytes within brain tumors, especially in brain tumor recurrence clusters. In this study, an implantable self-cascading catalytic therapy and antigen capture scaffold (CAS) that can boost catalytic therapy efficiency at post-surgery brain tumor and capture the antigens via urethane-polyethylene glycol-polypropylene glycol (PU-EO-PO) segments are developed for postoperative brain immunotherapy. The CAS consists of 3D-printed elastomers modified with iron (Fe2+) metal-organic frameworks (MOFs, MIL88) and acts as a programmed peroxide mimic in cancer cells to initiate the Fenton reaction and sustain ROS production. With the assistance of chloroquine (CQ), autophagy is inhibited through lysosome deacidification, which interrupts the self-defense mechanism, further enhances cytotoxicity, and releases antigens. Then, CAS containing PU-EO-PO groups acts as an antigen depot to detain autologous tumor-associated antigens to dendritic cells maturation and T cell augments for sustained immune stimulation. CAS enhanced the immune response to postoperative brain tumors and improved survival through brain immunotherapy.

Population Pharmacokinetic and Pharmacodynamic Study of Palbociclib in Children and Young Adults with Recurrent, Progressive, or Refractory Brain Tumors.

Background/Objectives: Palbociclib, an oral CDK 4/6 inhibitor, was evaluated in a Pediatric Brain Tumor Consortium (PBTC) phase 1 (NCT02255461; PBTC-042) study to treat children and young adults with recurrent, progressive, or refractory brain tumors. The objectives of this study were to characterize the palbociclib population pharmacokinetics in children enrolled on PBTC-042, to conduct a population pharmacodynamic analysis in this patient population, and to perform a simulation study to assess the role of palbociclib exposure on neutropenia and thrombocytopenia. Methods: The palbociclib population pharmacokinetics and pharmacodynamics were characterized in this patient population (n = 34 patients; 4.9-21.6 years old). Population pharmacokinetics were modeled using a one-compartment model with first-order absorption and elimination. Covariate analysis was performed, evaluating demographics, laboratory values, and concomitant medications. A pharmacodynamic model was used to describe the relation between palbociclib plasma exposure and changes in the ANC and platelet counts. Results: The population estimates for the apparent oral volume, apparent oral clearance, and absorption rate constant were 664.5 L/m2, 36.8 L/h/m2, and 0.48 h-1, respectively. The palbociclib apparent oral clearance was decreased in patients with higher AST values (p = 0.0066). The ANC and platelet pharmacodynamic models estimated that the median (5th-95th percentile) time individuals had grade 3 or greater neutropenia was 4 (0, 21) days. Simulations showed that given 75 mg/m2 palbociclib, 49% of the individuals were expected to have grade 3 or greater neutropenia. Conclusions: Palbociclib pharmacokinetics and pharmacodynamics were adequately characterized in this patient population, no unexpected adverse reactions were noted, and the drug was well tolerated.

18F-FET PET/CT can aid in diagnosing patients with indeterminate MRI findings for brain tumors: a prospective study.

This prospective study aimed to evaluate the diagnostic value of fluorine-18-labeled fluoroethyltyrosine (18F-FET) positron emission tomography (PET)/computed tomography (CT) in diagnosing brain tumors within an Asian patient population. Patients suspected of having primary or recurrent brain tumors were prospectively recruited. Each patient underwent 18F-FET and fluorine-18 fluorodeoxyglucose (18F-FDG) PET/CT on separate days within 1week. We calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy to compare the diagnostic performance of the two PET scans. The standardized uptake value (SUV) and tumor-to-background ratio (TBR) of the lesions were determined using static images. Additionally, time-activity curves (TACs) and time-to-peak (TTP) were generated from the dynamic PET images. From September 2019 to December 2023, 33 subjects were enrolled for reasons including suspected brain tumors (n = 20) or suspicious glioma recurrence (n = 8) on magnetic resonance imaging (MRI) and restaging for glioma (n = 5). Among the patients with suspected brain tumors or glioma recurrence on MRI, 25% had false-positive results. 18F-FET PET/CT accurately identified 86% of these false positives. The sensitivity, specificity, PPV, NPV, and accuracy of visual interpretation of 18F-FET PET/CT were 96.2%, 85.7%, 96.2%, 85.7%, and 93.9%, respectively. The corresponding 18F-FDG PET/CT values were 73.1%, 71.4%, 90.5%, 41.7%, and 72.7%. 18F-FET PET/CT demonstrated significantly higher sensitivity and accuracy than 18F-FDG PET (p = 0.031 and p = 0.030, respectively). Using TBRmean as an adjunct reference index enhanced the diagnostic accuracy of 18F-FET PET/CT, achieving a sensitivity and NPV of 100%. Wash-out TAC or TTP < 20min was associated with a PPV of 100% for brain tumors. 18F-FET PET/CT appears to be a valuable tool for assessing brain tumors with indeterminate MRI findings in this Asian cohort. 18F-FET PET/CT offers benefits over 18F-FDG PET in differentiating brain tumors from nontumor brain lesions, particularly when using semiquantitative analysis with TBR. This study was registered on CinicalTrial.gov (NCT06563024).

CNSC-06. NAVIGATING BRAIN CANCER: PATIENT STORIES AND MEDICAL BREAKTHROUGH

Abstract The complex interplay of genetic mutation, dys regulated signalling pathways, Epigenetic modifications and Interaction with tumor microenvironment are the major aggravating factors for Brain Tumors. Neurological complications involve Increased Intracranial pressure, Seizures, Motor and Sensory deficits, Aphasia, Hydrocephaly, Behavioral and personality changes, Cerebellar Symptoms. It is diagnosed in a sequential steps. Collecting good history from patient in primary then examining the patient all through and making some investigations to come to a final diagnosis. On asking history to a patient he complains of recurrent convulsions, Personality changes and some motor activity deficit and loss of few senses. On examination we can reveal defect in cranial nerve functions, Motor or sensory deficits, loss of reflexes and coordination. Then Investigations being the next step for diagnosis, We ask the patient to undergo for a test for Blood Biomarkers and CSF analysis in case of suspection of metastatic Brain tumors. Biopsy to obtain for Histopathological Examination. Histopathological examination is done for analysis of genetic mutations and molecular markers. The other imaging techniques like MRI, MRS, CT, PET, EEG are done. This gives a clear picture of what actually caused tumor and shows a way for treatment. Now the treatment involves both Medical and Surgical treatment. Medical treatment includes Chemotherapy along with radiation therapy where the drugs given are Temozolomide and targeted therapy included EGFR BRAF inhibitors for glioblastoma and low grade gliomas respectively. Tumor treating fields- Optune is given. Surgical treatment involves Craniotomy for removal of primary Brain tumors, Neuro Endoscopy if tumor is present in ventricles or base of Brain, Laser interstitial Thermal therapy for deap seated and recurrent brain tumors. This is all about the treatment and now the patient management is very important for further clinical help. Physical, occupational and speech therapy helps patients recover. Symptomatic approach for inoperable tumors Provide comprehensive support for patients nearing end of life, Emphasise confidence and Quality of life.

453MO A phase I study for safety, tolerability, pharmacokinetics, and anti-tumor activity of ABM-1310 in patients (pts) with BRAF V600 mutated recurrent primary brain tumours: Interim result

453MO A phase I study for safety, tolerability, pharmacokinetics, and anti-tumor activity of ABM-1310 in patients (pts) with BRAF V600 mutated recurrent primary brain tumours: Interim result

MR-guided laser interstitial thermal therapy in the treatment of brain tumors and epilepsy.

MR-guided Laser Interstitial Thermal Therapy (MRgLITT) is a minimally invasive neurosurgical technique increasingly used for the treatment of drug-resistant epilepsy and brain tumors. Utilizing near-infrared light energy delivery guided by real-time MRI thermometry, MRgLITT enables precise ablation of targeted brain tissues, resulting in limited corridor-related morbidity and expedited postoperative recovery. Since receiving CE marking in 2018, the adoption of MRgLITT has expanded to more than 40 neurosurgical centers across Europe. In epilepsy treatment, MRgLITT can be applied to various types of focal lesional epilepsy, including mesial temporal lobe epilepsy, hypothalamic hamartoma, focal cortical dysplasias, periventricular heterotopias, cavernous malformations, dysembryoplastic neuroepithelial tumors (DNET), low-grade gliomas, tuberous sclerosis, and in disconnective surgeries. In neuro-oncology, MRgLITT is used for treating newly diagnosed and recurrent primary brain tumors, brain metastases, and radiation necrosis. This comprehensive review presents an overview of the current evidence and technical considerations for the use of MRgLITT in treating various pathologies associated with drug-resistant epilepsy and brain tumors.

Surgically targeted radiation therapy versus stereotactic radiation therapy: A dosimetric comparison for brain metastasis resection cavities

BackgroundSurgically targeted radiation therapy (STaRT) with Cesium-131 seeds embedded in a collagen tile is a promising treatment for recurrent brain metastasis. In this study, the biological effective doses (BED) for normal and target tissues from STaRT plans were compared with those of external beam radiotherapy (EBRT) modalities. MethodsNine patients (n=9) with 12 resection cavities (RCs) who underwent STaRT (cumulative physical dose of 60 Gy to a depth of 5 mm from the RC edge) were replanned with CyberKnife® (CK), Gamma Knife® (GK), and intensity modulated proton therapy (IMPT) using an SRT approach (30 Gy in 5 fractions). Statistical significance comparing D95% and D90% in BED10Gy (BED10Gy95% and BED10Gy90%) and to RC + 0 to + 5 mm expansion margins, and parameters associated with radiation necrosis risk (V83Gy, V103Gy, V123Gy and V243Gy) to the normal brain were evaluated by a Wilcoxon-signed rank test. ResultsFor RC+0 mm, median BED10Gy90% for STaRT (90.1 Gy10, range: 64.1-140.9 Gy10) was significantly higher than CK (74.3 Gy10, range:59.3-80.4 Gy10, p=0.04), GK (69.4 Gy10, range: 59.8-77.1 Gy10, p=0.005), and IMPT (49.3 Gy10, range: 49.0-49.7 Gy10, p=0.003), respectively. However, for the RC+5 mm, the median BED10Gy90% for STaRT (34.1 Gy10, range: 22.2-59.7 Gy10) was significantly lower than CK (44.3 Gy10, range: 37.8-52.4 Gy10), and IMPT (46.6 Gy10, range: 45.1-48.5 Gy10), respectively but not significantly different from GK (34.1 Gy10, range: 22.8-47.0 Gy10). The median V243Gy was significantly higher in CK (11.7 cc, range: 4.7-20.1 cc), GK(6.2 cc, range: 2.3-11.9 cc) and IMPT (19.9 cc, range: 11.1-36.6 cc) compared to STaRT (1.1 cc, range: 0.0-7.8 cc) (p<0.01). ConclusionThis comparative analysis suggests the STaRT approach may treat recurrent brain tumors effectively via delivery of higher radiation doses with equivalent or greater BED up to at least 3 mm from the RC edge as compared to EBRT approaches.

Diffusion kurtosis imaging for different brain masses characterization

BackgroundDiffusion kurtosis imaging is an advanced magnetic resonance imaging technique that reveals additional information on the microstructure and micro-dynamics of different brain masses without the need for contrast agents. The aim of this study was to provide a comprehensive analysis of the role of MRI diffusion kurtosis and to compare it with magnetic resonance spectroscopy (MRS) and dynamic susceptibility contrast perfusion (DSC) in characterizing different brain masses, including gliomas, recurrent tumors, radiation necrosis, abscesses, and infarctions. Sixty-six patients with intracranial brain masses were enrolled in this prospective study. All patients were examined by conventional MRI sequences, DSC perfusion, MRS, and diffusion kurtosis imaging, with implemented b values which were 200, 500, 1000, 1500 and 2000s/mm2.ResultsMean kurtosis (MK) was higher (P < 0.001) in recurrent brain tumors than in radiation-induced necrosis; the optimal MK cutoff value for differentiation between them was 642 with 91.3% sensitivity and 85.7% specificity. Mean kurtosis was also higher (P < 0.001) in high-grade gliomas than in low-grade gliomas; the optimal MK cutoff value for differentiation between them was 639 with 91.6% sensitivity and 85.71% specificity. There was a good level of agreement between ADC and MD within the studied cases, with a correlation coefficient r = 0.815. MK had more sensitivity and specificity in differentiation between high- and low-grade gliomas, as well as RIN and tumoral recurrence, than MRS and DSC.ConclusionsDiffusion kurtosis imaging stands as an integral, noninvasive, and noncontrast tool for the characterization of various brain masses. It augments the capabilities of traditional and advanced MRI techniques, providing a deeper understanding of the microstructural changes in brain tissues.

Molecular imaging with 68Ga-PSMA PET/CT in high grade glioma: A biomarker for tumour neo-angiogenesis.

There are several promising radiotracers used for both staging and restaging of primary and recurrent brain tumours based on various mechanisms of tracer localization in tumour cells. 68Ga-PSMA PET has extremely low background uptake in normal brain tissue and consequently high tumour-to-brain ratio making it a promising imaging radiotracer for gliomas. 68Ga-PSMA demonstrates utility in evaluating high grade glioma during both initial workup or when suspecting recurrence. Herein the authors evaluate the role of this imaging modality and the potential future it holds in the management of high grade gliomas.

Deep learning-based deformable image registration with bilateral pyramid to align pre-operative and follow-up magnetic resonance imaging (MRI) scans.

The evaluation of brain tumor recurrence after surgery is based on the comparison between tumor regions on pre-operative and follow-up magnetic resonance imaging (MRI) scans in clinical practice. Accurate alignment of MRI scans is important in this evaluation process. However, existing methods often fail to yield accurate alignment due to substantial appearance and shape changes of tumor regions. The study aimed to improve this misalignment situation through multimodal information and compensation for shape changes. In this work, a deep learning-based deformation registration method using bilateral pyramid to create multi-scale image features was developed. Moreover, morphology operations were employed to build correspondence between the surgical resection on the follow-up and pre-operative MRI scans. Compared with baseline methods, the proposed method achieved the lowest mean absolute error of 1.82 mm on the public BraTS-Reg 2022 dataset. The results suggest that the proposed method is potentially useful for evaluating tumor recurrence after surgery. We effectively verified its ability to extract and integrate the information of the second modality, and also revealed the micro representation of tumor recurrence. This study can assist doctors in registering multiple sequence images of patients, observing lesions and surrounding areas, analyzing and processing them, and guiding doctors in their treatment plans.

TRLS-05. A PILOT STUDY TO ASSESS THE SAFETY, FEASIBILITY, AND PRELIMINARY EFFICACY OF A NEOEPITOPE-BASED PERSONALIZED DNA VACCINE APPROACH IN PEDIATRIC PATIENTS WITH RECURRENT BRAIN TUMORS

Abstract BACKGROUND Pediatric brain tumors present a heterogeneous group of neoplasms with limited treatment options, especially at relapse. Hence, innovative therapeutic strategies are imperative. Immunotherapy, specifically immunogenomics, utilizing personalized vaccines based on tumor-specific neoantigens, has emerged as a promising option in other tumors. However, the feasibility of this approach in pediatric brain tumors remain largely unexplored. METHODS This single institution feasibility study focuses on sequencing analyses of pediatric brain tumors to identify mutant tumor-specific antigens. The study employs tumor/normal exome sequencing and cDNA-capture sequencing to identify and confirm mutant antigens, respectively. An epitope prediction algorithm prioritizes these antigens with subsequent confirmation of binding to HLA class I molecules. The neoantigen DNA vaccine strategy, utilizing a polyepitope DNA vaccine, is designed to target up to 20 prioritized antigens. The TDS-IM v2.0 device facilitates the administration of the vaccine. The primary objective of the study is to determine the feasibility of adjuvant personalized neoantigen DNA vaccine administration in patients with recurrent or refractory pediatric brain tumors. RESULTS We anticipate the identification of actionable neoantigens in pediatric brain tumors to support the potential efficacy of personalized DNA vaccines. The proposed sequencing strategies, epitope prediction algorithm, and in vitrobinding studies aim to establish a comprehensive methodology for neoantigen identification and prioritization. During the meeting, we will present the study background, rationale, detailed methodology, and design to inform the brain tumor community of this study. CONCLUSION This feasibility study is poised to provide essential insights into the development of personalized neoantigen DNA vaccines for recurrent or refractory pediatric brain tumors and aims to demonstrate safety, feasibility, and potential efficacy in targeting mutant tumor-specific antigens. The findings from this study will lay the groundwork for future clinical trials, evaluating the impact of personalized immunotherapy on progression-free and overall survival rates in this challenging patient population.

Histopathological correlation of brain tumor recurrence vs. radiation effect post-radiosurgery as detected by MRI contrast clearance analysis: a validation study.

The differentiation between adverse radiation effects (ARE) and tumor recurrence or progression (TRP) is a major decision-making point in the follow-up of patients with brain tumors. The advent of immunotherapy, targeted therapy and radiosurgery has made this distinction difficult to achieve in several clinical situations. Contrast clearance analysis (CCA) is a useful technique that can inform clinical decisions but has so far only been histologically validated in the context of high-grade gliomas. This is a series of 7 patients, treated between 2018 and 2023, for various brain pathologies including brain metastasis, atypical meningioma, and high-grade glioma. MRI with contrast clearance analysis was used to inform clinical decisions and patients underwent surgical resection as indicated. The histopathology findings were compared with the CCA findings in all cases. All seven patients had been treated with gamma knife radiosurgery and were followed up with periodic MR imaging. All patients underwent CCA when the necessity to distinguish tumor recurrence from radiation necrosis arose, and subsequently underwent surgery as indicated. Concordance of CCA findings with histological findings was found in all cases (100%). Based on prior studies on GBM and the surgical findings in our series, delayed contrast extravasation MRI findings correlate well with histopathology across a wide spectrum of brain tumor pathologies. CCA can provide a quick diagnosis and have a direct impact on patients' treatment and outcomes.

A Spatial Interpolation Approach to Assign Magnetic Resonance Imaging-Derived Material Properties for Finite Element Models of Adeno-Associated Virus Infusion Into a Recurrent Brain Tumor.

Adeno-associated virus (AAV) is a clinically useful gene delivery vehicle for treating neurological diseases. To deliver AAV to focal targets, direct infusion into brain tissue by convection-enhanced delivery (CED) is often needed due to AAV's limited penetration across the blood-brain-barrier and its low diffusivity in tissue. In this study, computational models that predict the spatial distribution of AAV in brain tissue during CED were developed to guide future placement of infusion catheters in recurrent brain tumors following primary tumor resection. The brain was modeled as a porous medium, and material property fields that account for magnetic resonance imaging (MRI)-derived anatomical regions were interpolated and directly assigned to an unstructured finite element mesh. By eliminating the need to mesh complex surfaces between fluid regions and tissue, mesh preparation was expedited, increasing the model's clinical feasibility. The infusion model predicted preferential fluid diversion into open fluid regions such as the ventricles and subarachnoid space (SAS). Additionally, a sensitivity analysis of AAV delivery demonstrated that improved AAV distribution in the tumor was achieved at higher tumor hydraulic conductivity or lower tumor porosity. Depending on the tumor infusion site, the AAV distribution covered 3.67-70.25% of the tumor volume (using a 10% AAV concentration threshold), demonstrating the model's potential to inform the selection of infusion sites for maximal tumor coverage.

Distribution of Bevacizumab into the Cerebrospinal Fluid of Children and Adolescents with Recurrent Brain Tumors.

To date, evidence has been lacking regarding bevacizumab pharmacokinetics in the cerebrospinal fluid (CSF). This study assessed the penetration of bevacizumab, as part of a metronomic antiangiogenic treatment regimen, into the CSF of children, adolescents, and young adults with recurrent brain tumors. Serum and CSF concentrations, malignant cells, and vascular endothelial growth factor A (VEGF-A) were analyzed in 12 patients (5-27 years) following 10 mg/kg bevacizumab intravenous biweekly administration (EudraCT number 2009-013024-23). A population pharmacokinetic model including body weight, albumin, and tumor type as influential factors was extended to quantify the CSF penetration of bevacizumab. Apart from in serum (minimum concentration/maximum concentration [Cmin/Cmax] 77.0-305/267-612 mg/L, median 144/417mg/L), bevacizumab could be quantified in the CSF (0.01-2.26mg/L, median 0.35 mg/L). The CSF/serum ratio was 0.16 and highly variable between patients. Malignant cells could be detected in CSF before initiation of treatment in five of 12 patients; after treatment, the CSF was cleared in all patients. VEGF-A was detected in three patients before treatment (mean ± SD: 20 ± 11 pg/mL), and was still measurable in one of these patients despite treatment (16 pg/mL). This pharmacokinetic pilot study indicated penetration of bevacizumab into the CSF in a population of children, adolescents, and young adults with recurrent brain tumors.

1232 Outpatient Stereotactic Needle Biopsy Is a Cost-effective Strategy for Brain Tumor Patient Decision-making That Enhances Clinical Trial Accrual

INTRODUCTION: Although neuroradiological techniques have expanded, stereotactic needle biopsy is a simple, ubiquitous,and immediate strategy for established or potential brain tumor patients with atypical clinical and/or radiographic findings. METHODS: Outpatient stereotactic needle biopsies performed by a single surgeon from August 2020 through November 2022 were retrospectively reviewed. Electronic medical records were queried for clinical, perioperative, and tumor demographics. Financial records were queried for insurance and payment reports. Descriptive statistics were used to characterize comparisons among collected variables. RESULTS: 107 consecutive stereotactic needle biopsy procedures were conducted in adult brain tumor patients. All biopsies were performed using a single needle-pass in the outpatient setting, targeting supratentorial lesions in 89.7% of cases. Tissue diagnosis was established in 96% of procedures, with glioma being the most common histology. No intraoperative or perioperative complications occurred. Four patients (3.7%) were admitted overnight due to urinary retention (n = 2) and asymptomatic tract hemorrhage (n = 2), respectively. Insurance approval was sought preoperatively from non-commercial (31.7%) and commercial (68.3%) payors and approved in all cases. Postoperatively, 30.8% of patients received an experimental therapeutic on the basis of tissue analysis. CONCLUSIONS: We report the largest experience to date with outpatient stereotactic needle biopsy in newly-diagnosed and recurrent brain tumor patients. Our findings identify this strategy as a cost-effective alternative to advanced imaging that facilitates clinical trial accrual through tissue acquisition.

Abstract 5115: Designing targeted approaches for recurrent medulloblastoma

Abstract Designing targeted therapies for recurrent medulloblastomaPediatric brain tumors are the leading cause of cancer-related death in children, with medulloblastoma (MB) being the most common type. Despite significant progress in the field, approximately 30% of children with MB will relapse. Recurrent MB is commonly metastatic and virtually none of these patients will live beyond the one-year hallmark. These sobering statistics highlight the significant unmet need for effective therapies for recurrent MB. The likely underlying cause of the constant failure of our current clinical approaches, which are based on data obtained from disease models recapitulating primary tumors, is the disparity in genomic and transcriptomic data between primary and relapsed disease. Because of these disparities, we hypothesize that by conducting mechanistic studies and drug screens in relapse disease models, we can improve the outcomes for children with recurrent MB. Our data, obtained through a bioinformatics mining approach to predict tumor response, enabled us to identify a clinically relevant candidate drug for the treatment of recurrent MB: Minnelide. This compound acted on MYC to reduce tumor growth and the metastatic dissemination of tumors with the genetic background often found in relapsed MB patients. Additionally, to further support the translational relevance of our data, Minnelide increased the efficacy of adjuvant therapeutics used in the clinical management of MB. Our findings not only highlight the potential for repurposing Minnelide to treat children with recurrent MB, but also the potential of our research approaches aimed at identifying novel therapeutics for relapsed cancers. Citation Format: Jezabel Rodriguez Blanco. Designing targeted approaches for recurrent medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5115.

Insights into the glioblastoma tumor microenvironment: current and emerging therapeutic approaches.

Glioblastoma (GB) is an intrusive and recurrent primary brain tumor with low survivability. The heterogeneity of the tumor microenvironment plays a crucial role in the stemness and proliferation of GB. The tumor microenvironment induces tumor heterogeneity of cancer cells by facilitating clonal evolution and promoting multidrug resistance, leading to cancer cell progression and metastasis. It also plays an important role in angiogenesis to nourish the hypoxic tumor environment. There is a strong interaction of neoplastic cells with their surrounding microenvironment that comprise several immune and non-immune cellular components. The tumor microenvironment is a complex network of immune components like microglia, macrophages, T cells, B cells, natural killer (NK) cells, dendritic cells and myeloid-derived suppressor cells, and non-immune components such as extracellular matrix, endothelial cells, astrocytes and neurons. The prognosis of GB is thus challenging, making it a difficult target for therapeutic interventions. The current therapeutic approaches target these regulators of tumor micro-environment through both generalized and personalized approaches. The review provides a summary of important milestones in GB research, factors regulating tumor microenvironment and promoting angiogenesis and potential therapeutic agents widely used for the treatment of GB patients.

Abstract A050: Ferritin, associated with worse overall survival in recurrent GBM, is reduced by combination of HDACi, ONC206 and radiation

Abstract Background: GBM is the most common primary brain malignancy with dismal prognosis. Current standard of care is chemoradiation&amp;surgery. The main issue with GBM is the resistance &amp; recurrence. GBM can have high Ferritin levels associated with disease progression &amp; immunosuppression in the GBM TME. Ferritin light chain (FTL), a key protein in iron metabolism, is mutated in GBM leading to high ferritin levels (both light&amp; heavy chain) &amp; is associated with poor survival of (GBM) patients in part due to inhibition of ferroptosis. Panobinostat is a histone deacetylase inhibitor with antineoplastic &amp; antiangiogenic effects in glioma. Imipridone ONC206 is under Phase I clinical development in treatment of adult &amp; pediatric patients with newly diagnosed and/or recurrent primary brain tumors (NCT04732065 and NCT04541082).We investigated the novel combination of irradiation, Panobinostat and ONC206 with regard to GBM cell line sensitivity&amp;ferritin levels. Materials &amp; methods: We investigated cell viability and drug synergies of ONC206 plus Panobinostat with or without radiation in 4 human GBM cell lines at 72 hours. Changes in Ferritin level treatment in U87 &amp; U251 cells were measured using cytokine profiling at 24 h time point. Information regarding recurrent cases of adult GBM from TCGA &amp;GlioVis were used for survival data. Results: We previously have shown the synergy between Panobinostat, Irradiation and ONC206 (2023 AACR meeting). Treatment of U87 cells with Panobinostat and ONC206 at their IC50s +/- 4 Gy radiation at 24h time point led to reduction in secreted ferritin levels (Panobinostat alone: 26.3% decrease; ONC206 alone: 14.7% decrease; RT 4Gy alone 14.7% decrease; triple therapy: 32.2% decrease). In panobinostat treated U251 cells there was a 10% increase in ferritin at 24 h. ONC206 resulted in a reduction by 34.71%, 4 Gy RT caused a slight increase of 4% in ferritin amount while the triple showed 49.96% reduction in ferritin levels. mRNA expression of FTL gene (Ferritin Light Chain) is significantly higher in GBM tumors compared to normal brain tissue. From TCGA 17 cases of recurrent gliomas with FTL mutation were available with median survival of less than a year. In data from GlioVis of recurrent GBM cases 263 patients had high FTL with median survival of 12.6 months compared to 262 patients with low FTL with median survival of 14.9 months. Conclusions: GBM with high ferritin correlates with poor patient survival. FTL is associated with cell proliferation &amp;angiogenesis of GBM cells &amp; is protective from ferroptosis in glioma cells. ferritin may be a therapeutic target in recurrent &amp; therapy resistant cases of GBM and ferroptosis modulating drugs &amp;can be a novel treatment option. ONC206 &amp; Panobinostat with irradiation is a novel combination &amp; can be considered for temozolomide or radiation-resistant &amp; recurrent cases. More studies are needed to investigate the mechanism &amp; impact of ferritin in disease progression, therapy resistance&amp; ferroptosis targeting therapeutics. We are currently exploring these directions including in vivo studies. Citation Format: Vida Tajiknia, Wafik El Deiry, Lanlan Zhou, William Macdonald, Praveen Srinivasan. Ferritin, associated with worse overall survival in recurrent GBM, is reduced by combination of HDACi, ONC206 and radiation [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr A050.

Brain and Brain Stem Necrosis After Reirradiation for Recurrent Childhood Primary Central Nervous System Tumors: A PENTEC Comprehensive Review

Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation. A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies. Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD22; assuming α/β value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD22 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P = .46). Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation.