tbuckley/cabot-search huggingface dataset:
TMOD-17. FOXR2-ACTIVATED CNS NEUROBLASTOMA ORIGINATES FROM THE MEDIAL GANGLIONIC EMINENCE LINEAGE
Authors: Hitomi Royston, Autumn Hampton, Dhruv Bhagat, Evonne Pinto, Miriam Emerson, Kosuke Funato
Journal: Neuro-Oncology (2024)

Abstract FOXR2-activated CNS neuroblastoma is a rare subtype of pediatric brain tumor characterized by the elevated expression of the transcription factor FOXR2 due to genomic rearrangement. However, the precise pathogenic mechanisms, including the cell type of origin and the function of FOXR2, are not fully understood. An expression profile analysis of patient tumors showed increased expression of the marker genes associated with the Medial Ganglionic Eminence (MGE) in the ventral forebrain such as NKX2.1 and SOX6. Based on this result, we hypothesized that FOXR2-activated CNS neuroblastoma originates from the MGE lineage. To test this hypothesis, we overexpressed FOXR2 in human embryonic stem cell-derived MGE progenitors and, as a control cell type, cortical progenitors. Our data showed that FOXR2 overexpression resulted in a significantly increased proliferation in the MGE progenitors but not in the cortical progenitors, indicating a cell-type-specific effect of FOXR2. When injected into the brain of immunodeficient mice, FOXR2-expressing MGE progenitors formed tumors that molecularly resemble patient tumors, while FOXR2-expressing cortical progenitors did not. To further dissect the underlying molecular mechanisms, we conducted an RNA-seq experiment and found that FOXR2 overexpression activated the MEK/ERK signaling pathway through a suppression of the endogenous RAS inhibitor DIRAS3. Moreover, the FDA-approved MEK inhibitor trametinib significantly suppressed the proliferation and induced cell death in FOXR2-expressing MGE progenitors in vitro with the IC50 value of 30 nM. Collectively, our study has revealed the cell type of origin of FOXR2-activated CNS neuroblastoma and identified the MEK/ERK pathway as a critical downstream of FOXR2 that can be targeted therapeutically.
TMIC-29. IMMUNE SPECIFIC IMAGING TECHNIQUES IN GLIOBLASTOMA: SELFI MRI IDENTIFIES AGGRESSIVE AND IMMUNOSUPPRESSIVE BIOLOGICAL FEATURES THAT CONTRIBUTE TO THERAPEUTIC RESISTANCE
Authors: Jared Stoller, Daniel Schwartz, Doonyaporn Wongsawaeng, Samantha Holland, Cooper Stateler, Cymon Kersch, Alicia Starkey, Leslie Muldoon, Prakash Ambady, Ahmed Raslan, Aclan Dogan, Olabisi Sanusi, Christina Harrington, Edward Neuwelt, Ramon Barajas
Journal: Neuro-Oncology (2024)

Abstract Gadolinium (Gd) enhanced MRI is nonspecific for identifying aggressive glioblastoma biology. Glioblastoma-associated macrophages (GAMs) are pivotal in regrowth. Segregation and Extravascular Localization of Ferumoxytol Imaging (SELFI) is a quantitative immune specific MRI technique. SELFI+ values quantify M2 GAMs by phagocytized Ferumoxytol (Fe), while SELFI- values delineate intravascular Fe, cerebral blood volume. The relationship between SELFI and biology driving therapeutic resistance remains unknown. We aimed to determine if SELFI identified immunosuppressive GAMs and biology contributing to poor outcomes, a capability not yet achievable in clinical practice. This prospective study included four patients with glioblastoma. All underwent preoperative Gd and Fe (7 mg/kg up to 510 mg) enhanced MRI allowing for image guided biopsy based on Gd enhancement and FLAIR hyperintensity. RNA was analyzed on GeneChip Clariom Arrays. Intraoperative biopsy location was referenced to MRI for placement of volumes of interest (VOIs). VOIs quantified MRI phenotype and SELFI values. Gene Set Enrichment Analysis (GSEA) assessed differential expression between MRI features. T-test assessed differences in SELFI (p &amp;lt;0.05) and GSEA significance was assessed by normalized enrichment score (NES) and false discovery rate (FDR) q-value. Four patients provided 36 image guided tissue samples with sufficient quality to assess the causal relationships between MRI features and transcriptomics. Stratification by patient MGMT methylation status (N= 3 unmethylated) demonstrated Gd+ regions had significantly elevated SELFI+ values (Mean±SD, Gd+ = 0.24±0.17, Gd- = 0.08±0.09, P&amp;lt;0.01). GSEA demonstrated that tissues with elevated SELFI+ and lowered SELFI- values were comprised of significantly upregulated hypoxia and transforming growth factor-beta (TGFβ) signaling; among others (NES&amp;gt;1.5, FDR q-value&amp;lt;0.05). SELFI MRI uniquely quantifies glioblastoma by localizing sites of biological aggressiveness known to contribute to therapeutic resistance and disease recurrence. Patient enrollment continues to further define the causal relationships between SELFI, GAMs, and glioblastoma biology.
DDEL-09. AS1411 APTAMER-CONJUGATED NANOSPHERES FOR TARGETING GLIOBLASTOMA THERAPY
Authors: Chae-Yong Kim, Yoon-Kyu Song, Kyeongjin Seo, Kihwan Hwang, Kyung Mi Nam
Journal: Neuro-Oncology (2024)

Abstract Postoperative chemotherapy remains essential for treating glioblastoma (GBM), with nanocarrier-based drug delivery emerging as the most efficient method. However, non-specific delivery across the blood-brain barrier (BBB) can limit drug accumulation in tumors and cause damage to nearby tissues. As cancer progresses, angiogenic processes lead to the formation of an irregular blood-tumor barrier (BTB), necessitating nanodrug platforms for precise targeting and efficient drug delivery to cancer cells. In this study, we aimed to demonstrate targeted cancer therapy by selectively identifying tumor cells overexpressing nucleolin (NCL) protein using Dox-loaded AS1411 aptamer-conjugated nanospheres. Drug nanocarriers were synthesized from small molecules with sizes ranging from 100 to 300 nm to facilitate drug delivery. Selective drug delivery and cellular uptake were demonstrated for NCL-positive GBM cells (U87 and U251) compared to NCL-negative normal human astrocyte (NHA) cells. Flow cytometric analysis using FAM dye-labeled AS1411 aptamer-conjugated nanospheres confirmed that drug delivery to GBM U87 and U251 cells was actively targeted by specific AS1411-NCL interactions. Confocal laser scanning microscopy and cytotoxicity analysis confirmed that inoculation of Dox-loaded AS1411 aptamer-conjugated nanospheres induced selective internalization in GBM U87 and U251 cells. Moreover, to evaluate cytotoxicity and anti-tumor effects after treatment with PBS, Apt-Nanospheres, Free Dox, and Dox-Apt-Nanospheres, the results were analyzed through cell counting kit (CCK-8) analysis, evaluation of differences in 3D tumor sphere radii, and an in vivo GBM xenograft tumor model. The AS1411 aptamer-conjugated nanosphere drug delivery system was developed for dual-target treatment of GBM. AS1411-mediated specific recognition and drug accumulation significantly enhanced binding to NCL-positive U87 and U251 cells and improved cytotoxicity efficiency compared to Free Dox. Additionally, this study demonstrated that the active targeting model using aptamer-mediated drug delivery was more effective in improving drug penetration and retention in tumor cells than non-specific enhanced permeability and retention (EPR)-mediated delivery and passive drug delivery.
INNV-12. CUTANEOUS TOXICITIES OF MITOGEN-ACTIVATED PROTEIN KINASE INHIBITORS IN CHILDREN AND YOUNG ADULTS WITH NEUROFIBROMATOSIS-1
Authors: Zsila Sadighi, Sanjna Tripathy, Brianna Peacock, Anisha Patel
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. Cutaneous adverse events (CAEs) are common and may hinder patients’ abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1. METHODS We reviewed institutional medical records of patients under 30 years with a diagnosis of “NF1,” “NF2,” or “other neurofibromatoses” on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response. RESULTS The median age of 40 patients with NF1 was 14 years old. Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%) (Table 1). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%) (Figure 1). Twenty-three out of the 28 cases of acneiform eruption were in post-pubertal patients (82.1%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi (Table 2). There was no significant association between CAE presence and tumor response (p=0.39). CONCLUSIONS MEK inhibitors have been demonstrated as a valuable treatment, but CAEs complicate the ability to stay on the treatment. Most patients in our cohort developed a CAE, demonstrating its prevalence in this population. Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.
IMMU-20. CIRCULATING CELL-FREE DNA DIRECTLY INHIBITS T CELL RESPONSES AND CONTRIBUTES TO SYSTEMIC IMMUNOSUPPRESSION IN GLIOBLASTOMA
Authors: Alexandra Hoyt-Miggelbrink, Rachael Reesman, Delaney Anani-Wolf, Michael Hansen, Christian Pfaller, Cori Fain, Aaron Johnson, Katayoun Ayasoufi
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is an aggressive form of brain cancer with poor survival despite standard of care. Checkpoint inhibitors aimed to revive dysfunctional T cells have significantly improved outcomes in other cancers, but have failed GBM. GBM patients have severe peripheral immunosuppression, including severe lymphopenia, immune organ atrophy, and defective T cell responses. This immunosuppression is a critical barrier to patient survival and the success of immunotherapies. Using parabiosis, we demonstrated that serum-derived factors were sufficient to drive hallmark features of immunosuppression, including inhibition of ex vivo T cell proliferation. This factor was nonsteroidal in nature and had molecular weights greater than 100kDa. Mass-spectrometry and pathway analysis of the suppressive serum implicated proteins involved in DNA response elements, cell death, and DNA-histone complexes. We hypothesized that the factor is cell-free DNA (cfDNA). Confirming this, serum levels of cfDNA are increased in glioma-bearing mice. Moreover, exposure to cfDNA from serum of glioma-bearing mice was sufficient to directly and potently inhibit T cell proliferation ex vivo. Interestingly, exposure to genomic DNA was not sufficient to induce proliferation defects in T cells, highlighting the unique features of cfDNA. Importantly, reducing cfDNA content using DNaseI partially restored proliferation capacity. We determined that the T cell proliferation defects were independent of DNA sensing mechanisms through AIM2, implicating a novel pathway of DNA sensing in T cells. Finally, to determine the origin of the cfDNA, we employed methyl-seq. The chromatin signature most closely represented neutrophils. This highlights a potential role for neutrophils-derived cfDNA as a targetable strategy in GBM. Together, we contend that cfDNA induces immunosuppressive effects in GBM and devising strategies to reduce circulating cfDNA could be a therapeutic approach to improve T cell functions and outcomes in GBM patients.
SURG-35. NEURONAVIGATED INTRAOPERATIVE ULTRASSOUND X SODIUM FLUORESCEIN FOR BRAIN METASTASIS: WHICH IS BETTER?
Authors: Aline Lariessy Campos Paiva, João Luiz Vitorino Araujo, Renan Maximillian Lovato, Jean Gonçalves de Oliveira, José Carlos Esteves Veiga
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Improve quality of life with a maximum surgical resection is the main goal of neurosurgeons. Brain metastasis are even more prevalent because of patients are living more. The grade of resection and the maintenance of a good performance are fundamental for these patients perform adjuvant radiotherapy. There are several technologies that may help. Considering two of them that have an easier access and are cheaper, we compared a high definition ultrasound (BK 3000) coupled to neuronavigation system (Brainlab) and sodium fluorescein (SF). METHODS Adult patients with main radiological hypothesis of brain metastasis were included in a PhD study previously approved by ethics committee. 3-5mg/kg of SF was administered by intravenous infusion during anesthetic induction. An specific craniotomy transducer was used in all cases with shift correction in real time by neuronavigator. All procedures were guided by the same neurosurgeon. RESULTS High definition ultrasound allows an excellent tumor delimitation. SF helped to increase grade of resection however made confusion about what is infiltration and what is tumor and for this ultrasound were superior. Increased fluorescence is easily detected when compared to ultrasound information’s.. For both technologies, when the surgical site had blood, the evaluation about grade of resection is not accurate because in ultrasound appears a posterior shadow and considering SF it seems that there are not further tumor because blood does not have increased fluorescence. CONCLUSIONS US and SF are different tools which improve brain metastasis resection. In each moment of surgery one technology was superior or not. We used an specific probe for neurosurgery that has high quality and allowed detailed evaluations. These technologies helps surgeons take quick decision and optimized brain tumor removal. The neurosurgeon should be more familiar to US images because provide a real time evaluation with low cost.
NCMP-04. IMPLANTATION METASTASIS FOLLOWING BIOPSY OF THALAMIC GERMINOMA – A CASE REPORT AND REVIEW OF LITERATURE
Authors: Llarx Saundt Yu, Oliver Ryan Malilay, Joseph Erroll Navarro
Journal: Neuro-Oncology (2024)

Abstract Germ cell tumors commonly develop in the pineal and suprasellar regions, with the most common germ cell tumor being germinomas. In this report, a 22-year-old male presented with progressive right-sided weakness and his imaging was consistent a thalamic high grade glioma. A stereotactic biopsy was performed, revealing a germinoma, but radiation therapy was not done and patient was lost to follow up. He was readmitted due to ulcerative tumor growth at the previous skin incision, and imaging revealed tumor progression with implantation metastasis along the tract of the previous biopsy. The scalp tumor was excised and histopathologic studies confirmed that it was proliferation of the previous germinoma. He was discharged well but was unfortunately unable to follow up at the clinic. Thalamic germinomas are difficult to diagnose and treat because of their rarity. Here we underscore the importance of careful patient selection, precise biopsy techniques, thorough postoperative management and close radiographic surveillance to minimize the risk of implantation metastasis and promptly treat it if it occurs.
PATH-13. MOLECULAR AND BIOLOGY CORRELATIVE RESULTS FROM THE PHASE 1B TRIAL OF UNESBULIN (PTC596) WITH RADIOTHERAPY IN CHILDREN NEWLY-DIAGNOSED WITH DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) AND HIGH-GRADE GLIOMA (HGG): A REPORT FROM THE COLLABORATIVE NETWORK FOR NEURO-ONCOLOGY CLINICAL TRIALS (CONNECT)
Authors: Margot Lazow, Patricia Baxter, Shiva Senthil Kumar, Maya Mohamad, Alan Mackay, Joseph Stanek, Diana Rodriguez, Joshua Palmer, James Leach, Leonie Mikael, Diana Thomas, Christine Fuller, Daniel Boué, Christopher Pierson, John Breneman, Xiao-Nan Li, Ralph Salloum, David Ashley, Peter de Blank, Eugene Hwang, Sarah Leary, Ashley Plant, Michael Fisher, Susan Chi, Mythili Murala, Marla Weetall, Mark Rance, John Baird, Dhiren D’Silva, Kylie O’Keefe, Jeffrey Leonard, Clinton Stewart, Chris Jones, Elaine Mardis, Maryam Fouladi, Rachid Drissi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Within the CONNECT1702 trial of unesbulin (tubulin-binding agent causing BMI-1 modulation) with radiotherapy in patients with DIPG/HGG, tumor tissue was analyzed at diagnosis and/or autopsy for biology correlatives, enabling comprehensive, longitudinal molecular characterization. METHODS Whole genome sequencing, RNA-sequencing, and Western blot analyses were performed on tumor, normal brain, and peripheral blood mononuclear cells (PBMCs). RESULTS Tumor tissue from diagnosis (n=11) and/or autopsy (n=7) was analyzed for 16 patients (DIPG=9; HGG=7). Western blot analyses demonstrated 1) BMI-1 overexpression in baseline tumor compared to normal brain and 2) primary on-target effect of BMI1-modulation causing M-phase mitotic arrest when comparing pre- and post-treated PBMCs (increased H3S10-phosphorylation). Among 9 DIPG patients, alterations in the following genes were identified: H3-3A (H3.3) (n=5), H3C2 (H3.1) (n=2, both with co-occurring ACVR1 and PIK3CA mutations), TP53 (n=5), ATRX (n=2), and PPM1D (n=2). Tumors from two longer DIPG survivors were H3.1-, ACVR1-mutant (overall survival [OS]=26 months) and MET-amplified (OS=18 months); one patient with H3.3K27M-DIPG had germline MSH6 mutation (Lynch syndrome) (OS=12.6 months). Among 7 HGG patients, alterations in the following genes were identified: H3-3A (n=5), TP53 (n=3), NF1 (n=3), PDGFRA (n=1), EGFR (n=1), and PIK3CA (n=1). A BRAFV600E mutation was observed in the thalamic HGG patient (H3.3K27M) with greatest progression-free survival (&amp;gt;23 months). Early leptomeningeal metastases occurred in one DIPG patient with BCOR alteration and one HGG patient, with MYCN amplification identified in the spinal metastasis, but not intracranial disease. From gene set enrichment analyses, pathways enriched in patients with longer survival included telomerase regulation and ATP synthesis, whereas pathways enriched in patients with shorter survival included interneuron development, neuron semaphorin signaling, and gamma aminobutyric signaling. CONCLUSIONS Comprehensive molecular profiling of diagnostic and post-mortem tumor tissue provides valuable early biological insight, elucidating potential genomic biomarkers predictive of outcome and response to M-phase alteration and BMI-1 modulation in DIPG/HGG.
NIMG-14. HEAD-TO-HEAD COMPARISON OF18F-FET PET AND68GA-PSMA-11 PET IN DISTINGUISHING SMALL VOLUME TUMOR PROGRESSION VS TREATMENT-RELATED CHANGE IN POST-STANDARD OF CARE TREATMENT OF HIGH-GRADE GLIOMA USING DYNAMIC ACQUISITION AND KINETIC MODELING
Authors: Jesus Ocana, Mark Green, Wendy Territo, Gary Hutchins, Michael Veronesi, Kathryn Nevel, Shafique Umber
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND The inability to accurately distinguish between tumor progression and treatment-related changes in patients with high-grade glioma on routine imaging can negatively impact patient management and in some cases, outcome. Various imaging methods have been used to address this issue, including 18F-fluoro-ethyl-tyrosine (FET) PET and MR perfusion. However, these methods may not provide reliable results in cases of small lesion size or hemorrhage within the treatment site. The prostate-specific membrane antigen (PSMA) has been observed to be expressed by neovasculature in brain tumors. Since PSMA cannot cross the blood brain barrier, uptake of PSMA in the brain carries high-level of suspicion for residual tumor. Still, further work is needed to better understand PSMA uptake in the tumor bed following standard of care (SOC) treatment and to compare to currently available neuro-oncologic radiotracers, such as FET. We hypothesize that PSMA imaging of glioma neovasculature will provide unique diagnostic information that will aid in the differentiation of small volume tumor progression from treatment-related changes in the post-SOC treatment setting. METHODS Patients who underwent clinical Expanded Access PET/MR imaging with 18F-FET were re-imaged in a research protocol that collected a brain 68Ga-PSMA-11 PET/CT scan, as well as a repeat 18F-FET PET/CT. Kinetic modeling of dynamic radiotracer uptake was performed. Scans were assessed for correlation with subsequent imaging and changes in clinical management. RESULTS All PSMA scans that were performed were concordant with the initial clinical FET scan, subsequent imaging follow up and appropriate changes in clinical management. The PSMA-detected site was confirmed to be tumor in a single case with subsequent tissue sampling. One patient who was started on bevacizumab after their clinical FET demonstrated a significant decrease in uptake on the research FET scan, but persistent uptake on PSMA. CONCLUSION PSMA may effectively show tumor recurrence in post-SOC treatment high-grade glioma patients.
CSIG-04. ANTI-TUMOR RESPONSE OF ONCOMAGNETIC MONOTHERAPY IN GLIOBLASTOMA
Authors: Arvind Pandey, Shashank Hambarde, David Baskin, Santosh Helekar
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) is the most lethal primary malignant brain tumor with a median survival of 15–20 months. Concurrent temozolomide (TMZ) chemotherapy and radiation (XRT) remain the current standard of care (SOC) treatment for newly diagnosed GBM. The addition of tumor treating fields (TTFs) improves median survival for newly diagnosed GBM from 16 to 20.9 months. This modest improvement underscores the urgent need to identify a new treatment modality as a safe and effective therapy. PURPOSE The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) in vitro. We studied the cellular and molecular effects of Oncomagnetic monotherapy (OMT) on GBM cell lines and investigated immune response in a syngeneic mouse model. RESULTS OMT significantly reduces cell proliferation and cell survival in vitro. OMT induces persistent ROS primarily by increasing superoxide level in cancer cells and reduces mitochondrial-membrane potential in GBM cells. It also induces DNA damage and arrests cells in G1-phase of the cell cycle. Whole-body Oncomagnetic stimulation caused a substantial retardation of tumor growth and reduction of the contrast-enhanced tumor volume in 9.4T MRI scans. OMT showed significant increase in overall survival in treated mice. We also observed upregulated immune response indicated by RNA sequencing data obtained from OMT-treated GBM cells as well as in treated GBM mouse tumor sections by imaging mass cytometry analysis. The tSNE analysis of various immune clusters suggests significant increase in immune response by activating CD4+, CD8+, murine-macrophages and M1-macrophages located at tumor site in the treated group. CONCLUSION The obtained data indicate significant anti-tumor response by inhibiting cancer signaling pathways and an increased immune response. Our findings suggest unique mechanism of action for OMT stimulation and provide a strong rationale for standalone OMT for GBM.