tbuckley/cabot-search huggingface dataset:
BIOM-20. EVALUATING THE POTENTIAL OF PSMA TARGETING IN CNS TUMORS: INSIGHTS FROM LARGE-SCALE TRANSCRIPTOME PROFILING
Authors: Adam Kraya, Komal Rathi, Run Jin, Varun Kesherwani, Adam Resnick, Ali Nabavizadeh
Journal: Neuro-Oncology (2024)

Abstract PURPOSE Prostate-specific membrane antigen (PSMA) is a well-established target in prostate cancer therapy that has shown potential as a theranostic target across non-central nervous system (CNS) and CNS tumor types. We aimed to investigate the pan-tissue expression pattern of the PSMA-encoding gene FOLH1 to assess whether transcriptome profiling can inform tumor theranostics. EXPERIMENTAL DESIGN We assessed FOLH1 expression from the Open Pediatric Cancer Project (OpenPedCan, n = 2132 specimens), The Cancer Genome Atlas (TCGA, n = 10411 specimens), and the Genotype Tissue Expression Project (GTEx, n = 17382 specimens) in relation to published reports of PSMA radionuclide uptake. RESULTS When comparing FOLH1 expression across tumor versus normal tissues, we found that non-CNS tumors exhibiting elevated expression of at least two-fold (FDR &amp;lt; 0.05) were reported to have successful PSMA radionuclide uptake in contrast to tumors with less than a two-fold elevation or with lower expression of FOLH1 relative to normal. Notably, CNS tumors universally exhibited lower expression of FOLH1 relative to normal brain tissue, but we observed considerable variation in the expression of blood-tumor barrier (BTB) components associated with reports of BTB integrity and uptake of PSMA radiotracers. CONCLUSIONS Large-scale transcriptomics data may help guide the application of PSMA-based radionuclide therapies in non-CNS tumors, but care should be taken to account for BTB effects in CNS tumors when assessing the potential for radionuclide success. Our analysis demonstrated that FOLH1 showed a lack of tumor-specific expression for both adult and pediatric CNS tumors when compared to normal brain tissue, suggesting that PSMA is not a desirable target in this disease type. This study highlights the utility of utilizing large-scale molecular data to guide the selection of theranostic targets.
CTIM-32. PHASE I/II STUDY OF STEREOTACTIC RADIOSURGERY WITH CONCURRENT OLAPARIB FOLLOWED BY ADJUVANT DURVALUMAB AND PHYSICIAN’S CHOICE SYSTEMIC THERAPY IN SUBJECTS WITH BREAST CANCER BRAIN METASTASES (SOLARA)
Authors: Colette Shen, Yara Abdou, Linda Chen, Xianming Tan, Gaorav Gupta, Filipa Lynce, Mina Lobbous, Erica Stringer-Reasor, Carey Anders
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite progress in the treatment of brain metastasis for HER2+ breast cancer, outcomes for patients with HER2-negative breast cancer brain metastases remain poor. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective in combination with radiation therapy as a DNA damage response inhibitor. Triple-negative breast cancer (TNBC) has higher rates of homologous recombination deficiency compared to other subtypes, and together with HER2-negative, BRCA-mutated breast cancer would be particularly sensitive to PARP inhibition. PARP inhibition has also demonstrated promising efficacy combined with immunotherapy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials. In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable intracranial control and survival in patients with brain metastases. We hypothesize that this biologically-driven combination will enhance local control of SRS-treated brain metastases through synergy with PARP inhibition, while controlling micrometastatic disease via potentiation of the immune response. METHODS We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) breast cancer brain metastases [NCT04711824]. A total of 41 patients are planned for enrollment at 8 sites. The primary objectives are to evaluate safety and tolerability (Phase I) and determine intracranial disease control at 6 months (Phase II). Secondary objectives include assessing intracranial and global progression-free survival, overall survival, and intracranial and extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells and DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. As of May 2024, phase I has been completed without dose-limiting toxicity, and phase II is currently enrolling. Funding/drug provision from AstraZeneca.
CSIG-03. MT-125 INHIBITS NON-MUSCLE MYOSIN IIA AND IIB, SYNERGIZES WITH ONCOGENIC KINASE INHIBITORS, AND PROLONGS SURVIVAL IN GLIOBLASTOMA
Authors: Steven Rosenfeld, rajappa kenchappa, Laszlo Radnai, Natanael Zarco, Athanassios Dovas, Ashley Haddock, Peter Canoll, Gavin Rumbaugh, Patrick Griffin, Theodore Kamenecka, Courtney Miller
Journal: Neuro-Oncology (2024)

Abstract We have shown that members of the non-muscle myosin II (NMII) family of molecular motors are non-redundant drivers of both invasion and proliferation in glioblastoma (GBM), consistent with the canonical roles NMII isoforms play in cell motility and cytokinesis. However, we have also found that NMII also has a non-canonical role by regulating oncogenic signaling pathways relevant to GBM pathogenesis. This unexpected finding has led us to identify and characterize MT-125, a highly specific small molecule inhibitor of the two predominant NMII isoforms in GBM (NMIIA and NMIIB), and we have studied its effects in pre-clinical GBM models. MT-125 has high brain penetrance and retention; an excellent safety profile in rodents and canines with no changes in metabolic or hematologic indices after prolonged administration; is well-tolerated with daily dosing for at least 85 consecutive days; blocks GBM invasion and cytokinesis, consistent with the canonical roles of NMII; and prolongs median survival by 35% as a single agent in murine GBM models. MT-125 increases signaling along both the PDGFR- and MAPK-driven pathways through a mechanism that involves the upregulation of reactive oxygen species, leading to oncogene addiction to these pathways. As a consequence, MT-125 is synthetically lethal when combined with FDA-approved, CNS-permeant inhibitors of PDGFR and mTOR in vitro. Combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined PI3 Kinase/mTOR inhibitor, in vivo doubles median survival in a highly aggressive murine orthotopic GBM model. Furthermore, combining MT-125 with sunitinib produces tumor free remissions of &amp;gt;100 days--2.5-fold greater than median survival of either drug alone—in approximately 40% of mice. Our results provide a powerful rationale for developing NMII targeting strategies to treat cancer and demonstrate that MT-125 has strong clinical potential for the treatment of GBM.
CNSC-16. ASSOCIATION BETWEEN RESTING-STATE-NETWORK FUNCTIONAL CONNECTIVITY AND SURVIVAL IN RECURRENT GLIOMAS DIAGNOSED USING FET PET
Authors: Michel Friedrich, Jan-Michael Werner, Joachim P Steinbach, Michael Sabel, Ulrich Herrlinger, Marc Piroth, Gabriele Stoffels, Christian P Filss, Philipp Lohmann, Nadim J Shah, Maximilian I Ruge, Felix M Mottaghy, Roland Goldbrunner, Karl-Josef Langen, Gereon R Fink, Martin Kocher, Norbert Galldiks
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Functional connectivity between glioma-infiltrated brain tissue and remote cortical regions has been linked to overall survival (OS) in patients with newly diagnosed glioblastoma. We studied the association of functional connectivity between tumor and resting-state networks and OS in patients with recurrent gliomas. PATIENTS AND METHODS The study included 82 patients (26-81 years; median ECOG performance score, 0) with recurrent gliomas (grade 4 glioblastoma, n=57; grade 3 and 4 astrocytoma, n=12; grade 2 and 3 oligodendroglioma, n=13) who had undergone first-line therapy. Diagnosis of recurrence was confirmed by amino acid PET using the tracer O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). FET PET and resting-state functional MRI were simultaneously acquired on a 3T hybrid PET/MR scanner. We performed a seed-based dual regression analysis to determine the functional connectivity between metabolically active tumors and seven canonical resting state networks. RESULTS Average functional connectivity was highest in oligodendrogliomas (z-score, 6.9±1.9) and was inversely related to the tumor grade (p=0.031). Univariate Cox regression analysis revealed a significant (p&amp;lt;0.05) positive association between OS and tumor connectivity with the visual, somatomotor, and dorsal attention networks. Subsequent stepwise multivariate Cox regression analysis refined this association to the dorsal attention network alone (HR, 0.88; 95% CI, 0.80-0.97; p=0.007). Patients with the highest functional connectivity (z-score&amp;gt;8.3, n=21) had a median OS of 31.4 months, while those with the lowest functional connectivity (z-score&amp;lt;4.3, n=21) had 10.6 months. Functional connectivity between tumors and the dorsal attention network showed an independent association with OS (HR, 0.90; 95% CI, 0.81-0.99; p=0.033) in a multivariate model, including various prognostic factors. CONCLUSION Recurrent gliomas exhibit significant functional connectivity to most of the major known resting-state networks, highest in oligodendrogliomas. The data suggest that high functional connectivity between the tumor and the dorsal attention network is an independent prognostic factor for improved OS.
BIOM-50. SERIAL INTRACRANIAL CEREBROSPINAL CELL-FREE DNA FOR DISEASE MONITORING IN PATIENTS WITH GLIOMAS
Authors: Cecile Riviere-Cazaux, Xiaoxi Dong, Mo Wei, Rahul Kumar, Lucas Carlstrom, Cody Nesvick, Katherine Andersen, Matthew Hoplin, Ignacio Jusue-Torres, Noor Malik, Ugur Sener, Michael Ruff, Joon Uhm, Jian Campian, Jeanette Eckel-Passow, Timothy Kaufmann, David Routman, Sani Kizilbash, Shidong Jia, Pan Du, Arthur Warrington, Terry Burns
Journal: Neuro-Oncology (2024)

Abstract Improved response assessment methods are needed for patients with gliomas. Intracranial cerebrospinal fluid (CSF) is longitudinally accessible and provides an abundance source of candidate biomarkers, such as cell-free DNA (cfDNA), for disease monitoring. To evaluate the clinical feasibility of molecular profiling from longitudinal intracranial CSF, CSF was acquired from patients with CSF access devices, including Ommaya reservoirs and ventriculoperitoneal shunts. cfDNA was extracted and analyzed via PredicineCARE (Next Generation sequencing) or PredicineSCORE (low pass whole genome sequencing). Five patients (2 females, 3 males; median age: 40 years, range 32-64 years) underwent longitudinal intracranial CSF collection via Ommaya reservoirs (n=4) or VP shunt (n=1). In total, forty-eight CSF samples were obtained (median volume: 4.00 mL; 0.5-5 mL), with 39 samples (81.3%) yielding sufficient cfDNA for variant profiling. Our initial findings suggest that tumor fraction increased by 6.28x, 2.87x, and 8.31x with radiographic progression in three patients. Tumor fraction decreased by 0.08x and 0.04x in two patients with paired immediate pre-versus-post chemoradiation samples. Despite ongoing pseudoprogression in one patient, tumor fraction decreased to unmeasurable levels from a post-resection baseline of 0.26. Patient-specific tumor-associated variant allelic frequencies (VAFs), including TP53, PTEN, TERT, and CDKN2A/B, decreased within individual patients after resection and chemoradiation. In two patients with isocitrate dehydrogenase (IDH) mutant gliomas, decreasing IDH1 VAF after resection and chemoradiation correlated with decreased CSF D-2-hydroxyglutarate (D-2-HG) levels (0.64x and 0.62x, respectively, for the first patient, and 0.01x and 0.07x for the other patient). Both CSF IDH1 VAF and CSF D-2-HG increased a patient who had radiographic progression (2.56x and 9.21x, respectively). Moreover, CNB decreased below the limit of quantification during treatment and increased above the limit at progression. In conclusion, longitudinal CSF cfDNA can feasibly be obtained via CSF access devices in patients with gliomas during their disease course toward evaluating candidate monitoring biomarkers.
CSIG-06. BRAF GERMLINE MUTATIONS AND PREDISPOSITION TO BRAIN TUMORS
Authors: Nouha Bouayed Abdelmoula, Balkiss Abdelmoula, Walid Smoui, Khaled Trigui, Rim Louati
Journal: Neuro-Oncology (2024)

Abstract We report on two BRAF-mutated children and discuss genetic counseling regarding predisposition to brain tumors. Molecular analysis of the PTPN11 gene and twelve other genes in the RAS-MAPK pathway was carried out in a series of 54 dysmorphic patients with suspected Rasopathies. Two heterozygous BRAF germline mutations were detected in two 7-year-old girls, at exon 6 and 12 respectively. Both patients had the distinctive facial appearance of cardio-facio-cutaneous syndrome (CFC) type 1. Patients with CFC are rare and characterized by phenotypic and genetic heterogeneity, with overlaps with Noonan syndrome. While nearly 75% of CFC cases have germline BRAF mutations, the frequency of BRAF mutations is inferior in Noonan and LEOPARD syndromes. BRAF mutations in CFC are often found in the cysteine-rich domain of the BRAF protein (exons 6, 11, 12, 13, 14, 15 and 16). Conversely, somatic BRAF mutations are more common, grouped into classes according to their kinase activity level, and have been associated with a variety of malignancies, including pediatric and adult brain tumors (low- and high-grade gliomas, glioblastomas and low-grade astrocytomas). BRAF V600E is the most common somatic mutation, but other mutations are currently being identified. Many of these mutations are within the kinase domain, while others are located across the gene and have less well-understood functional consequences. Germinal V600E mutation has been described once, in a CFC patient having a severe phenotype. Nevertheless, it seems that patients with germline BRAF mutations and gliomas have not yet been reported. Given the rarity of CFC, it is unclear whether there is a high risk of brain tumors. Further molecular studies will enable us to refine recommendations for the prevention, monitoring and care of people with germline BRAF mutations, given the success of BRAF inhibitors in certain cancers, with encouraging results in gliomas.
STEM-08. LIPID SATURATION HOMEOSTASIS PRESENTS A TARGETABLE VULNERABILITY IN MYC-AMPLIFIED GROUP 3 MEDULLOBLASTOMA
Authors: Stefan Custers
Journal: Neuro-Oncology (2024)

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain cancer, originating from the cerebellum. Despite advancements in standard of care (SoC), MB remains fatal for 30% of patients. Tumor relapse, spinal metastasis and treatment resistance are the most prevalent in MYC-driven Group 3 MB (G3-MB). Patients surviving SoC are faced with life-long neurocognitive and neurodevelopmental deficits. These issues highlight the urgent need for improved treatment modalities. Reprogramming of cellular lipid metabolism is an emerging hallmark of cancer and may yield novel cancer-specific therapeutic options. Here we explore the lipidome of both G3-MB and its proposed cell of origin, human neural stem cells (hNSCs) by comparing untargeted lipidomics using Liquid-Chromatography-Mass Spectrometry (LC-MS). Comparative analyses revealed a differential abundance of distinct lipid species in G3-MB, with an overall reduced saturation level of fatty acids (FAs). These findings implicate the de novo lipid synthesis (DNL) pathway. We identified the enzymes involved in DNL to be essential for MB survival in our genome-wide CRISPR KO screen. Additionally, mRNA expression of the DNL enzymes increases at relapse in our SoC-adapted murine patient-derived xenograft (PDX) model. Pharmacological and genetic targeting of the DNL enzyme Stearoyl-CoA Desaturase 1 (SCD1) selectively targets G3-MB. Furthermore, small molecule treatment of SCD1 demonstrates efficacy against G3-MB PDX models in vivo. We identified SCD expression as a prognostic marker in Group 3 and 4 MB patients and identified possible pathways for MB treatment. Overall, these findings indicate that SCD1 is a potent target for the treatment of G3-MB.
SURG-24. MAXIMAL SAFE RESECTION OF INSULAR GLIOMAS: AN EVALUATION OF SURGICAL AND PROGNOSTIC OUTCOMES IN 461 CASES
Authors: Nadeem N Al-Adli, Jacob S Young, Jing Li, Daniel Quintana, Abraham Dada, Grazia Menna, Jasper K W Gerritsen, Ramin A Morshed, Shawn L Hervey-Jumper, Mitchel S Berger
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Insular gliomas are challenging to resect due to nearby functional cortical/subcortical structures and delicate Sylvian/sub-insular vascularity. Motor/language mapping and surgical experience are necessary for maximal safe resection (MSR). METHODS Outcomes were retrospectively evaluated following MSR in the largest single-institution series to date. 461 cases, between 1997 and 2022, were classified according to the Berger-Sanai system. Contrast-enhancing (CETV) and non-contrast-enhancing (nCETV) tumor volumes were calculated manually. RESULTS The final cohort comprised 226 high-grade (IDH-mutant, n=82) and 226 low-grade (IDH-mutant, n=101) tumors. Median nCETV was 47.7ml (grade 2, n=226), 72.6ml (grade 3, n=136), and 46.8ml (grade 4, n=90). Median CETV was 22ml for grade 3 and 13.6ml for grade 4 tumors. Most were classified as Zone I (37%), IV (8.6%), or I+IV (15%). For high-grade tumors, median CE-EOR was 96.1% (range, 29.7-100), which was highest in Zone I (100%), and supra-maximal resection was achieved in 5 cases. For low-grade tumors, median nCE-EOR was 82.4% (range, 28.4-100), which was highest in Zone 4 (85%). Additionally, initial nCETV in low-grade tumors was not associated with nCE-EOR, even when controlling for location. New postoperative motor deficits by discharge were significantly higher in Zones II (24%), I+II (22%), and III (23%). For dominant-hemisphere tumors, language deficits were highest in Zone I+II (44%), Giant (32%), and Zone II+III (29%) tumors. At 3 months, language deficits persisted in Giant (7.1%) tumors and motor deficits persisted in Giant (6.4%) and Zone II (5.9%) tumors. Median overall survival (OS) was 114.6 (grade 2), 108.6 (grade 3), and 14.7 (grade 4) months. In primary high-grade tumors, OS was longer with CE-EOR &amp;gt; 97.1% (36.8 vs.14.7 months, p=.04) and nCE-EOR of &amp;gt; 80.8% (91.3 vs. 20.2 months, p&amp;lt;.001). CONCLUSIONS In a high-volume academic center, surgical resection of insular gliomas with cortical/subcortical mapping can achieve excellent EOR with minimal language and motor morbidity.
BIOM-67. DIFFERENTIAL DNA METHYLATION PATTERNS IN THE CSF OF PATIENTS WITH DIFFUSE GLIOMAS
Authors: Daniel Wang, Mauli Shah, Srividya Arjuna, Antonio Dono, Chirag Patel, Jason Huse, Brittany Parker Kerrigan, Sophia Nguyen, Frederick Lang, Yoshua Esquenazi, Leomar Ballester
Journal: Neuro-Oncology (2024)

Abstract Studies have shown that different central nervous system (CNS) tumor types exhibit unique DNA methylation profiles. DNA methylation-based machine learning classification of CNS tumor tissue has been demonstrated to be highly-accurate in differentiating between tumor types, including between diffuse glioma subtypes. While similar analyses have been performed using cell-free DNA (cfDNA) from blood, few studies have looked at the potential of DNA methylation as a biomarker for diffuse gliomas using CSF-derived cfDNA. In this study, we analyzed CSF cfDNA methylation patterns in diffuse glioma patients. DNA methylation profiling of CSF of patients with glioblastoma, IDH-wildtype (GBM) (n=37), IDH-mutant diffuse gliomas (n=12), and non-neoplastic conditions (n=5) was performed using cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq). Methylation quantification was estimated for each genomic region. Significance testing was performed between diagnostic groups to discover differentially-methylated regions (DMRs). The 300 most differentially-methylated regions (DMRs) for each comparison (IDH-wildtype vs. IDH-mutant, IDH-mutant vs. control, IDH-wildtype vs. control), for a total of 900 DMRs, were utilized as features in dimensionality reduction analysis and machine learning. Out of ~1×107 defined genomic regions, there were ~7×105 DMRs between GBM and control samples and ~1.5×106 DMRs between GBM and IDH-mutant samples, accounting for ~7% and ~15% of the genome, respectively. Uniform manifold approximation and projection (UMAP) and hierarchical clustering analysis revealed that samples were mostly clustered by diagnosis. Random forest analysis of the 900 DMRs with an 80/20 train/test split resulted in an overall accuracy of 0.815. In conclusion, CSF cfDNA methylation profiles of diffuse glioma patients exhibit differential methylation patterns between IDH-mutant and IDH-wildtype tumors, as well as between tumor and control, and could be informative biomarkers for the diagnosis of patients with diffuse gliomas.
NCMP-01. EARLY RECURRENCE OF GLIOBLASTOMA MULTIFORM INVOLVING MULTIPLE BRAIN REGIONS ASSOCIATED WITH MUTATIONS IN EXON 4 OF ISOCITRATE DEHYDROGENASE 1 COMPLICATED BY GADOLINIUM-INDUCED ACUTE KIDNEY FAILURE: A CASE REPORT
Authors: Larrey Kasereka Kamabu, Oboth Ronald, Okiror Paul, Doddie Tansya, Serge Ibula, Alain Muka, Marius Kizito Polepole, Sem Mushagalusa Ruhambya, Louange Maha Kataka, Moise Muhindo Valimungighe, Hervé Monka Lekuya, Charles Kahindo Kangitsi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma multiform (GBM) remains one of the most aggressive primary brain tumors with high recurrence rates. Case presentation We present a case of a 43-year-old female, Yira, diagnosed with early recurrence of GBM involving multiple brain regions, accompanied by mutations in exon 4 of isocitrate dehydrogenase 1 (IDH1), a marker associated with poor prognosis. Additionally, this case was complicated by gadolinium-induced acute kidney failure on postoperative day 3. The patient initially presented with progressive neurological symptoms, including headache and cognitive decline. Multiplanar multiecho MRI of the brain was performed with IV contrast in orthogonal plane and revealed a moderate sized multilobulated heterogeneously and predominantly peripherally enhancing mass lesion with irregular margins and central non enhancing areas of necrosis arising from the right corona radiata, insular cortex, external capsule, lentiform nucleus, temporal, and frontal white matter with blood products. Perilesional edema was seen. Effacement of sulcal spaces. Right sylvian fissure, compression over right ventricle and midline shift of 8mm toward left side. There was dilatation of the left lateral ventricle with periventricular cerebrospinal fluid ooze. Uncal herniation was right side. On MR spectroscopy large choline, creatinine levels were seen in the lesion with reduced N-acetyl aspartate levels as compared to the normal parenchyma. Findings were suggestive of neoplastic lesion mostly high-grade glioma. Polymerase chain reaction sequencing confirmed missense mutation R132H in exon 4 of isocitrate dehydrogenase 1 gene. Despite maximal safe surgical resection, the patient developed recurrent GBM within three months, with gadolinium-based contrast agent exposure leading to acute kidney injury. CONCLUSION The combination of aggressive tumor behavior and complications from contrast agent administration highlights the challenges in managing recurrent GBM. This case underscores the importance of vigilant monitoring for complications in GBM patients, particularly those with IDH1 mutations, and the need for further research into novel therapeutic strategies.