tbuckley/cabot-search huggingface dataset:
RADT-06. IDENTIFICATION OF NEW RADIATION RESPONSE PREDICTOR GENES FOR GLIOBLASTOMACRUCIAL CONTRIBUTION OF THE LUNATIC FRINGE GENE (LFNG)
Authors: Asmaa Naim, abdallah baddou
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is adults’ most common aggressive primary intracranial tumor. The current standard of care involves maximal safe surgery followed by radiochemotherapy. OBJECTIVE our study was to identify genes that predict response to radiochemotherapy. MATERIALS AND METHODS We collected molecular and clinical data, including primary glioma mRNA expression, from two international online databases - TCGA and CCGA. A total of 76 cases were examined, with 41 patients in the TCGA cohort and 35 in the CCGA cohort. The patients were divided into two groups before assessing the data. Group 1 included patients who were alive at the time of the analysis, and Group 2 included patients who had passed away. Then, we performed a single-center Moroccan transcriptomic study involving 28 cases to assess the impact of the individualized gene in our environment. RESULTS The following genes, namely SRPX, S100A16, LFNG, CD5, CMBL, and TCTN2, are among the top genes co-overexpressed in TCGA and CGGA patients. We conducted a multivariate COX survival test, taking into account known prognostic clinical parameters, and found that the LFNG gene is the only marker of poor prognosis independent of other clinical markers in TCGA and CGGA patients treated with radiotherapy. Our results indicate that patients who overexpress LFNG have elevated IFNg levels and low granzyme B levels, while the levels of perforin and granzyme A remain unaffected by LFNG variation. Furthermore, our results demonstrate positive correlations between LFNG gene expression and four immune checkpoints (PD1, PDL1, CTLA4, and VISTA), but negative correlations only with TIM3. CONCLUSION Our findings suggest that LFNG could serve as a useful biomarker for identifying patients with poor prognosis and that LFNG expression may be associated with specific immune checkpoint expression patterns. These results have important implications for the development of new therapeutic approaches in the treatment of TCGA and CGGA patients.
CTNI-59. TUMOUR VOLUMES PREDICT PROGNOSIS AND RESPONSE TO TREATMENT WITH DEPATUXIZUMAB MAFADOTIN
Authors: Hui Gan, Eddie Lau, Sze Ting Lee, Sruti Pillai, Thierry Gorlia, Martin van den Bent, Andrew Scott
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Preclinical data demonstrates that tumor volumes predicted response to the anti-EGFR ADC Depatuxizumab mafadotin (Depatux-M) because of reduced drug delivery in large tumors. We investigated the impact of tumor volumes on outcomes with Depatux-M in the EORTC randomized phase 2 Intellance 2 study on recurrent glioblastoma (NeuroOncol 22(5):684). METHODS 260 patients were randomized to Depatux-M, Depatux-M with temozolomide, or control treatment (lomustine/temozolomide). Manual segmentation of enhancing tumor on baseline MRI scans was performed and compared with OS and PFS using SPSS Version 29.0: Kaplan-Meier survival analysis including log rank test and Cox regression analyses; categorical data were compared with Fishers’ exact test; correlation between 2D and 3D measurements with Pearson’s correlation. RESULTS MRI scans and data from 240/260 (92%) patients were available. Firstly, we confirmed that tumor volumes were a significant prognostic variable. Significant differences were seen in OS between the 0-20 vs 20-40 ml groups (321 vs 216 days, p&amp;lt;0.001) and between the 20-40ml vs 40+ groups (216 vs 150 days, p&amp;lt;0.001) with corresponding differences in PFS. Tumor volumes were also predictive of benefit from Depatux-M, with only patients with smaller tumors benefiting from Depatux-M. Patients in the 0-20 ml and 20-40 ml group group had superior OS when treated with Depatux-M compared to controls (356 vs 309 days, p=0.011 and 229 vs 178 days, p=0.028 respectively). Conversely, the 40 ml + group had no benefit (146 vs 152 days, p=0.875) as predicted. The benefit was maximal in the combination arm, with OS improvement in the 0-20 ml group (437 vs 309 days, p=0.007) and 20-40ml groups (225 vs 178 days, p=0.009). The impact of tumor volumes was confirmed in multi-variate analysis and superior to similar analysis with 2D RANO measurements. CONCLUSIONS Tumor volumes are an important prognostic variable in recurrent glioblastoma and modulate survival to large molecules like Depatux-M.
TMOD-30. DISRUPTION OF NORMAL RADIAL GLIA DEVELOPMENT IN AN NF2-ALTERED NEUROEPITHELIAL STEM CELL MODEL
Authors: Noah Burket, Victoria Dershem, Shelley Dixon, Scott Cooper, Steve Angus, Wade Clapp, Jignesh Tailor
Journal: Neuro-Oncology (2024)

Abstract NF2-related schwannomatosis is a tumor predisposition syndrome caused by mutations in the NF2 gene and associated with spinal ependymomas (SP-EPN). SP-EPNs are suspected to originate from aberrations in the radial glia (RG) cell lineage. These tumors are only effectively treated through high-risk surgical resection, emphasizing the critical need for identification of targets for medical therapy. Yet, the role of NF2-dependent disruption in RG cell development is poorly understood. We hypothesize that this mutation may be halting normal RG cell differentiation, resulting in a RG-like stem cell that is driving SP-EPN formation. An NF2-knockout was generated in neuroepithelial stem (NES) cells using CRISPR/Cas9. Knockouts were validated using Western blot and Sanger sequencing. In vitro differentiation was induced with removal of growth factors. NF2-knockout phenotypes were assessed with real-time polymerase chain reaction and compared with wildtype NES cells. Preliminary data has shown that NF2-knockout cells express similar levels of early pan-neural and neural stem cell genes compared to wildtype after CRISPR editing. The NF2-knockout cells retain this stem cell-like gene expression following attempted differentiation, whereas wildtype cells take on a primarily neural phenotype. The knockout cells also form what appears to be pre-neoplastic spheres when allowed to differentiate. NF2-knockout NES cells fail to differentiate normally compared to wildtype NES cells. They retain early RG-like markers, including SOX2, BLBP, and GFAP. Furthermore, formation of spheres when growth factors were removed hints at NF2 loss being relevant to formation of pre-neoplastic growths. Future work will include investigating downstream effects of NF2 loss in this model.
STEM-15. THE IMPACT OF TUMOR TREATING FIELDS (TTFIELDS) ON CANCER STEM-LIKE CELLS ISOLATED FROM THE SUB-VENTRICULAR ZONE OF GLIOBLASTOMA PATIENTS
Authors: Yamhilette Licón Muñoz, Rachel B Sidebottom, Samantha Varela, Christian A Bowers, Sara G M Piccirillo
Journal: Neuro-Oncology (2024)

Abstract Treatment of glioblastoma (GBM) is challenging due to its heterogeneous nature, invasive potential, and poor response to standard-of-care treatments. Areas of residual disease represent the source of the recurrent tumor that is fatal for GBM patients. However, targeting the residual disease is not offered as part of the standard of care because these areas are difficult to identify. Our laboratory was the first to identify and characterize residual disease in the sub-ventricular zone (SVZ) of the lateral ventricles of GBM patients. In this study, we are examining the impact of Tumor Treating Fields (TTFields) on treatment-resistant cancer stem-like cells (CSCs) isolated from the SVZ of 12 GBM patients using single-cell transcriptomics and functional phenotyping analysis. These cells are maintained in conditions that preserve the molecular profile of the original patient tumor, thus representing bona fide models to study the impact of TTFields on GBM residual disease. Our results show that: CSCs isolated from the SVZ from different individuals show different sensitivity to TTFields, the anti-proliferative effects of TTFields are maintained at different plating cell densities, and when the frequency of TTFields increase from 50 kHz to 200 kHz, CSCs undergo morphological changes (e.g., fewer spheres and fewer connections between cells). We used 100 μM Temozolomide and ionizing radiation (10 Gy) mimicking the standard of care of GBM patients, and the growth of the treatment-resistant CSCs was inhibited by TTFields (200 kHz). To elucidate how TTFields impact the cellular and molecular characteristics of CSCs in their microenvironment, ongoing work focuses on single-cell transcriptomics and functional phenotyping analysis. These results extend our understanding of the mechanisms of action of TTFields, specifically on how TTFields have the potential to alter the cytokine-mediated cross-talk between CSCs of the SVZ and their microenvironment.
RADT-11. FACTORS ASSOCIATED WITH LOCAL FAILURE AFTER STEREOTACTIC RADIATION TO THE SURGICAL BED OF BREAST CANCER PATIENTS WITH A SINGLE BRAIN METASTASIS
Authors: Ory Haisraely, Alicia Taliansky, Orit Person Kaidar
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Metastatic breast cancer is the second most common cancer associated with brain metastases (BCBM). In our study we evaluated variables that influence local control in this breast cancer patients with a single BCBM who underwent surgical resection and stereotactic radiation to resection cavity. METHODS After ethics approval, we conducted a retrospective review of the medical records of BCBM patients treated with stereotactic radiation for BCBM between 2011 to 2022. Only breast cancer patients with a single BCBM who underwent surgical resection and stereotactic radiation to the surgical cavity were included. Clinical and dosimetric variables were analyzed to evaluate their impact on local control. Statistical analysis included descriptive analyses. X2 test was used for categorical variables. Total dose, dose per fraction, biologically effective dose (BED), and planning target volumes were analyzed as both continuous and categorical variables at different thresholds. A binary regression model was applied to study variables shown to impact local control. RESULTS A total of 62 patients included local control was 70.9% at 12 months. HER-2 disease, luminal-B, size of BCBM, time from craniotomy, total dose, inclusion of corridor, and non-cystic lesion were significant for local control. CONCLUSION Our data supports previous publications about the importance of tumor bed delineation, dose and fractionation, and time from craniotomy as factors associated with better local control. Our study shows that the role of BCBM subtype and new systemic therapies in contributing to local and intracranial control should be further explored.
PATH-64. UNDERSTANDING MECHANISTIC UNDERPINNINGS OF MOLECULAR SUBGROUPS OF MENINGIOMA
Authors: Vijay Nitturi, Sean Lau, Elizabeth Ledbetter, Shervin Hosseingholi Nouri, Tiemo Klisch, Akash Patel
Journal: Neuro-Oncology (2024)

Abstract Meningiomas are the most common intracranial tumors. In the past, they were thought to be indolent and could be treated by resection. The current standard of care utilizes WHO histopathological grading to identify malignant potential. Our lab identified three molecular groups (MenG A, B, and C) using CNVs, methylation, and/or expression profiling with different biological characteristics. These groups were independently validated and predicted recurrence more reliably than WHO grade. MenG A is genomically stable but harbors tumors with point mutations, mainly in TRAF7, KLF4, and AKT1. On the other hand, MenG B and C tumors have chromosome 22q arm deletion or loss of merlin, the protein product of the NF2 gene. Moreover, MenG B is characterized by DNA hypomethylation, while MenG C tumors show DNA hypermethylation and have additional chromosomal losses, most notably in chromosome 1p. Lastly, while MenG A/B are indolent, MenG C – comprising approximately 28% of meningiomas – recur frequently and are refractory to radiotherapy and/or surgery. How can two groups of tumors with the same driver mutation behave so differently? Hence, our lab is interested in (1) what molecular pathway/factor(s) are necessary for becoming any meningioma, and (2) what mechanisms are critical for the aggressiveness of MenG C. Here, we investigate the role of TRAF7 in meningioma biology. Toward this end, we study interactors, modulators, and individual mutations in cell culture. In addition, we use published exome sequencing and expression data to reveal possible connections between chromatin state and individual genes. In conclusion, a variety of underlying mechanisms drive meningioma tumorigenicity and aggressiveness. Elucidating these mechanisms could provide future therapeutic targets for currently untreatable meningiomas.
IMMU-21. OVEREXPRESSING CAR T-CELL GLUCOSE TRANSPORTER TO ENHANCE ANTI-TUMOR ACTIVITY IN GLIOBLASTOMA
Authors: Srabasti Sengupta, Linchun Jin, Diana Feier, Aryeh Silver, Avirup Chakraborty, Haipeng Tao, Nagheme Thomas, Maryam Rahman, Catherine Flores, Paul Castillo, Matthew Sarkisian, Jianping Huang, Duane A Mitchell, Loic P Deleyrolle
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Despite aggressive interventions, Glioblastoma (GBM) remains as a challenge for neuro-oncologists. Standard treatments are often followed by disease recurrence. Adoptive cell therapies have emerged as a viable therapeutic for brain malignancies. CAR-T cell therapy has generated substantial interest because of its efficacy and specificity in treating various cancers. Despite these efficacies, studies reveal limitations of CAR-T therapy due to the altered metabolic environment in GBM. GBM tumors shift towards aerobic glycolysis, regardless of oxygen availability leading to massive glucose consumption. This results in impeding T-cell glycolysis and activation. OBJECTIVE The GBM microenvironment provides local restraints via metabolic competition suppressing antitumor immunity, specifically inhibiting infiltration and tumoricidal functions of host and adoptively transferred tumor-reactive T-cells. In our study, we manipulated the metabolic fitness of the therapeutic T-cells to enhance their tumoricidal activity, by overexpressing glucose transporter GLUT1 and GLUT3. We show that this manipulation can enhance their anti-tumor activity. METHODS The T-cell glucose metabolic pathway was modulated via glucose transporter overexpression. The functionality of metabolically modified T-cells was investigated in murine and human models. RESULTS We demonstrated that tumor cells impose glucose restriction when competing for glucose with T-cells leading to T-cell hypo responsiveness. Overexpression of glucose transporters such as Glut1 and Glut3 increased T-cell glucose utilization and provide survival advantage leading to enhanced T-cell activation in glucose-restricted conditions. The metabolic modifications regulate T-cell efficacy by enhancing intra-tumoral trafficking. We tested this approach in the context of CD70CAR T cell therapy. It was established that glucose transporter overexpression in CD70 CAR T-cells not only improves intracranial tumor invasion but also elicit functional anti-tumor cell response thus improving survival. CONCLUSIONS This study integrates fundamental concepts of tumor and immune metabolism in the design of immunotherapy and confirms that immunometabolism represents a viable target for new cancer therapy to treat brain tumors.
QLTI-19. PEDIATRIC NEURO-ONCOLOGISTS NAVIGATING AN ADULT WORLD: A TALE OF TWO CENTERS
Authors: Bradley Gampel, Ruham Alshiekh Nasany, Colin Hill, Marina Kushnirsky, Dalissa Tejera, Thiago Muniz, Macarena De La Fuente, Julie Bennett
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Adolescent and Young Adult Neuro-Oncology(AYA-NO) patients are a distinct cohort with an overlap of tumors found in childhood and adulthood. For adult patients with pediatric-type Central Nervous System tumors, optimal work-flow to manage these patients is unclear. METHODS We examine the work-flow of pediatric neuro-oncologists starting AYA-NO clinics within two high volume adult institutions: the University of Miami(Florida, USA) and the Princess Margaret Cancer Centre(Toronto, Canada). RESULTS Over 18 months, the AYA-NO clinics managed 167 patients total with several key differences emerging in both institutions between the pediatric and adult work-flows. Adult providers commonly have neurology backgrounds, while pediatric providers mostly have hematology/oncology backgrounds. In pediatrics, providers typically meet the patient inpatient before pathology results, adult providers meet their patients in outpatient settings once histopathology results are available. Outpatient management in pediatric oncology centers typically includes labs, infusion centers, provider rooms, and social workers in one area while adults, due to the larger volume, have these services on separate units. Chemotherapy related differences included the primary provider for inpatient admissions and the emphasis of adult institutions on outpatient administration when feasible. Psychosocial factors such as the variety of caregivers, increased opportunity for patient autonomy in decision-making, and the increased fragmentation in care magnifies the importance of providers forming a strong rapport with AYA-NO patients. End of life care is vastly different including the inability for adult patients to receive palliative treatment in hospice care and the availability medically-assisted death. CONCLUSION Pediatric neuro-oncologists building AYA-NO workflows within adult settings can provide unique expertise for AYA-NO patients with pediatric-type tumors. Growing AYA-NO clinics can benefit from allocating AYA CNS specific resources such as chemotherapy/targeted therapy provider education, a dedicated hospital/clinic space, chemotherapy nursing, a care coordinator, and a social worker with experience treating this patient population.
EPID-35. COLLISION TUMORS AT THE SKULL BASE: UNVEILING A PETROCLIVAL MENINGIOMA COEXISTING WITH A GROWTH HORMONE-PRODUCING PITUITARY ADENOMA
Authors: Yoon Choi, Frank Hsu, Jenny Dai-Ju, Edward Kuan, Vivek Patel
Journal: Neuro-Oncology (2024)

Abstract Collision tumors are rare occurrences characterized by coexistence of two histologically different tumor types within the same anatomical location. While collision tumors involving skull base meningiomas and pituitary adenomas are uncommon, they pose distinct diagnostic challenges. We report the case of a 57-year-old female initially diagnosed with petroclival meningioma WHO 1, subsequently found to harbor a collision tumor with a growth hormone-producing pituitary adenoma. The patient initially presented with aphasia, right-sided weakness, and gait instability, prompting a diagnosed of left petroclival mass with left temporal horn entrapment. Patient underwent craniotomy and partial resection of the tumor in 2022 and was diagnosed with meningothelial meningioma, WHO1. The patient had history of uncontrolled diabetes and physical features of large hands with hypertrophied terminal phalangeal tufts but patient reported that she has had similar hands since childbirths for decades. Screening pituitary function tests were ordered due to the petroclival meningioma involving suprasellar region, revealing significantly elevated growth hormone, and insulin-like growth factor-1(IGF-1) levels, raising suspicion for pituitary adenoma. Subsequent endoscopic resection of the sellar mass via a transsphenoidal approach in 2024 confirmed the presence of somatotroph pituitary neuroendocrine tumor. Retrospectively growth hormone producing pituitary adenoma likely contributed to patient’s uncontrolled diabetes and coarse, large hands. This case highlights the importance of a high index of suspicion for collision tumors, particularly in patients with skull base tumors involving supra sellar region, especially when presenting with atypical clinical features.
CTNI-71. RELA FUSION-POSITIVE EPENDYMOMA, DIFFUSE MIDLINE GLIOMA AND GRADE 4 IDH MUTANT ASTROCYTOMA TREATED WITH VAL-083 UNDER EXPANDED ACCESS: CASE REPORTS
Authors: Carlos Kamiya-Matsuoka, Shaio-Pei Weathers, Stephanie Knight, Teresa Hanna, John Langlands, Dennis Brown, Vinay Puduvalli
Journal: Neuro-Oncology (2024)

Abstract RELA fusion-positive ependymoma is associated with supratentorial location, higher WHO grade and poor prognosis. Diffuse Midline Glioma (DMG) is a relatively rare CNS tumor, originating in the midline location of the brain. Surgical intervention is restricted to biopsy and radiation. Grade-4 astrocytoma, is highly aggressive with rapid progression. Standard treatment includes surgery and radiation therapy, with limited systemic options other than clinical trials for recurrent disease. VAL-083 is a DNA-targeting agent which rapidly induces inter-strand DNA cross-links at O6- and N7-guanine inducing double-strand breaks causing cell death and acts independent of MGMT DNA repair in high-grade gliomas. We report on 4 patients who had recent disease progression and unmethylated MGMT promoter status treated with VAL-083 under an expanded access program: Case #1: a 47-yo male diagnosed with IDHwt, RELA fusion-positive ependymoma. Case #2: an 18-yo male diagnosed with IDHwt, MAP2K1 and RELA fusion-positive ependymoma. Case #3: a 25-yo male diagnosed with IDHmut Grade 4 astrocytoma, with ATRX, INPP4A, RET and TP53 mutations. Case #4: a 21 yo male diagnosed with IDHwt DMG of the brain stem. All patients had multiple recurrences, received radiation and multiple systemic treatment regimens. They received VAL-083 (30 mg/m2 for 3 days every 21 days) under an expanded access program. Patients with ependymoma received 6 and 5 cycles of VAL-083, (case 1 and 2, respectively), while the patients with IDHmut Gr 4. astrocytoma and DMG received 5 and 18 cycles of VAL-083, respectively. No adverse events were reported and no dose reductions were required. These cases highlight that VAL-83 may be a treatment option for recurrent RELA fusion-positive ependymoma, Gr4. IDHmut astrocytoma, and DMG refractory to other treatment regimens. Additional outcomes related to these cases will be presented at the meeting. Clinicaltrials.gov Identifier: NCT03138629. The treatment plans for the EA patients were approved by MD Anderson Cancer Center IRB