tbuckley/cabot-search huggingface dataset:
STEM-04. UNVEILING GLIOBLASTOMA ORIGIN-CELLS: ISOLATION AND CHARACTERIZATION FROM THE SUBVENTRICULAR ZONE
Authors: Ran Joo Choi, Se-Young Jo, Eunchae Yeo, Hyeong-Cheol Oh, Euna Jo, Jin-Kyung Shim, Hyun Jung Kim, Joo Ho Lee, Jihwan Yoo, Seonah Choi, Ju-Hyung Moon, Eui-Hyun Kim, Se Hoon Kim, Jong Hee Chang, Hyun Seok Kim, Jeong Ho Lee, Hoon Kim, Sangwoo Kim, Seok-Gu Kang
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) may originate from somatic mutations within the subventricular zone (SVZ). We investigated putative GBM origin-cells in the SVZ with somatic mutations implicated in GBM development. We hypothesized these origin-cells have unique properties compared to tumor-derived GBM tumorspheres (TSs). We isolated, characterized, and analyzed mouse transcriptomes of GBM origin-cells and GBM TSs, and sought to identify potential human GBM origin-cells within the SVZ. Using a mouse model with somatic mutations (Trp53/Pten/hEGFRvIII) induced within the SVZ, we demonstrated that mutated cells in the SVZ migrate to the cortex and form GBM. We isolated mouse GBM (mGBM) origin-cells from the SVZ and mGBM TSs from the tumors, comparing their characteristics, transcriptome, and tumorigenic potential upon orthotopic or SVZ injection. To identify potential human GBM origin-cells, single-nucleus RNA sequencing (snRNAseq) was performed on human GBM SVZ specimens. Our investigation revealed intriguing properties and distinct gene expression patterns in GBM origin-cells. mGBM origin-cells from the SVZ somatic mutation model demonstrated enhanced stemness and invasiveness compared to control SVZ cells. These cells exhibited site-specific tumorigenic capacity: cortical injection of mGBM origin-cells failed to induce tumor formation, while re-injection into the SVZ led to migration to the cortex and tumor development. RNA sequencing revealed significant gene expression differences between mGBM origin-cells and mGBM TSs despite similar mutation profiles, suggesting distinct identities. snRNAseq analysis of human GBM SVZ specimens (pathologically tumor-free) identified cells with chromosomal aberrations characteristic of early GBM development, including chromosome 7 gain / 10 loss. These findings suggest potential human GBM origin-cells within the SVZ. This study describes a distinct population of GBM origin-cells within the SVZ, different from tumor-derived cancer stem cells. These GBM origin-cells exhibit unique properties, including enhanced stemness and invasiveness, and display site-specific tumorigenic capacity, forming tumors only in the SVZ environment. Further research into the factors that cause GBM origin-cells in the SVZ to migrate and form tumors in the cortex is crucial.
NCOG-50. LONG TERM-SURVIVAL OF AN ELDERLY PATIENT WITH GIANT CELL CEREBELLUM GLIOBLASTOMA (GBM)
Authors: Chunxiao Ma, Yoon Jae Choi, Jerica Lomax, Uvin Ko, Dan Beverly Fu, Joon Myung, Xiao-Tang Kong
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Primary cerebellar glioblastoma (GBM) in adult is very rare and accounts for 1% of all GBM. Giant cell variant cerebellar GBM is even rarer. Because of the rarity, its molecular feature, the response to the standard treatment, and biological behavior of tumor progression are not well understood. CASE REPORT An 80 yo male presented with headache, nausea, vomiting and ataxia in 2019. Brain MRI was notable for a large enhancing cerebellar mass. Surgical resection was completed, and pathology was giant cell GBM. Molecular studies showed IDH-wildtype, CDKN2A/B copy number loss, positive TP53 G262V mutation as well as KIT and KDR amplification. The patient underwent standard 6-week concomitant temozolomide (TMZ) and radiation therapy. He only completed 3 cycles of low dose adjuvant temozolomide and two cycles of lomustine due to intolerance of both chemotherapy agents. After that the patient has been off treatment and received brain MRI surveillance over past 4 years. Two years later, his brain MRI showed new punctuate lesions in the radiation field. Suspecting the radiation necrosis; the patient underwent observation. Later, more nodular enhancing lesions developed at the outside region of the radiation field. Tumor progression was considered but the patient wished no biopsy or re-radiation. The new small nodular lesions on MRIs over past two years have behaved unusually with small fluctuations among mild progression, stabilization, or regression. His physical functions have been preserved with a Karnofsky Performance Status scale of 90% with normal cognition. DISCUSSION The patient, who is now 85 years old, has surpassed a 4.5-year survival mark, which is remarkable compared to the supratentorial and the cerebellar GBM with a few months’ survival mark in elderly patients. Our experience emphasizes the different behavior (good response) of a very rare giant cell cerebellar GBM to the standard treatment for newly diagnosed GBM.
CSIG-26. TARGETING EPIGENETIC DYSREGULATION AND ADAPTIVE RESISTANCE MECHANISMS IN DIPG/DMG
Authors: Eric Xin, Xiaowen Zhong, Chris Huang, Richard Lu
Journal: Neuro-Oncology (2024)

Abstract Diffuse intrinsic pontine gliomas (DIPG/DMG) are devastating pediatric brain tumors with very limited treatment options and a uniformly fatal prognosis. The recurrent histone H3K27M mutation in DIPG disrupts epigenetic regulation, leading to the hypothesis that this mutation-induced dysregulation creates a vulnerability to epigenetic targeting. We conducted a screening of compounds targeting epigenetic enzymes to identify potential inhibitors of patient-derived DIPG cell growth. High-throughput screening identified chaetocin, a fungal metabolite, as a potent inhibitor of DIPG cell growth. Chaetocin treatment selectively decreased proliferation and increased apoptosis in DIPG cells, significantly extending survival in DIPG xenograft models while restoring H3K27me3 levels. The loss of the H3K9 methyltransferase SUV39H1 also inhibited DIPG cell growth. Transcriptomic and epigenomic profiling showed that SUV39H1 loss or inhibition downregulated stemness and oncogenic networks, including growth factor receptor signaling. However, D2 dopamine receptor (DRD2) signaling adaptively upregulated, conferring resistance. Combining chaetocin with the DRD2 antagonist ONC201 or radiotherapy synergistically enhanced antitumor efficacy. This study reveals a therapeutic vulnerability in DIPG cells by targeting the SUV39H1-H3K9me3 pathway and compensatory signaling loops. Combining SUV39H1-targeting chaetocin with other agents, such as ONC201, may offer a new strategy for effective DIPG treatment. The findings suggest that chaetocin, by targeting and suppressing the H3K9me3 methyltransferase SUV39H1, inhibits DIPG tumor growth by downregulating stemness-related genes and growth factor signaling pathways. Overall, the study highlights a new therapeutic vulnerability in DIPG through the SUV39H1-H3K9me3 epigenetic pathway and compensatory signaling loops, suggesting an effective treatment strategy for DIPG.
SURG-45. OUTCOMES OF PATIENTS RECEIVING SURGICAL RESECTION AND STEREOTACTIC RADIOSURGERY VS. STEREOTACTIC RADIOSURGERY ALONE FOR MOTOR CORTEX METASTASES
Authors: Ryan Juncker, Guilherme Finger, Matthieu Weber, Kyle Wu, Mark Damante, Daniel Kreatsoulas, James Bradley Elder
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Local therapy for brain metastases typically involves stereotactic radiosurgery (SRS), with surgical resection considered for larger and/or symptomatic tumors. For lesions in eloquent areas, surgical management is controversial given the risks of neurologic deficits. This study compared clinical outcomes in patients with motor cortex metastases who received surgery + SRS or SRS alone. METHODS Patients treated for motor cortex metastases from 1/2018 – 12/2022 were identified. Demographic/preoperative variables included age, gender, race, tumor histology, adjuvant therapies, pre-treatment neurological exam, and Karnofsky Performance Scale. Treatment variables included the number of brain metastases, maximum tumor diameter, and radiation dose/number of fractions. Outcome measures included post-treatment neurological exam, seizures, and overall survival (OS). RESULTS 351 charts were identified – 80 surgery + SRS and 271 SRS alone. 50 consecutive patients in each group were included in this analysis. Surgery + SRS patients were younger (59.0 vs. 63.9; P=0.020) with larger tumors (2.8 vs. 0.83cm; P&amp;lt;0.001), while the SRS only group had more brain metastases per patient (2 vs. 6; P&amp;lt;0.001). No differences were seen in the remaining demographic/preoperative variables. Pre-treatment, surgery + SRS patients had significantly increased frequency (45/50, 90% vs. 25/50, 50%; P&amp;lt;0.001) and severity (4 vs. 5; P=0.001) of motor deficits, and a higher likelihood of seizures (25/50, 50% vs. 8/50, 16%; P&amp;lt;0.001). Despite the surgery + SRS group being more symptomatic pre-treatment, the frequency and severity of motor deficits and seizures was similar between cohort’s post-therapy. Surgery + SRS patients also demonstrated higher rates of pre- to post-treatment improvement in motor function (29/45, 64% vs. 3/25, 12%; P&amp;lt;0.001) and longer OS from the date of treatment (7.5 vs 4 months; P=0.021). CONCLUSION Given the equivalent neurological outcomes, higher rates of functional improvement, and improved oncologic outcomes, surgery should be a consideration for patients with brain metastases in eloquent areas, particularly those with symptomatic lesions.
SURG-53. LONG TERM FOLLOW-UP OF RESECTION PLUS CESIUM-131 BRACHYTHERAPY FOR PREVIOUSLY IRRADIATED RECURRENT BRAIN METASTASES
Authors: Irini Yacoub, Robert J Young, Anne S Reiner, Alexandra Gantini-Larsen, Yoshiya Yamada, Luke R G Pike, Simone Krebs, Antonio Damato, David Aramburu-Nunez, Kenny Kwok Hei Yu, Cameron Brennan, Viviane Tabar, Nelson S Moss, Brandon S Imber
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Recurrent brain metastases (rBM) after previous radiosurgery present a clinical dilemma, as the advantages of reirradiation need to be weighed against the potential of significant radiation toxicity. Salvage resection with Cs-131 brachytherapy offers improved dosimetry due to reduced integral dose to healthy brain compared to repeat radiosurgery. We previously reported initial results of rBM treated with resection and salvage Cs131 brachytherapy; we present an updated analysis of tumor control with extended follow-up. METHODS We analyzed consecutive patients with rBM previously treated with radiosurgery, who underwent salvage resection plus implantation of Cs131 seeds (GammaTile, GT Medical Technologies). The prescribed brachytherapy dose was 60 Gy at 5mm from the cavity. Median follow-up was calculated using reverse Kaplan-Meier. Local recurrence was defined by new nodular contrast enhancement with hyperperfusion within 5mm of the resection cavity. Marginal recurrence was defined as &amp;gt;5mm but not beyond 1cm from the cavity. Local control and overall survival (OS) from brachytherapy were analyzed using Kaplan-Meier. RESULTS Twenty-five patients underwent Cs131 implantation in 30 tumor cavities. The median presurgical rBM maximal diameter was 2.95 cm (range 1.1-6.3). The most common histology was lung adenocarcinoma (n=8, 27%) followed by breast (n=7, 23%) and renal cell (n=3, 10%). Radiographic gross- or near-total resection was achieved in 80% of lesions. The median number of Cs131 seeds implanted was 17, (range 6-30), (median strength 3.5 U/seed). With median follow-up of 37 months (95%CI:29-45), twelve and 24-month OS was 55% and 41%, respectively. Four tumors recurred (3 in-field, one marginal) for a 1- and 2-year local control rate of 87% and 81%, respectively. Data for adverse radiation effects is under analysis and will be presented. CONCLUSIONS With over 3 years of follow-up, intraoperative brachytherapy with collagen-embedded Cs131 implants was associated with durable local control for this challenging clinical scenario. A randomized Phase II trial of Cs131 vs. standard of care for rBM (NCT04690348) is actively accruing.
NCOG-05. HEALTH-RELATED QUALITY OF LIFE (HRQOL) IN THE PHASE 2 FIREFLY-1 (PNOC026) TRIAL OF THE TYPE II RAF INHIBITOR TOVORAFENIB IN RELAPSED/REFRACTORY (R/R) PEDIATRIC LOW-GRADE GLIOMA (PLGG)
Authors: John (Devin) Peipert, Patricia A Baxter, Sandie Yu, Nina Oestreicher, Susan Zelt, Pablo Hernáiz Driever, Simon Bailey, Geoffrey McCowage, David S Ziegler, Olaf Witt, Hyoung Jin Kang, Timothy E Hassall, Jung Woo Han, Andrea T Franson, Michal Yalon Oren, Helen Toledano, Valérie Larouche, Mohamed S Abdelbaki, Nada Jabado, Nicholas G Gottardo, Nicolas U Gerber, Nicholas S Whipple, Devorah Segal, Susan N Chi, Liat Oren, Enrica E K Tan, Sabine Mueller, Lindsay B Kilburn, Karsten Nysom, Dong-Anh Khuong-Quang, Daniel B Landi, Jasper van der Lugt, Sarah E S Leary, Sébastien Perreault, Angela J Waanders, Darren Hargrave, Cassie Kline, Chris McKenna, Peter Manley, Sandya Govinda Raju, Jordan R Hansford
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Despite favorable long-term survival, ongoing disease and treatment-related morbidity substantially impact the HRQOL of patients with pLGG. Tovorafenib is a selective, CNS-penetrant, type II RAF inhibitor. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) showed clinically meaningful responses and a manageable safety profile in pLGG. Vision remained stable or improved in 89% of evaluable patients with optic pathway gliomas (Nysom K, et al. Neuro-Oncol. 2023). METHODS FIREFLY-1 arm 1 patients 6 months–25 years of age with RAF-altered r/r pLGG received tovorafenib 420 mg/m2 weekly (600 mg max) in 28-day cycles. Exploratory measures included longitudinal assessment of PedsQL in patients ≥2 years of age. PedsQL 3.0 Cancer Module child self-reports Total Score and 8 subscales were used to assess HRQOL from 0 (worst)–100 (fewer problems/symptoms) (as of December 22, 2022) baseline (BL) to cycle 13 (C13) in patients ≥5 years of age. RESULTS For the PedsQL 3.0 Cancer Module, 51 completed self-reports at BL, and 32 at C13 due to continued attrition over time. Median Total Score was 81.5 (range: 46.3-100) at BL and 85.2 (range: 50-100) at C13. At C4, 16% worsened (decrease &amp;gt;10 points) and 11% improved (increase &amp;gt;10 points); by C13, 11% worsened and 33% improved. For Cognitive Problems, patients scored a median of 75 (range: 5-100) at BL and 85 (range: 20-100) at C13, with 11% and 26% improved at C4 and C13, respectively. A similar trend was seen with Nausea. Pain and Hurt remained even throughout (median: 87.5). Treatment Anxiety was not a major concern (median: 100, C1-C13); Procedural Anxiety improved over time (median: 58.3 BL; 79.2 at C13). CONCLUSIONS HRQOL generally remained stable, or improved, in the majority of patients with r/r pLGG during the first year of treatment with tovorafenib.
CSIG-34. TYROSINE PHOSPHORYLATION OF NON-CANONICAL NF-ΚB P52 PROMOTES GLIOMA GROWTH AND CHEMORESISTANCE IN GBM
Authors: Riley Driscoll, Longtao Wu, Giovanna Bernal, Mahalia Dalmage, Liam Spurr, Bakhtiar Yamini
Journal: Neuro-Oncology (2024)

Abstract p52 is a nuclear factor-κB (NF-κB) transcription factor that comprises the non-canonical NF-κB pathway. The impact and mechanism of non-canonical NF-κB signaling remains understudied in glioblastoma (GBM). Subunit post-translational modification is a known mechanism of NF-κB activation, however phosphorylation of p52 has never been demonstrated. Elevated tyrosine kinase activity is a known-feature of GBM and portends worse survival. Further, p52 has been shown to upregulate factors that likely promote invasion of GBM, thereby reducing survival. Activation of p52 may serve as a link between increased kinase activity and poor survival in GBM. p52-knockout cell lines were generated using the CRISPR-Cas9 system and assessed for growth and survival differences in vitro and in syngeneic murine glioma models. Public glioma datasets and an institutional cohort were surveyed to corroborate p52-dependent survival differences in GBM. To determine whether p52 is post-translationally modified, we performed tandem mass spectrometry on p52 in GBM cells. Interacting factors were also analyzed and tested for site-specific modification of p52 via co-IP studies. We then generated PTM-null, knock-in glioma cell lines using CRISPR-CAS9 editing to demonstrate the functional significance of p52 PTMs, which were assessed using assays of relative cell growth, stemness, chemosensitivity and survival. Finally, we performed unbiased analysis of the p52 PTM-dependent transcriptome via RNA-seq. p52 loss significantly reduced glioma growth rate in vitro and improves murine survival. Retrospective analysis of GBM in patients suggests that p52 levels are negatively prognostic. Mass spectrometry identified multiple p52 PTMs with tyrosine phosphorylation sites as top hits. Identified phospho-tyrosine residues specifically interact with SRC-family kinases. PTM site editing significantly reduces glioma cell growth and stemness while enhancing chemosensitivity, reflecting broad transcriptome level changes. In sum, p52 activity enhances GBM growth and chemoresistance, which is partially modulated by tyrosine-specific phosphorylation. p52 warrants investigation as a therapeutic target in GBM, possibly in combination with kinase inhibitors and standard alkylating chemotherapy.
CSIG-35. RAB3B DICTATES MTORC1/S6 SIGNALING IN CHORDOMA AND PREDICTS RESPONSE TO MTORC1-TARGETED THERAPY
Authors: Tong Meng
Journal: Neuro-Oncology (2024)

Abstract Chordoma is a rare mesenchymal malignancy, exhibiting a high tendency to postoperative recurrence and poor prognosis. To date, its tumorigenic regulatory mechanisms remain elusive leading to a lack of effective therapeutic targets and drug sensitivity indicators. Here, via transcriptome and proteome analyses, we unveiled RAB3B as the prominent oncogenic regulator in chordoma. Multidimensional tissue samples further indicated its overexpression and enhancer-associated high transcriptional activity in chordoma. Notably, RAB3B ablation attenuated the chordoma cell growth, stemness, migration and tumorigenicity in vivo and in vitro. Through determining the RAB3B-mediated program in chordoma, we identified that RAB3B was highly associated with PI3K-AKT-mTOR signaling and directly bound to S6. Mechanistically, RAB3B increased the S6K-mediated phosphorylation of S6 by physically interacting with dephosphorylase DUSP12, to block its dephosphorylating of p-S6 specifically at S235/236. Pharmacological targeting mTORC1 pathway via dactolisib and rapamycin dramatically impeded the RAB3B-induced chordoma cell oncogenesis, while RAB3B knockout desensitized mTORC1 inhibition. Clinically, RAB3B/p-S6 suggested a good prognostic value and response to mTORC1 inhibitors for chordoma patients. Altogether, this work uncovers RAB3B as a novel activator of mTORC1 pathway, and suggests the oncogenic and predictive roles of RAB3B/p-S6 in chordoma, indicating therapeutic potentials of mTORC1-targeted therapy in advanced chordoma patients with aberrant RAB3B/p-S6 hyperactivation.
CTIM-22. MEDIAN AND 2 YEARS SURVIVAL OF NEWLY DIAGNOSED UNMETHYLATED MGMT GLIOBLASTOMA PATIENTS TREATED WITH TEMFERON IMMUNO-GENE THERAPY
Authors: Marica Eoli, Francesca Farina, Valeria Cuccarini, Bernhard Gentner, Matteo Barcella, Elena Anghileri, Maria Grazia Bruzzone, Matteo Carrabba, Quintino Giorgio D’Alessandris, Francesco DiMeco, Valeria Ferla, Alberto Franzin, Paolo Ferroli, Filippo Gagliardi, Francesco Legnani, Alessia Capotondo, Stefania Mazzoleni, Pietro Mortini, Alessandro Olivi, Roberto Pallini, Monica Patanè, Rosina Paterra, Bianca Pollo, Marco Saini, Silvia Snider, Luigi Naldini, Carlo Russo, Fabio Ciceri, Gaetano Finocchiaro
Journal: Neuro-Oncology (2024)

Abstract TEM-GBM is an open-label, Phase 1/2a dose-escalation study aimed to evaluate the safety and efficacy of a myeloid cell-targeted therapy (Temferon) in up to 27 newly diagnosed GBM patients with unmethylated MGMT (uMGMT). Temferon, consists of autologous Hematopoietic Stem Progenitor Cells (HSPCs) genetically modified with a lentiviral vector to deliver IFN-α2 within the tumor microenvironment by Tie-2 expressing macrophages. As of 21st May 2024, 24 GBM patients in 8 cohorts received incremental doses of Temferon and 6 are still alive. For all patients, median overall survival (OS) and median progression free survival reach 17 months and 8.3 months from first surgery, respectively. The interim survival rate at 2 years in Temferon-treated patients is 30% (6 of 20 patients; 3 patients excluded as follow-up is below 1 year). The mOS and the % of patients surviving up to 2 years are currently higher than previously reported for uMGMT patients treated as per standard practice (12.7 months and 14,8%, respectively). Two out of the six patients did not receive any additional treatment lines up to two years after 1st surgery. The other four patients instead received a 2nd treatment line (bevacizumab, regorafenib, Gamma-Knife, metronomic Temozolomide, Lomustine) as per the PI judgment, on average after 443 days from 1st surgery (333 days from Temefron - range 223-1030 days from first surgery). Specifically, Bevacizumab administration started 12 months after 1st surgery for one patient and 19 months for the other 2 patients at 5 mg/kg. The data further confirms the initial evidence on safety and tolerability of Temferon and highlight the potential to prolong the survival of patients affected by uMGMT GBM.
CNSC-61. NEURONAL-ACTIVITY DEPENDENT MECHANISMS OF SMALL CELL LUNG CANCER PATHOGENESIS
Authors: Solomiia Savchuk, Wengang Wang, Kaylee Gentry, Elana Carleton, Carlos Biagi, Belgin Yalçın, Lijun Ni, Hannah Farnsworth, Rachel Davis, Yin Liu, Lehi Acosta-Alvarez, Griffin Hartmann, Elisa Pavarino, Jenna LaBelle, Angus Toland, Pamelyn Woo, Fangfei Qu, Mariella Filbin, Mark Krasnow, Keith Ligon, Julien Sage, Bernardo Sabatini, Michelle Monje, Humsa Venkatesh
Journal: Neuro-Oncology (2024)

Abstract Neural activity is increasingly recognized as a crucial regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth both through paracrine mechanisms and through electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses. Outside of the CNS, innervation of tumors such as prostate, breast, pancreatic, and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression. However, the extent to which the nervous system regulates lung cancer progression, either in the lung or when metastatic to the brain, is less well understood. Small cell lung cancer (SCLC) is a lethal high-grade neuroendocrine tumor that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that SCLC cells in the brain co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. With in vivo optogenetic stimulation, we show that glutamatergic and GABAergic cortical neuronal activity each drive proliferation of SCLC through both paracrine and synaptic neuron-cancer interactions. In the brain, SCLC cells form bona fide neuron-to-SCLC synapses evident on immunoelectron microscopy for the first time for non-brain derived malignancy. Using electrophysiology and two-photon calcium imaging, we find that SCLC cells exhibit depolarizing currents with consequent calcium transients in response to neuronal activity. SCLC cell membrane depolarization is sufficient to promote the growth of intracranial tumors. We also demonstrate reciprocal effects of SCLC on neurons, manifesting as increased neuronal synaptogenesis and elevated field potentials in regions of the tumor. Finally, in the lung, vagus nerve transection markedly inhibits primary lung tumor formation and development and awards survival benefit in spontaneous genetic SCLC model, highlighting a critical role for innervation in overall SCLC growth. Taken together, these studies illustrate that neuronal activity plays a crucial role in dictating SCLC pathogenesis in both the lung and the brain.