tbuckley/cabot-search huggingface dataset:
IMMU-48. CRACKING THE ROLE OF ONCOMETABOLITES IN VIROIMMUNOTHERAPY FOR PEDIATRIC MALIGNANT BRAIN TUMORS
Authors: Marc Garcia Moure, Andres R Lopez-Rivas, Akhila Parthasarathy, Dong Ho Shin, Hong Jiang, Jiasen He, Han Nhat Tran, Kyuson Yun, Reyes Hernandez-Osuna, Marta M Alonso, Timothy N Phoenix, Derek A Wainwright, Juan Fueyo, Candelaria Gomez-Manzano
Journal: Neuro-Oncology (2024)

Abstract Diffuse midline gliomas (DMGs) are among the most frequent and lethal pediatric tumors. The standard of care for DMGs is palliative, resulting in a median survival of 12 months. Viroimmunotherapy is an emerging alternative treatment for these tumors. Our group developed a platform of oncolytic adenoviruses that was translated to the clinic. Specifically, Delta-24-RGD was recently tested in a Phase I clinical trial for patients with newly diagnosed DMG (NCT03178032) with encouraging results. To further stimulate the immune arm of this therapy, we developed Delta-24-RGDOX, expressing the T-cell activator OX40L (NCT03714334, NCT04714983). Using bulk RNAseq, we showed that treatment with Delta-24-RGDOX upregulated the immunosuppressive immunometabolic IDO-AhR pathway. Of importance, treatment with Th1-related cytokine IFNg resulted in the upregulation of IDO1 expression in a panel of human and murine DMG cells. In agreement with these data, we showed synergy between the oncolytic virus and several IDO1-AhR inhibitors in tumor and immune cell co-cultures, as indicated by T-cell activation and proliferation. To further dissect the reshaping of the TME in clinically relevant DMG models treated with Delta-24-RGD or Delta-24-RGDOX, we performed scRNA seq analysis. We showed a pronounced T-cell infiltration in virus-treated animals versus control-treated mice, further confirmed by flow cytometry. Additionally, Th1 and CD8 effector memory subsets were preferentially enriched in the Delta-24-RGDOX group, indicating an enhanced proinflammatory shift. Importantly, we detected, for the first time, upregulation of IDO-AhR downstream effectors in the myeloid compartment in the virus-treated groups. Interestingly, we detected IL4I1 in myeloid cells, a recently discovered checkpoint upstream of AhR never described in the context of virotherapy. Preliminary data using a combination of Delta-24-RGDOX and AhR inhibitors prolongs the survival of glioma-bearing mice. Collectively, our in vivo and in vitro data support the rationale to propel a future clinical trial combining Delta-24-RGDOX with AhR inhibitors for DMG.
NIMG-21. EARLY-STAGE GLIOBLASTOMA AND MOLECULAR ANALYSIS REVEAL THE RADIOLOGICAL INITIATION OF IDH WILDTYPE GLIOBLASTOMA
Authors: Ichiyo Shibahara, Ryota Shigeeda, Yasushi Orihashi, Yoko Tanihata, Kazuko Fujitani, Yuri Hyakutake, Mariko Toyoda, Sumito Sato, Takuichiro Hide, Toshihiro Kumabe
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GB), IDH wildtype, is an aggressive and malignant tumor that necessitate early surgical intervention upon radiological suspicion. Consequently, the natural growth dynamics of GB remain not fully understood. Previous studies have examined GB growth using multiple MRIs between initial radiological diagnosis of GB and preoperative MRI, but these studies have short-term intervals between MRIs (defined as shortGB-cohort). Unless GB growth is a constant phenomenon, shortGB cannot estimate radiological initiation. In this study, we focused on early-stage GB (eGB), characterized by small, nonspecific lesions on MRI that eventually progress to classic GB findings. We compared three cohorts: 49 cases of eGB. 68 cases of shortGBt, and 23 cases of eGB from previous publications (other-eGB). Molecular analyses revealed that TERT promoter mutations, EGFR amplification/gain, CDKN2A hemi/homozygous deletion, and PTEN hemi/homozygous deletion were consistent between eGB and shortGB. Our analysis indicated that the radiological initiation of GB in eGB was -0.84 years (95% confidence interval (CI): -1.09 to -0.68), compared to -0.35 years (95%CI: -0.46 to -0.28) in shortGB. In eGB, factors such as age &amp;lt; 65, MIB1 &amp;gt; 30%, TERTp mutation, and the presence of copy-number alterations (CNA) in EGFR/PTEN/CDKN2A, with or without TERTp mutation, correlated with faster tumor progression. In cases without these alterations, the estimated radiological initiation was -2.31 years (95%CI: -100 to -0.80), indicating slower progression. The ShortGB-cohort did not show any significant changes based on these factors, suggesting it does not actually reflect tumor origin. The other-eGB cohort presented radiological initiation between -0.92 and -0.15 year, consistent with our eGB-cohort. This study investigates the radiological origin of GB using extremely rare cases of eGB, providing insights into the radiological pathophysiology and its association with molecular alterations in IDH-wildtype GB.
IMMU-52. A NOVEL MHC-INDEPENDENT MECHANISM FOR CD8+ T CELL KILLING
Authors: Emily Lerner, Karolina Woroniecka, Daniel Wilkinson, Aditya Mohan, Selena Lorrey, Jessica Waibl-Polania, Lucas Wachsmuth, Alexandra Hoyt-Miggelbrink, Joshua Jackson, Xiuyu Cui, John Sampson, Anoop Patel, Mustafa Khasraw, Michael Gunn, Peter Fecci
Journal: Neuro-Oncology (2024)

Abstract The long-accepted paradigm for both cellular and antitumor immunity relies upon tumor cell kill by CD8+ T cells recognizing cognate antigens presented in the context of target cell major histocompatibility complex class I (MHC I) molecules. Likewise, a classically described mechanism of tumor immune escape is tumor MHC-I downregulation. Here, in contrast to the decades old model of T cell immunity, we instead report that CD8+ T cells maintain the capacity to kill tumor cells that are entirely devoid of MHC-I expression. This capacity proves to be dependent instead on interactions between T cell NKG2D and tumor NKG2D ligands (NKG2DL), the latter of which are highly expressed on MHC-loss variants. Necessarily, tumor cell kill in these instances is antigen-independent, although prior T cell antigen-specific activation is required and can be furnished by myeloid cells or even neighboring MHC-replete tumor cells. In this manner, adaptive priming can beget innate killing. These mechanisms are active in vivo in mice, as well as in vitro in human tumor systems, and are obviated by NKG2D knockout or blockade. These studies challenge the long-advanced notion that downregulation of MHC-I is a viable means of tumor immune escape, and instead identify the NKG2D/NKG2DL axis as a therapeutic target for enhancing T cell-dependent anti-tumor immunity against MHC loss variants.
DDDR-20. CLINICAL EFFICACY OF PYROTINIB COMBINING WITH STEREOTACTIC RADIOSURGERY IN HER2-POSITIVE BREAST CANCER BRAIN METASTASES
Authors: Juanjie Zhen, Shoaib Bashir, Yanying Yang, Hui Wang, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Up to 50% of patients with breast cancer (BC) and human epidermal growth factor receptor 2 (HER2) positive present with disease progression in brain metastases (BM). Pyrotinib, an oral irreversible pan-HER receptor tyrosine kinase inhibitor, has shown efficacy in active central nervous system (CNS) metastases. However, clinical efficacy of pyrotinib combining with stereotactic radiosurgery (SRS) in BCBM is unclear. METHODS This retrospective, observational study collected data from 52 HER2+ BC patients with brain metastasis who received pyrotinib-based therapy in Guang dong Sanjiu brain hospital from 2019 to 2023. Among these patients, 36 received pyrotinib-based therapy combining with SRS concurrently, or within 1 months. Age, stage at diagnosis, dates of BM, primary tumor subtypes, prior systemic therapy, CNS-directed local therapy, the objective response and survival status were collected. The assessment of adverse effects was based on CTCAE 4.0. RESULTS 34 patients were evaluable for efficacy (median age: 51.5). With a median follow-up duration of 19.6 months, 1 patient (0.3%) achieved CR, while 27 patients (79.4%) had PR, resulting in an ORR of 82.3%. The median CNS PFS was 13.2 months (95% CI, 4.9-21.7). Median overall survival (OS) was 22.6 months (95% CI, 17.5-27.6). The most common grade 3 or worse treatment-emergent adverse event was diarrhea (6 [17.6%]). CONCLUSIONS Our results suggest that pyrotinib combining with SRS is associated with promising efficacy and a satisfactory safety profile for Her2+ breast cancer brain metastases.
IMMU-42. UNRAVELING THE ROLE OF NLRX1 IN GLIOBLASTOMA TUMOR MICROENVIRONMENT
Authors: Durgesh meena, Sushmita Rajkhowa, Sushmita Jha
Journal: Neuro-Oncology (2024)

Abstract •Gliomas are primary brain tumors that develop from glial cells within the central nervous system (CNS) and are among the deadliest human cancers. Glioblastoma (GBM) is the most aggressive glioma. Innate immune cells such as microglia and macrophages account for &amp;gt;50% of the cellular population within the GBM microenvironment. Innate immune cells express pattern recognition receptors (PRRs). NLRX1 is a PRR that regulates diverse signaling pathways and cellular processes including antiviral signaling, ROS production, apoptosis, autophagy, metabolic homeostasis, etc. Additionally, the tumor-suppressive and tumor-promoting functions of NLRX1 have been observed in many cancer types. For example, the tumor-suppressive role of NLRX1 has been observed in colitis-associated carcinogenesis, pancreatic cancer, and primary breast cancer. In contrast, the tumor-promoting role of NLRX1 was found in basal-like and metastatic breast carcinoma. Hence, the effect of NLRX1 on cancer may be context-dependent on cancer type or cell type aided by differences in the microenvironment. Further, how NLRX1 regulates GBM pathophysiology remains largely unexplored. This study aims to determine the expression pattern of NLRX1 in GBM cells and GBM-associated innate immune cells and investigate how NLRX1 expression regulates various cellular processes in GBM cell lines to regulate GBM pathophysiology. We report that NLRX1 is differentially expressed in GBM cell lines, GBM-associated innate immune cells, and glioma patient tissues. si-RNA-mediated silencing of Nlrx1 decreases the ability of the GBM cell line, LN-229 to proliferate and migrate. Further, Nlrx1-/- GBM cells show increased tunneling nanotube (TNT) formation capabilities. TNTs help in metabolic homeostasis maintenance by enabling the exchange of subcellular organelles such as mitochondria and endoplasmic reticulum. Nlrx1-/- GBM cells exhibit attenuated ability to form 3D spheroids. This research will aid the understanding of GBM pathophysiology, leading to novel diagnostic/prognostic markers and the discovery of signaling pathways that, in turn, may help create better GBM therapy approaches and improve overall survival.
QLTI-08. PREDICTING POOR HIGH-VALUE CARE OUTCOMES FOLLOWING SURGICAL RESECTION OF MULTIFOCAL GLIOBLASTOMA
Authors: Sachiv Chakravarti, Ritvik Pulya, Atharv Oak, Sruthi Ranganathan, Adrian Jimenez, Debraj Mukherjee
Journal: Neuro-Oncology (2024)

Abstract Presenting with dismal prognoses, treatment of multifocal GBM (mGBM) requires extensive medical infrastructure. Individualized assessment for patients at risk of extended length of stay (LOS) and nonroutine discharge disposition, described as high-value healthcare outcomes, has not previously been described. To develop predictive models for extended LOS and nonroutine discharge disposition for mGBM patients. All mGBM patients undergoing surgical resection at our institution (January 1, 2009-December 31, 2020) were included. Predictive models for nonroutine discharge disposition (discharge to a non-home environment) and extended LOS [upper quartile of the LOS for all patients included in the present study’s cohorts (&amp;gt;6 days)] were developed using multivariate logistic regression models. Optimism-corrected C-statistics for each model were calculated using 1000 bootstrapped samples in order to correct for potential bias associated with the limited population size. The Hosmer-Lemeshow test was used to evaluate model goodness of fit and calibration. A total of 137 mGBM patients were included in the present study. Most patients were male (40.1%), white (83.2%), not Hispanic/Latino (97.8%), not married (55.5%) and underwent elective surgery (85.4%). The average age among our patient cohort was 55.41 ± 13.17, the average KPS score was 77.23 ± 14.54 and the average mFI-5 was 0.613 ± 0.760. On bivariate analysis, older age (p=0.015) and decreasing Karnofsky Performance Status (KPS) score (p&amp;lt;0.001) were significantly associated with nonroutine discharge disposition while emergency admission (p=0.010) and increasing frailty (mFI-5) score (p=0.003) were significantly associated with extended LOS. On multivariate analysis, increasing age (p=0.031) and decreasing KPS (p&amp;lt;0.001) predicted nonroutine discharge while emergent admission (p=0.023) and greater mFI-5 (p=0.044) predicted extended LOS. Our models for nonroutine discharge and extended LOS had optimism-correct c-statistics of 0.7507 and 0.7309 respectively and displayed adequate calibration. Following external validation, our models may have utility as a risk stratification tool for this multifocal GBM patient populations.
NIMG-22. QUANTITATIVE BRIGHTNESS ANALYSIS OF 5-ALA FLUORESCENCE IN GLIOMA SURGERY
Authors: Takashi Kon, Yusuke Kobayashi, Katsuyoshi Shimizu, Tohru Mizutani, Yosuke Sato
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE The 5 aminolevulinic acid (5-ALA) is used for intraoperative tumor visualization in neurosurgery. We hypothesized that glioma may vary in pathology according to the brightness of 5-ALA fluorescence, which we quantified and compared with the pathological results of glioma. METHODS From 2019 to 2023, we investigated 28 glioma patients who underwent surgery with 5-ALA. The pathological diagnosis was based on classification of WHO 2016. The 5-ALA was administered before surgery, and the brightness of 5-ALA fluorescence was quantified. RESULTS Seventeen cases of glioblastoma (GBM), four cases of anaplastic astrocytoma (AA), three cases of oligodendroglioma (OL), and four cases of low grade glioma (LGG) were examined. The mean (SD) brightness of 5-ALA fluorescence was 155.9 (56.0) in GBM, 180.5 (64.7) in AA, and 66.3 (18.8) in OL. The brightness in OL was significantly lower than that in GBM and AA (Scheffe’s test, p&amp;lt;0.05). All LGGs showed negative in the brightness. CONCLUSIONS The brightness of 5-ALA fluorescence was shown to vary by pathology, which may contribute to intraoperative diagnostic support.
TMOD-23. LENTIVIRAL-INDUCED BRAIN GLIOMAS IN RAT MODEL
Authors: Michelle Zhang, Yuliya Lakhina, Marybeth Yonk, Kelly Poth, Stewart Neill, Zhaobin Zhang, Hemza Assed, Muhibullah Tora, Anthony Donsante, Thais Federici, Kecheng Lei, Nicholas Boulis
Journal: Neuro-Oncology (2024)

Abstract High-grade gliomas are the most common type of malignant intracranial tumor with dismal five-year prognostic outcomes despite developments in chemoradiotherapy and surgical intervention. Distinct oncogenes associated with tumorigenesis and progression have been identified, providing targets for potential therapeutic interventions and modeling efforts. In this study, we evaluated the efficacy of vectors targeting EGFR and PTEN, individually and in combination to produce high-grade brain gliomas. Four groups of rats underwent intracranial stereotaxic injection of lentiviral vector into the forceps minor of the corpus callosum. All animals were weighed and monitored for behavioral deficits three times per week for 90 days. Upon signs of clinical morbidity or at 90 days post-inoculation, tissues were harvested and analyzed using hematoxylin and eosin and immunohistochemical staining. Rats injected with the combination of the EGFR and the sh-PTEN vectors exhibited declines in weight, survival, and motor function compared to the control. The combination of the EGFR and sh-PTEN vectors was the only condition to induce tumorigenesis with histopathological confirmation of high-grade identity as confirmed by immunohistochemistry showing the most positivity for GFAP and SOX2 compared to the control. Significant increases in Ki-67 characterized combination tumors as highly proliferative. Increased oxidative stress and angiogenesis were supported by significant increases in 4HNE, SMA, and HIF-1α in the tumors compared to other treatment groups. Thus, the present model of high-grade rat brain glioma provides a potential model to assess pathogenic pathways and evaluate therapeutic strategies.
TMOD-20. RAPID PROCESSING AND BIOBANKING OF RESECTED BRAIN TUMOR TISSUE TO GENERATE PATIENT-DERIVED BRAIN TUMOR EXPLANT ORGANOIDS (GBOS) FOR PRECLINICAL STUDIES
Authors: Helen Palethorpe, Chloe Shard, Conor Ryan, Daniel Wenholz, Quach Truong, Kaitlin Scheer, Niclas Skarne, Ashwini Patil, Rebecca Ormsby, Santosh Poonnoose, Kimberley Alexander, Hui Gan, Bryan Day, Naresh Kumar, John Wilkinson, Guillermo Gomez
Journal: Neuro-Oncology (2024)

Abstract Improved preclinical tools are urgently needed to translate new brain cancer treatments. Patient-derived brain tumor explant organoids (GBOs) offer promise for studying tumor cells in a relevant human tumor microenvironment and predicting patient responses to therapy. However, generating GBOs is time-consuming, costly, and technically challenging, hindering the creation of comprehensive biobanks covering the spectrum of brain tumor heterogeneity. This work presents a semi-automated method for producing GBOs, involving tumor tissue processing, size selection, and same-day cryopreservation, reducing generation time to less than 1 hour. We established a biobank of 24 GBOs from 33 samples (11 males and 13 females) with primary (n=13, GBO Yield (GY)&amp;gt;90%) and recurrent (n=5, GY&amp;gt;90%) glioblastomas, high-grade gliomas (HGG, n=2, GY≤50%), and low-grade gliomas (LGG, n=2 with GY&amp;gt;90%, n=2 with GY≤50%). Using GBO size and propidium iodide as readouts, we used this biobank to compare anticancer activities of novel idronoxil-conjugated benzopyran compounds (NX786, NX904/904E1) against Bortezomib (100% cell death reference). NX786 and NX904/904E1 reduced GBO growth (≥50%) in all primary glioblastoma and one (of two) recurrent glioblastoma GBOs with milder effects in LGG GBOs. Two (of four) primary glioblastoma, one (of two) recurrent glioblastoma, and one LGG GBOs exhibited significant cell death (&amp;gt;60%) in response to NX904/904E1. In contrast, NX786 induced cell death in one (of three) primary glioblastoma (34% cell death) and one (of two) recurrent glioblastoma (71% cell death) GBOs but not in LGG GBOs, together showcasing varied responses across different brain tumors. Highly-passaged GBOs lacking the non-malignant tumor microenvironment were more susceptible to these treatments, underlining the tumor microenvironment’s critical role in responses to anticancer agents. We provide a new method for efficient processing and cryopreserving GBOs, enabling the establishment of large biobanks for patient-specific preclinical drug testing across brain tumor subgroups in a clinically relevant human 3D model.
CTNI-50. CLINICAL EFFICACY AND PK/PD RESPONSE IN A PHASE 0/2 STUDY OF NIRAPARIB PLUS RADIOTHERAPY FOR NEWLY-DIAGNOSED, MGMT-UNMETHYLATED GLIOBLASTOMA
Authors: Nader Sanai, Yoshie Umemura, Tigran Margaryan, Jennifer Molloy, Hualin Zhang, William Knight, Jocelyn Harmon, Amy Hong, John Wanebo, Kelly Braun, William R Kennedy, Michael Garcia, Igor Barani, Wonsuk Yoo, An-Chi Tien, Artak Tovmasyan, Shwetal Mehta
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is a PARP1/2-selective inhibitor. This Phase 0/2 study evaluates tumor pharmacokinetics (PK), pharmacodynamics (PD), and clinical efficacy of niraparib plus fractionated radiotherapy in newly diagnosed, O6-methylguanine methyltransferase (MGMT)-unmethylated glioblastoma (GBM). METHODS Newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 (cohort 1) or 8-10 hours (cohort 2) following the last dose. Tumor tissue (gadolinium-enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation vs non-irradiated control. A PK response was defined as unbound [niraparib] &amp;gt; 5-fold biochemical IC50 (19 nM) in non-enhancing tumor. Patients with MGMT-unmethylated tumors and a PK response were eligible for Phase 2 dosing of niraparib plus radiotherapy followed by niraparib monotherapy. RESULTS All Phase 0 patients (n=46) met the PK threshold. The mean unbound concentrations of niraparib in non-enhancing tumor regions were 335.1 nM (cohort 1; n=43) and 331.9 nM (cohort 2; n=3). Ex vivo PAR suppression was observed in 73% of the patients (24/33). 71.4% patients with unmethylated tumors were enrolled into Phase 2. Five patients in Phase 2 experienced Grade 4 thrombocytopenia related to niraparib and all adverse events resolved without sequelae. At a mean clinical follow-up of 13.4 months, median overall survival was 20.3 months. CONCLUSIONS Niraparib achieves pharmacologically relevant concentrations in non-enhancing, newly-diagnosed GBM tissue. Accompanying PD effects were observed in tumor tissue, no new safety signals were observed, and clinical outcomes were promising. A global Phase 3, open-label, randomized 2-arm study comparing niraparib versus temozolomide in adult patients with newly diagnosed, MGMT-unmethylated glioblastoma is underway.
TMOD-21. MOUSE MODEL TO CONDITIONALLY EXPRESS A DIFFUSE MIDLINE GLIOMA DERIVED MUTATION IN THE ONCOGENIC PHOSPHATASE PPM1D
Authors: Vennesa Valentine, Harrison Liu, Abby Groth, Spencer Maingi, Avneesh Saravanapavan, Joshua Tolliver, Nerissa Williams, Lixia Luo, David Kirsch, Zachary Reitman
Journal: Neuro-Oncology (2024)

Abstract Diffuse Midline Gliomas (DMGs) are incurable brain tumors of children and adults, and there is an urgent need for new therapeutic approaches. Their location within critical areas of the brain precludes complete surgical removal. While current treatment mainly relies on radiation therapy, its efficacy remains palliative. DMGs commonly harbor truncating mutations in the Mn2+/Mg2+-dependent protein phosphatase 1D (PPM1D), leading to a gain-of-function in PPM1D by enhancing protein stability and activity. Thus, investigating PPM1D protein expression and its regulatory mechanisms is crucial for understanding its oncogenic role and identifying therapeutic targets. To address this, we developed a Ppm1d-loxP-exon6-loxP-exon6-E518X-tag mouse allele (Ppm1d-FL). This allele allows conditional expression of DMG-derived truncating mutations from the endogenous Ppm1d locus when the loxP sites are recombined in the presence of Cre recombinase. Tosimulate primary gliomas, we utilized the RCAS/tv-a retrovirus system and Cre/loxP recombination platforms. Mouse pups were injected with RCAS retroviruses bearing oncogenic platelet-derived growth factor B, Cre recombinase, and luciferase reporter genes into the brainstem. We confirmed that Cre leads to expected recombination of Ppm1d-FL, leading to expression of DMG-derived truncated Ppm1d-E518X-Tag mRNA. We examined tumor-free survival data, which indicates accelerated tumor formation with Ppm1d-FL compared to littermate controls with wildtype Ppm1d. The tumors demonstrated expression of molecular biomarkers commonly found in DMGs. Single-cell RNA sequencing has identified pathways activated or inactivated upon Ppm1d mutation. These data shed light on the complex interplay between PPM1D mutations and glioma pathogenesis and may guide the design of therapies that target PPM1D molecular pathways.