tbuckley/cabot-search huggingface dataset:
DDDR-36. LOOKING AROUND THE CORNER: PREDICTING SYNERGY OR FUTILITY TO COMBINATION OF ARSENIC TRIOXIDE PLUS MNK1 INHIBITORS IN GLIOBLASTOMA
Authors: Charles Shaffer, Nanyun Tang, Yue Hao, Angela Baker, Michael Berens
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is the most prevalent type of malignant tumor within the central nervous system. The five-year survival rate of 6.8% highlights the challenges inherent to exceptionally heterogeneous tumors that grow behind the blood brain barrier. The protracted dearth in new agents approved for GBM begs innovative strategies by which to approach clinical trials. Arsenic trioxide (ATO) is the standard of care for myelodysplasia and relapsed or refractory acute promyelocytic leukemia. ATO has an idiopathic mechanism of action, but has shown beneficial effects in other solid tumors. Across six GBM PDX models a 10-fold difference in sensitivity manifests, indicative of underlying innate sensitivity or resistance to ATO. This resistance has been previously shown to correlate with MNK1 expression. In order to sensitize PDX models innately resistant to ATO we utilized combination therapy with the MNK1 inhibitor AUM001 (AUM Biosciences, Singapore; NCT05462236). In high MNK1 expressing PDX models the combination of ATO + AUM001 induces cytotoxic synergy. Additionally, when narrowly measuring effects on the glioma stem cell population (ELDA), strong synergy was observed in models, including those failing to show such using bulk cell population viability assay. GSEA analysis revealed differential high enrichment in gene sets related to oxidative phosphorylation in the models failing to show synergy. Such criteria could act as exclusionary criteria (futility) for clinical trials by excluding such putative non-responder patients from the treatment population. Synergistic models showed enrichment in gene sets related to epithelial/mesenchymal transition, skeletal and sensory organ development, and regionalization. These signatures could serve to prioritize patient inclusion in clinical trials of ATO in combination with AUM001, enriching the fraction of responsive glioma patients. Such molecular signatures may bring precision medicine in early-stage clinical trials to advance promising new agents and combinations of agents to full FDA approval.
CNSC-03. HIGH EXPRESSION OF PICCOLO AND SYNTAXIN-1A IN PAEDIATRIC MEDULLOBLASTOMA DUE TO BOTH: HIGH NEURONAL FRACTION AND ENDOGENOUS EXPRESSION
Authors: Marco Timmer, Saskia Kuhl, Roland Goldbrunner
Journal: Neuro-Oncology (2024)

Abstract Emerging evidence indicates that the “healthy” nervous system contributes to the pathogenesis of cancer. Tumor cells were found to form ultra-long protrusions with distinct synapses, mainly in the infiltrative zone, resulting in a neuron-to-brain tumor synaptic communication. Located at the presynapse, proteins of the cytomatrix of the active zone have been identified to maintain highly specialized functions in neurons. Further, the proteins were shown to be involved in progression in various tumors, but little is known about their role in brain tumors. This study examined the expression of CAZ proteins in glioma and medulloblastoma. Tumor samples of Astrocytoma, glioblastoma, pilocytic astrocytoma and medulloblastoma were obtained during neurosurgical resection. Transcription rate of following CAZ proteins was measured via qPCR: SNAP25, VAMP1, VAMP2, SYT1, PCLO, BSN, STX1A. To examine amount of neuronal tissue TUBB3 and for glial fraction GFAP were quantified. A medulloblastoma cell line (DAOY) was furthermore analyzed to evaluate origin of high expressed proteins. Medulloblastoma showed high expression of PCLO (pilocytic astrocytoma vs. medulloblastoma p=0.0126) and STX1A (pilocytic astrocytoma vs. medulloblastoma p=0.0006) compared to. Likewise a high transcriptional level of TUBB3 could be seen with significance to pilocytic astrocytoma (2.2 ± 1.4 vs. 0.2 ± 0.17; p = 0.0018), which could indicate a high amount of neuronal tissue in given medulloblastoma samples. To rule out a causal link between high proportion of neuronal tissue and high CAZ expression, a paediatric medulloblastoma cell line was analysed. High expression of PCLO and STX1A in absence of TUBB3 was shown (3.8 and 2.01 vs. 0.059), indicating endogenous expression of CAZ proteins in medulloblastoma.
NCOG-09. ASSOCIATIONS OF COGNITIVE FUNCTION WITH BRAIN STRUCTURE, COMT GENOTYPE, AND PSYCHOLOGICAL FACTORS IN MELANOMA PATIENTS PRIOR TO ADJUVANT IMMUNE CHECKPOINT INHIBITOR THERAPY
Authors: Josefine T Danielsen, Robert Zachariae, Henrik Schmidt, Jepser F Kallehauge, Julie K Thomadsen, Jeffrey S Wefel, Lisa M Wu, Ali Amidi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cancer-related cognitive impairment (CRCI) presents a significant concern in cancer patients. Yet, limited research addresses its prevalence and potential underlying risk factors in melanoma patients, including neurobiological, genetic, and psychological factors. METHODS We assessed cognitive functioning, cognitive complaints, brain gray matter (GM) properties, COMT genotype, and psychological factors (fatigue, anxiety, depression, insomnia severity, sleep difficulties, quality of life) in malignant melanoma patients (MMPs) before treatment with immune checkpoint inhibitors (ICIs) and compared with matched healthy controls (HCs). A total of 47 MMPs and 53 HCs were enrolled. Between-group differences were tested, and statistical associations between cognitive function and brain GM properties, COMT polymorphisms, and psychological factors were explored. RESULTS MMPs exhibited significantly lower levels of cognitive functioning compared with HCs across multiple cognitive tests (all p’s&amp;lt;.05), with a high prevalence of clinically significant CRCI (68.1% VS 26.4%). Analysis of GM properties revealed volumetric differences in the left cuneus between MMPs and HCs with MMPs having smaller volume compared to HCs. In MMPs but not in HCs, statistically significant associations were found between WAIS-IV Coding and right precentral cortical thickness, TMT-A and left inferior parietal cortical thickness, and BVMT-R Delayed Recall and right postcentral GM volume (all p’s&amp;lt;.01). COMT polymorphisms were associated with self-reported cognitive complaints but not with objective cognitive performance. Compared with HCs, MMPs reported higher levels of fatigue, anxiety, insomnia severity, and sleep difficulties, and lower levels of quality of life (all p’s ≤.009). Additionally, self-reported cognitive complaints in MMPs were associated with different cognitive test performances (all p’s&amp;lt;.05), fatigue (p&amp;lt;.001) and anxiety (p&amp;lt;.045). CONCLUSIONS These findings underscore the importance of comprehensive cognitive and psychological assessments in MMPs referred for adjuvant ICI therapy. Understanding the complex array of symptoms including CRCI in this population can inform tailored interventions to improve quality of life and treatment outcomes.
DDDR-32. EXPLORING ANDROGENIC MODULATION IN GLIOBLASTOMA: POTENCY AND SELECTIVITY OF NOVEL NORETHINDRONE DERIVATIVES
Authors: Richard Dudley, Ryan Schneider, Carson Shoemaker, Lea Stitzlein
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Glioblastoma (GBM) represents the most frequently diagnosed malignant CNS tumor in adults and remains incurable. Despite the identification of several oncogenic drivers contributing to tumor formation, targeted therapy with brain-penetrant inhibitors has afforded little progress in survival outcomes. Interestingly, gender has been shown to increase the incidence of GBM, with men having roughly a 50-60% increase in incidence compared to women in the US. This statistic led to research on the involvement of and subsequent inhibition of androgen synthesis and signaling in cell culture models and tumor samples. METHODS To further investigate the potential involvement of steroidal hormones in GBM proliferation, our lab synthesized a series of norethindrone (NE) derivatives with varied molecular weights, steric bulk, and lipophilicity to modulate the androgenic activity of NE. The small library was tested in several GBM cell lines, including U87, A172, and T98G cells, using cell viability assays. RESULTS One derivative, a lipophilically modified version of NE synthesized via a one-pot click reaction, was shown to have improved potency compared with parental NE (&amp;gt;5-fold). The lipophilic NE derivative had IC50 value of 22 uM, 15 uM, and 35 uM in the U87, A172, and T98G cells, respectively. This molecule was tested in immortalized normal human astrocyte (NHA) cells and found to have an IC50 value of 34 uM suggesting some selectivity. DISCUSSION Given this derivative’s activity in GBM models and modest selectivity, we plan to screen it in additional GBM cell lines (LN-18 and U251) and eventually in glioma stem cell models. Future research will focus on identifying key targets involved in the mechanism of action, including the impact of lipophilic addition to the steroid nucleus and its effect on androgenic activity and downstream signaling. We will investigate these effects using RPPA and co-treatments with androgen receptor antagonists and 5-alpha reductase inhibitors.
CSIG-20. LIPOCALIN-2 DRIVES CELL-INTRINSIC FUNCTIONS IN GLIOBLASTOMA
Authors: Sabrina Wang, J Timken, Christopher Bishop, Loic Deleyrolle, Justin Lathia
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) continues to persist despite aggressive therapies, many of which are cytotoxic, and therapeutic failure is driven, in part, by the tumor cell’s ability to evade multiple forms of cell death, including ferroptosis. Lipocalin-2 (LCN2) functions to sequester iron and is considered an inflammatory marker through its function of limiting iron for bacterial usage; it has also been described to have pro and anti-tumorigenic effects depending on environmental iron status. In previously published studies in brain metastases, LCN2 promotes tumor cell proliferation by sequestering iron for cancer cells growth and survival, but the mechanisms of how LCN2 contributes to GBM progression is unknown. LCN2 expression in patient data revealed that high LCN2 expression is associated with reduced survival in GBM patients. A survey of mouse glioma models demonstrated a range of LCN2 secretion across models with KR158 and CPA being high and medium LCN2 secretors. LCN2 short hairpin knockdown of KR158 and CPA and decreased tumor cell viability and proliferation. Furthermore, when both KR158 and CPA control versus LCN2 knockdown cells were orthotopically implanted into mice, survival was increased. To understand if LCN2 impacted cell death dynamics, we investigated various cell death mechanisms and found that LCN2 knockdown increases tumor susceptibility to ferroptotic death by sensitizing cells to lipid peroxidation as well as reducing key anti-ferroptotic proteins GPX4 and xCT. To elucidate downstream mechanisms, we performed a phosphorylation array and discovered that phosphorylation of AXL, which has recently been linked to ferroptosis, is decreased with LCN2 knockdown. Moreover, AXL phosphorylation was localized to the nucleus, indicating that LCN2 knockdown attenuates AXL processing and downstream signaling. Overall, these findings indicate that LCN2 in GBM promotes tumor cell growth through AXL signaling and evasion of ferroptotic death, ultimately revealing a novel signaling network that can be leveraged for future therapeutic development.
ANGI-06. CEREBROSPINAL FLUID MAY BE THE MOST IMPORTANT PATHWAY FOR BRAIN METASTASES: A DATA-DRIVEN HYPOTHESIS AND CLINICAL IMPLICATIONS
Authors: Kyle Tuohy, Richard Dowd, Tao Ouyang, Krishnamoorthy Thamburaj, Dawit Aregawi, Inan Olmez, Alireza Mansouri, MIchael Glantz
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Hematogenous spread of brain metastases represents conventional wisdom. However, compelling physiologic evidence suggests that brain metastases may reach the CNS by way of the CSF either via the choroid plexus or directly from the bone marrow. We provide clinical evidence that invasion of brain parenchyma occurs through the CSF, and we model the therapeutic implications of this novel hypothesis. METHODS First, we assessed whether brain metastases were contiguous with a CSF space in 204 consecutive patients using pre-treatment MRI. Then, CSF was examined for malignant cells in 66 consecutive brain metastasis patients. Next, we contoured normal brain MRIs of 3 patients to calculate the percentage of brain within 5 mm of a CSF space. Finally, we queried an international neoplastic meningitis registry for patients with brain metastases to evaluate response to intra-CSF chemotherapy alone. RESULTS In 204 consecutive patients with brain metastases, the mean number of metastases was 4.63 (SD 6.26), and 85% of metastases touched a CSF space. In 67% of patients, all metastases touched a CSF space. In our consecutive cohort of 66 patients with CSF analysis, 44% with one, 46% with two, 63% with three, and 71% with &amp;gt;3 metastases had malignant cells in the CSF (R2=0.93, p=0.04). Brain contouring revealed that up to 75% of the brain parenchyma lies within 5 mm of a CSF space. Seven of 10 patients with both brain and CSF metastases receiving only intrathecal chemotherapy experienced disappearance or substantial reduction in the size of their metastases. CONCLUSIONS This data suggest that brain metastases may access the CNS through the CSF. Intrathecal chemotherapy can reach most brain metastases and can produce objective responses. We suggest that the CSF should be monitored in all patients with, or at risk for, brain metastases, and true cures may require treatment of the CSF space.
BIOM-16. A TARGETED GENE EXPRESSION BIOMARKER PREDICTS LOW GRADE MENINGIOMA RECURRENCE AND OVERALL SURVIVAL
Authors: Minh Nguyen, Ramin Morshed, Mark Youngblood, Haley Perlow, Calixto-Hope Lucas, Akash Patel, Joshua Palmer, Kathleen McCortney, Craig Horbinski, Stephen Magill, William Chen, David Raleigh
Journal: Neuro-Oncology (2024)

Abstract Targeted gene expression profiling improves risk stratification for meningiomas, but the utility of this approach for low grade meningiomas is incompletely understood. To address this, 466 meningiomas that were initially used to validate a 34-gene expression biomarker were combined with 270 previously unpublished samples for an analysis of biomarker performance in newly diagnosed (n=691) or recurrent (n=45) WHO grade 1 meningiomas treated with gross total (GTR) or subtotal resection (STR), and newly diagnosed WHO grade 2 meningiomas treated with GTR. Prediction of local freedom from recurrence (LFFR) or overall survival (OS) was measured using Cox proportional hazards models and the Kaplan-Meier method. The cohort included 736 patients, 69.4% female, with a median age at diagnosis of 58 years. There were 635 WHO grade 1 meningiomas, 498 with GTR and 133 with STR, and 101 WHO grade 2 meningiomas with GTR. The median follow-up was 4.6 years, the local recurrence rate was 12.0% and the rate of death was 8.4%. The biomarker classified 51.5% of meningiomas as intermediate risk and 9.6% as high risk. Combining the biomarker with extent of resection identified 19.7% as unfavorable (intermediate molecular risk with STR or high molecular risk), including 7.4% of newly diagnosed WHO grade 1 meningiomas with GTR. The risk score was prognostic for LFFR overall (hazard ratio per 0.1 increase in risk score 1.89, 95% confidence interval 1.58-2.25) and across WHO grades, extents of resection, and newly diagnosed or recurrent settings. Gene expression risk groups were prognostic for LFFR, with improved outcomes among low molecular risk compared to intermediate molecular risk (Log-rank, p=0.0002) and high molecular risk meningiomas (Log-rank, p&amp;lt;0.0001). These data suggest that a targeted gene expression biomarker can identify low grade meningiomas that are more likely to recur after surgery, possibly changing management for approximately one-fifth of cases.
EPID-06. ACROMEGALY AND THE RISK OF CANCER: A NATIONWIDE POPULATION-BASED LONGITUDINAL COHORT STUDY IN KOREARUNNING TITLE: ACROMEGALY AND THE RISK OF CANCER
Authors: Yeo Song Kim, Jae-Seung Yun, Hyunho Kim, Sin Soo Jeun, Jung Eun Lee, Bongseong Kim, Seung-Hyun Ko, Yu-Bae Ahn, Kyungdo Han, Seung-Ho Yang
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Previous reports on cancer risk in patients with acromegaly have inconsistent findings. Using a nationwide population-based cohort, we primarily investigated whether overall and site-specific cancer risk are increased in patients with acromegaly. MATERIALS AND METHODS The study included 2,382 acromegaly patients and 11,910 controls aged above 20, from 2006 to 2016. Cox hazards regression analysis was used, adjusting for baseline covariates. RESULTS Among the 2,382 patients with acromegaly, overall cancer occurred in 244 (10.2%), while the 11,910 controls had 707 (5.9%) occurrences (HR: 1.90 (95% CI: 1.63-2.22). Acromegaly patients had the highest relative risk for brain cancers with an HR of 6.80 (95% CI: 2.83-16.38) and significantly higher risk of lymphoma, thyroid cancer, multiple myeloma, pancreatic cancer, and colorectal cancer. Even after five years from the diagnosis of acromegaly, patients with acromegaly had a significantly higher incidence of cancer. Risk of cancer in general and stomach cancer in specific was significantly higher in patients under the age of 50 compared to older patients. There was no sex difference. CONCLUSIONS This nationwide longitudinal cohort study shows an increased risk of cancer in acromegaly patients. Active and long-term cancer screening is necessary to improve the prognosis in patients with acromegaly.
CNSC-45. EXTRINSIC ELECTRICAL MODULATION IMPACTS GLIOBLASTOMA TUMOR GROWTH BY DISRUPTING ITS INTERCELLULAR COMMUNICATION
Authors: Irina Palacin Aliana, Yasmina Eshac, Alicia Casanova Perez, Elian Saiz Cerda, Shashwat Tripathi, Hinda Najem, Amy Heimberger, Maciej Lesniak, Timothy Sita
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is an incurable primary malignant neoplasm of the central nervous system. GBM as an electrically active neoplasm diffusely colonizes healthy brain tissues, disrupting the neurotransmission balance and causing glioma-related epilepsy (GRE) in up to 50% of patients. Interestingly, GRE is an independent favorable prognostic factor for survival in GBM. The therapeutic induction of seizure may have a previously unexplored oncologic value in GBM. We have previously reported in CT-2A-bearing mice subjected to daily extrinsic electrical modulation (EEM) diminished tumor progression and increased overall survival relative to sham-treated mice, but the mechanism by which EEM produces its anti-tumor effect remains uncertain. Therefore, GBM-bearing mice (CT-2A cells xenografted into 5-7 weeks old C57BL/6 female mice, n=5/group) received either a single EEM of 2.0 millicoulombs (mC) or sham treatment. The mice were terminated at 3 hours, 24 hours, 4, 7, and 10 days post-EEM, and tumors and contralateral brain cortex were analyzed using bulk RNA-sequencing and Sequential immunofluorescence (SeqIFTM). SeqIFTM revealed how EEM activates neuronal activity via cFOS expression and induces tumor-specific cell damage through cleaved caspase-3 expression, without affecting healthy brain tissue. Furthermore, RNA-seq performed post-EEM revealed gene expression changes of not only synapse organization markers but also of several tumor-tumor and tumor-neuron connectivity key markers, such as growth-associated protein 43 (GAP43), neuroligin-3 (NLGN3), and glutamate receptors such as GRIA4 and GRIN1 between others. However, the expression of these markers diminished significantly 96h after-EEM, indicating a reduction in intercellular electrical communication by the inhibition of the neoplasm cells electrical integration with neuronal circuits by downregulating glutamatergic receptor expression, blocking the synapse-forming protein NLGN3, and the network-connecting protein GAP43. Taken together, our findings reveal how by the disruption of these critical interactions within the tumor microenvironment though EEM impacts on GBM growth making it more susceptible to therapeutic interventions.
EPCO-40. TRANSCRIPTIONAL TRAJECTORY INFERENCE OF IMAGE-LOCALIZED, MULTI-REGIONAL HIGH-GRADE GLIOMA BIOPSIES REVEALS DISTINCT POPULATION ECOLOGIES AND SEX-ASSOCIATED ENRICHED PATHWAYS
Authors: Lee Curtin, Kamila Bond, Kyle Singleton, Pamela Jackson, Christopher Sereduk, Chandan Krishna, Richard Zimmerman, Devi Patra, Kliment Donev, Maciej Mrugala, Nhan Tran, Leland Hu, Bernard Bendok, Osama Al-Dalahmah, Peter Canoll, Kristin Swanson
Journal: Neuro-Oncology (2024)

Abstract The intra- and inter-patient heterogeneity in high-grade glioma (HGG) continues to contribute to its poor prognosis. Clinical biopsies are often harvested from limited regions and typically are not image localized. Thus, they fail to capture the diversity within tumor regions, immune expression or normal cell abundances that play key roles in tumor development. It is important to gain an understanding of these subpopulation ecologies, their spatial resolution, and interactions between them that may then be exploited for future therapeutic benefit. Further, these may differ by patient characteristics such as sex, age at diagnosis and treatment status. Using an ongoing image-localized biopsy collection protocol, we have so far evaluated the bulk transcriptomics of 202 multi-regional biopsies from 58 patients to characterize HGG heterogeneity. These samples were processed through Monocle, a reverse graph embedding algorithm that groups samples into states and orders them along developmental trajectories. Deconvolution methods were previously used to predict relative abundances of 7 normal, 6 glioma, and 5 immune cell subpopulations for each sample, which we have now overlaid on the Monocle graph. Monocle classified HGG into 4 main states along a three-pronged trajectory. These states reveal distinct population ecologies with associated enriched gene pathways. We also note significant immune pathway enrichments that differ between state and patient-reported sex. Together, these algorithms reveal a simple transcriptomic trajectory that helps us understand the development and evolution of HGG. Characterizing the in vivo diversity within and between high grade gliomas is important for understanding prognosis, stratifying future treatments and ultimately improving patient outcome.