tbuckley/cabot-search huggingface dataset:
CSIG-16. A CX43-WNK1-C-MYC SIGNALING AXIS DRIVES GLIOBLASTOMA CANCER STEM CELL SURVIVAL
Authors: Erin Mulkearns-Hubert, Nicole Hajdari, Ellen Hong, Daniel Silver, Justin Lathia
Journal: Neuro-Oncology (2024)

Abstract Tumors represent a highly dynamic system that relies on coordinated signaling to drive growth and adapt to selective pressures, including those induced by anti-cancer therapies. Given the need for tumors to engage in rapid and coordinated cell-cell communication, mechanisms such as gap junction intracellular communication (GJIC) should be essential. However, the connexin proteins that make up gap junctions have traditionally been considered tumor suppressors based on the frequent loss of GJIC and lower connexin expression in tumor cells compared to non-neoplastic tissue. For this reason, connexin 43 (Cx43) has been proposed to suppress the growth of glioblastoma (GBM), the most common primary malignant brain tumor. However, recent data suggest that this tumor-suppressive effect is context dependent and that connexins can also function in a tumor-promoting role. Using next-generation sequencing techniques, we found Cx43 expressed at high levels in a panel of GBM patient-derived xenograft (PDX) CSCs and that these models rely on Cx43 for their survival and self-renewal. Mechanistically, depletion of Cx43 led to a dramatic loss of c-MYC expression through reduced phosphorylation of its upstream mediator WNK lysine-deficient protein kinase 1 (WNK1). Depletion of WNK1 phenocopied knockdown of Cx43 and reduced MYC protein and mRNA as well as tumor growth in vivo. Together, this work defines a novel signaling axis downstream of gap junction protein expression that promotes tumor growth and cancer stem cell phenotypes in GBM. Due to the difficulty in targeting both Cx43 and MYC, the identification of intermediate targetable signaling nodes may lead to improved therapies for patients with GBM.
TMIC-85. THE MECHANISM OF COMBINED HYDROGEN-CHEMICAL THERAPY BASED ON ACTIVE MAGNESIUM MICROMOTORS FOR INHIBITING GLIOBLASTOMA RECURRENCE BY MODULATING TUMOR MICROENVIRONMENT
Authors: Shiguang Zhao
Journal: Neuro-Oncology (2024)

Abstract OBJECTIVE This study aims to develop an innovative therapeutic strategy to prevent postoperative recurrence of Glioblastoma (GBM), a condition with poor prognosis and high recurrence rates. The focus is on exploring the efficacy of synergistic hydrogen-chemical therapy in inhibiting GBM recurrence, especially by reducing surgery-induced inflammation and enhancing the sensitivity of GBM cells to chemotherapy. METHODS The study employed the fabrication of Mg-Motor-DOX using a biodegradable polylactic acid-glycolic acid copolymer (PLGA) and gelatin containing Doxorubicin (DOX). The reaction of Mg with water produces hydrogen (H2), which aids in scavenging reactive oxygen species (ROS) and inflammation, alongside the specific release of chemotherapy drugs at the tumor site. A thermosensitive hydrogel was developed for in situ delivery of Mg-Motor-DOX to the tumor residual cavity. Additionally, RNA sequencing was used to study the transcriptional changes in the GBM tumor microenvironment (TME) induced by this therapy. RESULTS The study presents initial evidence of the in vivo efficacy of synergistic hydrogen-chemical therapy against GBM. The Mg-Motor-DOX mediated therapy not only scavenged ROS and reduced inflammation but also specifically released chemotherapy drugs at the tumor site, enhancing their effectiveness. RNA-Seq technology elucidated the molecular mechanisms underlying the therapy’s efficacy, revealing significant transcriptional changes in the GBM TME. CONCLUSION Synergistic hydrogen-chemical therapy, facilitated by Mg-Motor-DOX, shows promising potential in preventing the postoperative recurrence of GBM. This innovative approach effectively combines anti-inflammatory benefits and enhanced chemosensitivity, offering new strategies for GBM treatment. The molecular insights provided by RNA-Seq technology contribute to a deeper understanding of tumor treatment mechanisms, paving the way for future clinical applications.
BIOM-28. WHOLE EXOME TUMOR MOLECULAR PROFILING FROM CEREBROSPINAL FLUID (CSF): PRELIMINARY RESULTS OF A PILOT STUDY
Authors: Kyle Tuohy, Joanne Xiu, Theodore Nicolaides, Alireza Mansouri, Sonikpreet Aulakh, Christian Davidson, Jian Zhang, Maria Perdigones Borderias, David Spetzler, Mark Gilbert, Michael Glantz
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Tissue sampling for molecular profiling has become an integral part of the diagnosis, prognosis, and management of CNS malignancies. However, many tumors are surgically inaccessible, and even biopsy of accessible lesions conveys some risk, and the possibility of sampling error. We evaluated the accuracy and potential utility of CSF liquid biopsy for identifying mutations in patients with intracranial tumors. METHODS CSF samples were collected from ventricular reservoirs and stored at -80 degrees Celsius until analyzed. Cell-free nucleic acids were extracted, concentrated, and quantified. Samples over 110ng quantification were normalized to 110ng and input into library prep. Library prep was done using v3.5 of Caris Assure and whole exome sequencing in an S2 FC on a Novaseq 6000. Bioinformatic analysis was performed. RESULTS CSF samples were obtained from 20 patients (10 gliomas, 5 CNS lymphomas, 5 metastases), 19 of whom also had tumor specimens available. Two hundred eighty-one mutations were identified: 17 (6.6%) in tumor only, 184 (72.4%) in CSF only, and 80 (31.5%) in both. Key alterations found in CSF include: IDH, TERT, ATRX in gliomas, and MYD88, PIM1, BCL2, TERT in lymphomas. Glioma CSF with IDH1 mutations did not have PTEN mutations (with one exception, in which the CSF was collected 3 years after the tissue). Targetable mutations in metastases included PIK3CA, NF1, and BRCA. CONCLUSION These preliminary results suggest that CSF liquid biopsy may be useful for identifying mutations in primary and metastatic brain tumors. Serial sampling is feasible, and may disclose changes in diagnostic and/or driver mutations over time, with important therapeutic and diagnostic implications. Many mutations were found in CSF alone. CSF may capture the entire molecular landscape of the tumor, overcoming the sampling error inherent in tissue biopsies. Prospective studies are underway to further elucidate the clinical applications of this technique.
CNSC-23. CROSSTALK BETWEEN STROKE AND GLIOMA: ISCHEMIA-INDUCED NEURONAL ACTIVATION ON GLIOMA INFILTRATION
Authors: Christine Madamba, Qi Ye, Hyun Kyoung Lee
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma (GBM) is an aggressive primary brain tumor associated with dismal survival rates. GBM is difficult to treat due to its ability to invade neighboring brain regions, rendering complete surgical resection nearly impossible. Throughout tumor progression, several pathological changes occur in the tumor microenvironment (TME) including increased neuronal hyperactivity. Interestingly, these pathological features also occur in stroke, a leading global cause of death and disease burden. Clinical evidence from large cohort studies reveals a 10% risk of brain tumor development in stroke patients, suggesting a link between these two diseases. However, the intricacies of their association and whether stroke poses a long-term risk for GBM is unclear. To investigate this, we have developed innovative stroke-glioma mouse models to recapitulate and delineate the interrelationship between these two diseases. Our data using these models indicate a substantial increase in tumor growth and infiltration towards the infarct using both human GBM-patient derived glioma cells in immunodeficient mice as well as in immunocompetent de novo mouse GBM. Further, spatial manipulation of stroke and glioma induction revealed that glioma cells preferentially invade the contralateral hemisphere towards the stroke lesion compared to control. This suggests stroke-induced changes may trigger glioma cell infiltration. Histological analysis of the TME shows increased neuronal activity specifically excitatory neuron synaptic marker expression in the leading edge of glioma post-stroke compared to control. Overall, stroke induction may promote tumor growth and infiltration by modulating the TME through increasing excitatory neuronal activation. Together, this study aims to deepen our understanding of the influence of stroke on gliomas, paving the way for invaluable insights essential for identifying at-risk patients and the development of potential treatments for affected patients.
INNV-37. REAL-WORLD OUTCOMES AMONG HIGH GRADE IDH1-MUTANT GLIOMA PATIENTS TREATED WITH AN IDH INHIBITOR
Authors: Michal Nisnboym Ziv, Mallika P Patel, Maria Minor, Margaret O Johnson, Kristen Batich, Justin Low, Madison L Shoaf, Mustafa Khasraw, Annick Desjardins, Henry S Friedman, David M Ashley, Katherine B Peters
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) inhibitors are transforming the treatment of patients with non-enhancing grade 2 IDH-mutant gliomas. Uncertainty remains on the utility of IDH-inhibitors in high-grade IDH-mutant glioma patients that had prior therapies and have progressive disease. METHODS From October 2020 to December 2023, we identified high-grade IDH1-mutant patients treated with off-label ivosidenib, a mutant IDH1 inhibitor. We report their clinical and imaging characteristics. RESULTS In our cohort (n=18), the patient age range was 29-68 years with male predominance (n=11). Diagnoses included astrocytoma grades 3 (n=9) or 4 (n=2), and oligodendroglioma grade 3 (n=7). The median number of progressions prior to ivosidenib initiation was 2 (range 1-7). Fifteen patients had prior surgical resection, three had biopsy. Prior treatment exposures included radiation therapy (n=15), temozolomide (n=18), lomustine (n=5), bevacizumab (n=3), etoposide (n=1), optune (n=1) and a clinical trial (n=1). Mean time from diagnosis to ivosidenib treatment was 9.6 years (95% CI, 6.7 to 16.4 years). Karnofsky performance-status score upon initiation was 80 (n=6) or 90 (n=12). Thirteen patients had &amp;gt;1 cm enhancing disease, five had non-enhancing disease. Ivosidenib was initiated due to enhancing disease progression (n=11), non-enhancing disease progression (n=4), a combination of both (n=2) or temozolomide intolerance (n=1). Best radiographic responses per RANO criteria were partial response (n=2), minor response (n=3), stable disease (n=7), and progressive disease (n=6). Nine patients continue ivosidenib without disease progression, with a median treatment duration of 27.5 months (95% CI, 18.0 to 33.0 months). All had FLAIR stabilization/improvement and 45% (n=4) had improved enhancing disease. Nine patients discontinued ivosidenib due to progression, with a median treatment duration of 7 months (95% CI, 3 to 9 months). CONCLUSIONS These data suggest that treatment with an IDH inhibitor can provide disease control for some high-grade IDH-mutant glioma patients who had prior therapies and progressive disease. Future studies are needed to investigate this patients population.
QOL-20. NATIONAL BRAIN TUMOR SOCIETY BRAIN TUMOR QUALITY OF LIFE RESEARCH AGENDA
Authors: Danielle Leach, Bethany Kwan, Liz Salmi, Morgan Whaley, Kristin Odom, David Arons
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND QoL is a critical aspect of health care outcomes, particularly in the context of brain tumor treatment and survivorship. There are evidence gaps in optimal strategies for improving QoL among brain tumor patients and care partners. Understanding the multifaceted dimensions of QoL and identifying key areas for brain tumor QoL research can significantly enhance patient care and support. Engaging the brain tumor community in defining QoL outcomes and determining research priorities can help orient research resources to community needs and perspectives. OBJECTIVE To summarize the process and outcomes of an NBTS-led collaborative effort to co-design a comprehensive research agenda on QoL for brain tumor patients and care partners, as outlined in the “Brain Tumor QoL Research Agenda.” METHODS The agenda was developed through a collaborative effort involving experts in neuro-oncology, patients, care partners, patient advocacy groups, and healthcare professionals over a two-year period. A review of existing literature, patient experiences, and expert opinions informed the identification of key research priorities. A multistakeholder advisory group held monthly meetings where brain tumor QoL was defined. In 2023, we conducted two “Research Roundtables” for adults and pediatric/AYA. The World Cafe method captured data and a survey consensus process to validate findings. RESULTS The QoL research agenda delineates a multifaceted framework encompassing domains crucial for understanding and improving QoL in brain tumor patients. Key focus areas include symptom management, psychosocial support, care burden, treatment decision-making, survivorship issues, and health care delivery models. An RFP was released by NBTS with input from stakeholder advisors in April 2024. CONCLUSION The Brain Tumor QoL Research Agenda created a roadmap for advancing research efforts aimed at enhancing the QoL of individuals affected by brain tumors. By addressing the identified research priorities, healthcare stakeholders can work towards implementing effective interventions and policies to optimize patient outcomes and well-being. This program was funded through a Patient-Centered Outcomes Research Institute® (PCORI®) Eugene Washington PCORI Engagement Award (EACB-23261).
CNSC-18. A SCOPING REVIEW OF HISTONE 3.3 G34R/V HIGH-GRADE GLIOMA: EPIGENETIC AND MOLECULAR PROFILES, CLINICOPATHOLOGY, AND TREATMENT AVENUES
Authors: Kayen Tang, Melissa Cesaire, Taylor McDonald, Maria Castro, Sadhana Jackson
Journal: Neuro-Oncology (2024)

Abstract Survival of pediatric and young adults with malignant glioma remains poor despite progress in treatment. This is especially true for histone 3.3 G34R/V (H3.3G34R/V) mutated gliomas, which often present in adolescent and young adult patients. While treatments to date delay progression, post 5-year overall survival is exceedingly rare. Historically, there has been limited research on H3G34R/V mutant tumors, which likely contributes to lack of advancements in current treatments. This scoping review fills the current knowledge gap of H3G34R/V mutated gliomas and summarizes future targets and therapeutic options. In October 2023, MEDLINE, Embase, Cochrane Library, and Web of Science Core Collection were searched. Two reviewers screened all articles by title and abstract review and three independent reviewers extracted all studies meeting inclusion criteria relevant to H3G34R/V tumors (preclinical and clinical studies). Of the 2203 articles screened, 200 were deemed eligible. The 200 articles included 68 literature reviews, 9 systematic reviews, 54 preclinical studies, and 69 clinically oriented studies. We found that the United States and ACTA neuropathologica are the top country and journal contributors, respectively, to understanding molecular diagnosis, disease pathology, and potential targeted treatment options of H3.3G34R/V tumors. This literature collectively demonstrates the involvement of numerous oncogenes and tumor suppressor genes involved in RAS/MAPK, MYCN, NOTCH, and LIF/STAT pathways such as ATRX, PDGFRA, and TP53 in influencing the neural characteristics and prognostic outcomes of the tumor. While certain therapeutic modalities, including H3K9 methyltransferase inhibitors and bevacizumab-based therapy have exhibited preclinical efficacy and some indication of positive clinical outcomes, more research on agents that permeate the blood-brain barrier to impair growth are necessary. Additionally, further research into the supportive role of the tumor microenvironment that enables disease progression is warranted. Collectively, these studies will empower intelligent prospective clinical trials using H3.3G34R/V targeted therapies which enhance disease survival.
CTNI-19. MYCOPHENOLATE MOFETIL TARGETS GLIOBLASTOMA DE-NOVO PURINE METABOLISM TO OVERCOME CHEMORADIATION RESISTANCE IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: Yoshie Umemura, Nathan Clarke, Wajd Al-Holou, Ameer Elaimy, Andrew Scott, Denise Leung, Michelle Kim, Sean Ferris, Jennifer Thomas, Jason Heth, Matthew Schipper, Krithika Suresh, Theodore Lawrence, Daniel Wahl
Journal: Neuro-Oncology (2024)

Abstract Glioblastoma prefer de-novo purine synthesis while normal brain prefers resource-efficient salvage pathway. Mycophenolate mofetil (MMF) disrupts de-novo purine metabolism by inhibiting a key enzyme, IMPDH. The pre-clinical evidence of MMF improving radiation and temozolomide efficacy in glioblastoma models led to this first-in-human phase 0/1 trial (NCT04477200) to assess the tolerability of MMF with chemoradiation in glioblastoma, MPA accumulation, and purine synthesis inhibition in tumor. Tissues from eight phase 0 recurrent glioblastoma subjects, receiving MMF ranging 500-2000mg BID one-week pre-operatively, were analyzed using mass spectrometry. Both enhancing and non-enhancing tumor yielded &amp;gt;1µM active drug metabolite, and the GTP/IMP ratio was decreased by 75% in enhancing tumor in MMF-treated patients compared to untreated controls (p=0.009). In phase 1 study, adult patients were given MMF ranging 1000-2000mg PO BID using TITE-CRM dosing. Twenty-one recurrent glioblastoma patients (target N=30) received MMF one-week prior to and concurrently with re-irradiation (40.5 Gy) with no dose-limiting toxicities (DLTs). Thirty newly diagnosed glioblastoma patients received MMF one-week prior to and concurrently with chemoradiation, followed by MMF one-day before and during 5 days of each adjuvant temozolomide cycles. In the newly diagnosed cohort, there was no DLT with temozolomide and MMF, however, with both temozolomide and radiation, there were five DLT instances noted at 2000mg BID (G3 hemiparesis, G3 cognitive disturbance, G3 fatigue, G4 thrombocytopenia x2): all were reversible. Interim phase 1 median overall-survival in recurrent MGMT-methylated and unmethylated subjects were 16.1 (N=10) and 6.1 (N=11) months, and in newly diagnosed subjects, 27.2 (N=8) and 14.2 months (N=22) respectively. Median follow ups were 7.4 (recurrent) and 23.2 months (new diagnosis). MMF combined with chemoradiation is reasonably well tolerated in glioblastoma patients with promising evidence of drug accumulation in glioblastoma, effective target engagement and inhibition of purine synthesis, leading to a recommended phase 2 dose of MMF 1500mg BID.
NCMP-24. GLIOMA-RELATED EPILEPSY: ANTI-SEIZURE REGIMENS, TOLERABILITY AND SYMPTOM BURDEN
Authors: Shrey Patel, Oluwatosin Akintola
Journal: Neuro-Oncology (2024)

Abstract AIMS Seizures are often the presenting symptom in 30-40% of glioma patients, and play a significant role in patients’ quality of life and symptom burden. Many complex factors are considered when selecting anti-seizure medications (ASM) for the individual patient. This single institution study investigates physician practices, seizure control and adverse effect profiles of ASM regimens in glioma patients. METHOD A retrospective review was undertaken of the electronic health records of glioma patients from 2020-2022 who were followed at the University of Vermont Medical Center. RESULTS Ninety-four patients (90 glioblastoma IDH-WT, 1 astrocytoma, 2 oligodendroglioma, 1 radiological diagnosis of glioma) were included. Levetiracetam was the first line ASM in 93 patients including seizure prophylaxis patients per neurosurgical practice. 30 of the patients presented with seizures and required long term ASMs. 21 required a second-line ASM, 3 required a third-line ASM, and 20 experienced at least one adverse drug effect. 11.4% of patients experienced mood disturbances on levetiracetam, ranging from anxiety to mania. 5% of patients experienced generalized weakness and gait imbalance issues on levetiracetam. 25% of patients experienced breakthrough seizures over the course of their illness despite therapeutic levetiracetam &amp;gt; 1000mg/day. 10.4% of patients presented with breakthrough status epilepticus following the initiation of levetiracetam therapy. No statistically significant differences were seen in rates of breakthrough seizures based on extent of resection, functional status or sex. CONCLUSIONS Seizures are a major cause of morbidity in glioma patients. The overwhelming majority of patients included in this study were placed on levetiracetam as a first-line ASM. Most patients on long-term levetiracetam experienced at least one neuropsychiatric adverse effect. Further studies are required to investigate the efficacy and tolerability of ASM regimens in glioma patients and to understand methods for ASM regimen individualization for varying disease courses.
NCMP-27. NEUROLOGICAL COMPLICATIONS IN LUNG CANCER THERAPIES: UNVEILING THE ELEVATED RISKS IN CHEMOTHERAPY AND TARGETED TREATMENT APPROACHES
Authors: Swetha Manne, Joshua Currie
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Neurological complications due to lung cancer treatments are a common side effect, with prevalence ranging from 19% to over 80% depending on the drug administered. Peripheral neuropathy is the most common manifestation of chemotherapy associated neurotoxicity, but there are potential central nervous system impacts as well, such as seizures, dementia, and generalized cognitive impairment. Occurrence of similar effects is less commonly reported with targeted gene therapy for cancer, however the exact prevalence has not been determined. DESIGN/METHODS We searched the US Collaboration network through TriNetX for all cases of lung cancer, identified by ICD-10 code C34. Cohort A was defined as adults 18-70 years old that had lung cancer treated with cisplatin or etoposide. Cohort B was defined as adults 18-70 that had lung cancer treated with crizotinib, alectinib, or epidermal growth factor receptor tyrosine kinase inhibitors. Outcomes were evaluated from 1 day to 5 years after the indexed event. RESULTS We reported 15,268 patients with lung cancer that were prescribed chemotherapy agents matched with 6,490 patients with lung cancer that were prescribed tyrosine kinase inhibitors. Patients prescribed chemotherapy agents were at significantly higher risk for neurological complications post treatment when compared to those treated with tyrosine kinase inhibitors (p &amp;lt; 0.0001). CONCLUSIONS Patients diagnosed with lung cancer on chemotherapy 18-70 years old displayed higher associated risk of various neurological disorder diagnoses. Patients undergoing chemotherapy should be educated about this increased risk and talk with their providers about alternative treatments. Further research should be conducted on the range of potential neurological complications associated with chemotherapy regimens.