bluuebunny/crossref_metadata_2025 huggingface dataset:
NCOG-12. SURVIVAL OF THE ELDERLY: OUTCOMES OF VERY OLD GLIOBLASTOMA PATIENTS – RESULTS FROM AN AUSTRIAN MULTICENTER STUDY
Authors: Demetz Matthias , Hecker Constantin , Krigers Aleksandrs , Machegger Lukas , Kerschbaumer Johannes , Pöppe Johannes , Geiger Philipp , Spinello Antonio , Griessenauer Christoph J , Thomé Claudius , Schwartz Christoph , Freyschlag Christian
Published: November 2023

INTRODUCTION

Glioblastoma (GBM) outcomes in very old patients remain understudied. Limited data exist on outcomes and treatment options for this specific population, necessitating further research. Materials and

METHODS

We retrospectively analyzed all elderly GBM patients ( >65 years), who underwent treatment at two Austrian academic centers from 2007 to 2021. We conducted a comparative analysis between patients aged 65-79 years (old cohort) and a cohort of patients aged over 80 years (very old cohort).

RESULTS

387 patients were included, 43 of them over 80 years of age at the time of surgery. Median preoperative Karnofsky Performance Score (KPS) amounted to 80, median preoperative tumor volume was 26.44cm3. Among elderly patients 283 (75%) underwent resection and 61 (25%) only biopsy. 66.5% of the elderly cohort underwent adjuvant treatment following the EORTC protocol. 88 patients (25.6%) experienced preoperative seizures. Among the very old cohort 29 patients (67%) underwent resection and 14 (33%) biopsy only. 42.5% received adjuvant treatment, 5 patients (11.6%) presented with preoperative epilepsy. Mean PFS was 8.9 months in old patients and 8.4 months in very old patients. Kaplan Meier Analysis revealed a mean OS of 12.8 vs 10.7 months respectively. Elderly patients showed significantly better preoperative KPS (p=0.033) as well as higher preoperative tumor volumes (p=0.039). Old patients showed significantly higher incidences of both preoperative (p=0.043) and postoperative (p=0.032) epilepsy. Furthermore, old patients underwent significantly more often resection (p=0.020) and adjuvant therapy (p=0.009) compared to very old patients. However, survival analysis showed no statistic differences regarding PFS and OS between the two groups (p >0.05).

CONCLUSION

Despite preexisting unfavorable prognostic features, we could not find any significant differences between old and very old GBM patients. Hence, the treatment of glioblastoma in very old patients should adopt a more inclusive approach considering the patient's overall health status and comorbidities.
NCOG-15. COMPARATIVE ANALYSIS OF GLIOMA INDUCED IMPAIRMENT MODELS
Authors: Kaur Jasleen , Aabedi Alexander , Brandes Kirsti , Hervey-Jumper Shawn
Published: November 2023

Speech is produced by the coordination of neural networks involved in language processing and motor control of vocal outputs, both of which can be disrupted by diffuse gliomas. Natural language is the instinctual written or spoken language profile that an individual has developed throughout his or her lifetime. Recent psycholinguistic analyses suggest that patterns of natural language may be an accurate measure for assessing clinical and behavioral conditions. One important feature of natural language is speech onset. Speech delays are common complaints among patients with glioma. Here, we assess the relationship between speech onset and histologic-molecular features of glioma. Speech onset was defined as acoustic measure of the interval of time between the release of the oral constriction in a stop consonant and the onset of subsequent voicing. Audio samples and video analysis of oral kinetics were analyzed from patients with newly diagnosed low- and high-grade glioma. Features were extracted by manual segmentation and aligned for each trial with high-density electrode arrays to record task specific responses from gliomas projecting to the cortical surface. A total of 1,120 stimuli (672 = picture naming (PN) and 448 auditory naming (AN) trials were presented. As expected, patients with glioblastoma had higher picture and auditory naming error rates (p < 0.001, Mann-Whitney U test) compared with diffuse low-grade gliomas. Assuming speech errors produce slower response times, we next measured only correct behavioral responses which demonstrated 7% slower speech initiation responses (p < 0.0001, Mann-Whitney U test) when comparing patients with glioblastoma and diffuse low-grade gliomas. Slowed speech responses did not require glioma infiltration into canonical cortical speech areas of the lateral prefrontal cortex and superior temporal gyrus. Finally, we identified electrophysiological biomarkers of speech errors. These results deepen our understanding of speech processing impairments, which are not based purely on coding errors.
NCOG-21. TESTING AND VALIDATION OF A DIFFUSE GLIOMA COGNITIVE RESERVE MODEL
Authors: Brandes Kirsti , Kaur Jasleen , Hervey-Jumper Shawn
Published: November 2023

Behavioral and cognitive symptom severity varies widely across patients with glioma because of unknown mechanisms. The concept of cognitive reserve (CR) recognizes that there are individual differences in each person’s brain reserve capacity and this theory accounts for the common disconnection between the degree of brain injury and its symptom manifestations. CR is a fixed variable throughout an individual’s life and works by recruitment of dormant yet redundant neural networks, and by efficient information modulation. New strategies to treat cognitive impairments have been encumbered by a lack of models that accurately reflect human disease. Here, we measure the Cognitive Reserve Index (CRI) in a registry of 450 patients with WHO grade 2-4 glioma. Transient behavioral impairments were induced by anesthetic medications propofol, dexmedetomidine, and remifentanil during standard of clinical care. We administered and analyzed 48 picture naming (PN) and 32 auditory stimulus naming (AN) trials per patient both before and after drug administration with impairments defined as a decline in task performance by more than one standard deviation from the mean. We discovered that the CRI in patients with glioma follows a normal distribution, like the general US population. Next, we found a significant decline in task performance in a subgroup of patients in both PN and AN. Electrode arrays in vivo to record human local field potentials from glioma infiltrated cortex demonstrated electrophysiological biomarkers of cognitive decline. Further elucidation and validation of CR measures in patients may significantly influence the delivery and timing of cancer directed therapies.
NCOG-29. THE NEURO-ONCOLOGY MAGNITUDE OF CLINICAL BENEFIT SCALE (NEURO-MCBS) AS A COMPREHENSIVE AND CLINICALLY RELEVANT ASSESSMENT TOOL TO DETERMINE CLINICAL BENEFIT FROM TARGETED THERAPIES IN CNS TUMORS
Authors: Kurz Sylvia C , Renovanz Mirjam , Rieger Johannes , Bombach Paula , Grosse Lucia , Rieger David , Hucker Svenja , Hille Hanni , Hippler Melina , Oener Oeznur , Ruhm Kristina , Beha Janina , Malek Holly S , Moeller Yvonne , Bitzer Michael , Malek Nisar , Tabatabai Ghazaleh
Published: November 2023

BACKGROUND

Once first-line therapy options fail, there are no effective therapy options for most neuro-oncological conditions, including glioblastoma, gliomas, and brain metastases, thereby representing a high unmet clinical need. Novel targeted therapy options are often explored in small phase-I studies or are given as off-label therapies. Assessment of treatment efficacy in this setting is challenging and should incorporate outcome measures such as progression-free survival (PFS) or objective response rate (ORR) as well as clinical parameters. To address this, we developed the Neuro-Oncology Magnitude of Clinical Benefit Scale (Neuro-MCBS) as a comprehensive clinical tool to assess treatment efficacy in patients with CNS tumors who receive off-label targeted therapies outside of clinical trials. We prospectively evaluated the feasibility and clinical utility of the Neuro MCBS in a neuro-oncology patient cohort enrolled in MTB@ZPM.

METHODS

MTB@ZPM (NCT03503149) is a longitudinal observational study that provides comprehensive molecular profiling, consensus-guided and ranked targeted therapy recommendations and collection of prospective clinical outcome data. The Neuro-MCBS (grade 1 + 2=clinical benefit, grade 3=minimal benefit, grade 0=no benefit) was applied and correlated with PFS, the PFS2/PFS1 ratio, performance status (KPS, ECOG), and imaging parameters.

RESULTS

From February 1st, 2022 until January 31st, 2023, 70 patients were enrolled. While only a minority of n=17/36 (47%) glioblastoma and n=2/8 (25%) IDH-mutant astrocytoma patients benefited from targeted therapies, n=7/8 (88%) meningioma, n=9/10 (90%) brain metastases, and n=5/8 (63%) other tumor patients achieved a Neuro-MCBS of 1 or 2, i.e. derived clinical benefit from the molecularly based therapy.

CONCLUSIONS

The Neuro-MCBS is a comprehensive and clinically relevant assessment tool that incorporates clinical, imaging, and survival outcome data to determine the degree of clinical benefit from targeted therapies in patients with primary and secondary CNS tumors. Its incorporation into clinical practice provides an objective outcome measure of clinical utility vs. futility of targeted therapies.
NCOG-35. WEIGHING BENEFITS OF IMPROVED LONG TERM SURVIVAL AGAINST THE EFFECTS OF POST-RADIOTHERAPY NEUROCOGNITIVE DECLINE: ROLE OF RADIOTHERAPY FOR TREATMENT OF PEDIATRIC PRIMARY CNS NEOPLASMS
Authors: Brown Nolan , Kuo Cathleen , Nguyen Oanh , Gendreau Julian
Published: November 2023

OBJECTIVE

To comprehensively review and weigh benefits of radiotherapy for pediatric primary central nervous system (CNS) tumors, which lengthens survival in the setting of potentially debilitating morbidity, including post-radiotherapy neurocognitive decline.

METHODS

In this review, the authors examined all the published literature analyzing results of clinical trials, case series, and technical notes on patients undergoing radiotherapy for the treatment of tumors of the central nervous system, with an emphasis on neurocognitive decline and survival outcomes.

RESULTS

Radiotherapy is an essential component of the treatment regimen for pediatric medulloblastoma. A recent trial demonstrated association between contemporary treatment protocols and significant post-radiotherapy neurotoxicity. A new protocol for WNT 2-driven medulloblastoma has been proposed and is undergoing testing: 18 Gy in 10 fractions plus a tumor-bed boost of 36 Gy in 20 fractions for a total primary site dose of 54 Gy in 30 fractions without concurrent chemotherapy followed by the standard six cycles of adjuvant systemic chemotherapy. Maximal surgical resection remains the mainstay of therapy for low grade glioma, as radiation therapy is reserved for subsequent recurrence or progression. Management paradigms are similar for high grade gliomas and ependymomas. Overall, radiotherapy allows for greater lifetime survival but also lengthens the morbidity from late effects, especially neurocognitive decline. This is largely due to the unintended consequence of radiation- induced damage to the normal neural tissue caught in the beam trajectory. Advancements in photon-based radiotherapy confined the volume of the brain that was irradiated to fit the tumor margins more closely; however, the advent of PBRT further allows for greater sparing of normal neuronal tissue, by maximizing energy deposition at the tumor location while minimizing energy deposition both proximal and distal to the tumor target.

CONCLUSION

Future research is needed to develop interventions for those already suffering from the late effects of post-radiotherapy neurocognitive decline.
NCOG-38. UNDERSTANDING GLIOMA IN LI-FRAUMENI SYNDROME: HIGHLIGHTING THE VALUE OF SCREENING AND GENE SEQUENCING
Authors: Padilla Hannah , Carabenciov Ivan , Uhm Joon , Neth Bryan
Published: November 2023

Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant disorder characterized by a germline mutation in the TP53 gene that confers an increased risk of developing cancers, including brain tumors. There is continued need to understand how LFS diagnosis impacts clinical management and outcomes of gliomas. We report the clinical course of two patients from our Neuro-Oncology. Patient 1 is a male who was diagnosed with a low-grade astrocytoma, IDH1 mutant at age 20 status post gross total resection. Given radiographic concern for tumor progression, he underwent re-resection 8 years later. Pathology showed gliosis with TP53-mutant cells. Next-generation sequencing (NGS) was positive a germline TP53 mutation, consistent with LFS. He is currently in surveillance 12 years after diagnosis without need for radiation or chemotherapy. Patient 2 is a female who was diagnosed with glioblastoma, IDH wildtype, MGMT promoter unmethylated at age 40. She was asymptomatic at the time of diagnosis as the tumor was found during routine screening. She underwent gross total resection, radiation with concurrent and adjuvant temozolomide. She is now 5 years from last treatment without recurrence. These cases illustrate the clinical spectrum of glioma in LFS. Both patients have had prolonged periods of survival without progression, even accounting for respective tumor type. Patient 1 was only diagnosed with LFS after radiographic concerns for progression. Using NGS to diagnosis LFS was clinically important, as previous reports have shown greater propensity for malignant transformation of low-grade glioma in LFS. Patient 2 was diagnosed with glioblastoma during screening and has had no recurrence. This highlights the value of early diagnosis and treatment of gliomas in patients with LFS, even if asymptomatic at discovery. Further research is needed to understand the clinical spectrum of glioma in LFS and to optimize the care of this unique patient population.
EXTH-05. ANTI-TUMOR IMMUNE RESPONSE OF ONCOMAGNETIC MONOTHERAPY IN GLIOBLASTOMA
Authors: Pandey Arvind , Hambarde Shashank , Baskin David S , Helekar Santosh A
Published: November 2023

BACKGROUND

Glioblastoma (GBM) is the most lethal primary malignant brain tumor with a median survival of 15–20 months. Concurrent temozolomide (TMZ) chemotherapy and radiation (XRT) remain the current standard of care (SOC) treatment for newly diagnosed GBM. The addition of tumor treating fields (TTFs) improves median survival for newly diagnosed GBM from 16 to 20.9 months. This modest improvement underscores the urgent need to identify a new treatment modality as a safe and effective therapy.

PURPOSE

The noninvasive Oncomagnetic device developed in our laboratory selectively kills glioblastoma (GBM) in vitro by generating the spinning oscillating magnetic field (sOMF) which disrupts electron transport chain, leading to a marked increase in reactive oxygen species (ROS) and consequently to cancer cell death. We studied the cellular and molecular effects of sOMF treatment on GBM cell lines and investigated the immune response to Oncomagnetic monotherapy (OMT) in a syngeneic mouse model.

RESULTS

sOMF significantly reduces cell proliferation and cell survival in vitro . It induces DNA damage and arrests cells in G1-phase of the cell cycle. Whole-body sOMF stimulation caused a substantial retardation of tumor growth and reduction of the contrast-enhanced tumor volume in 9.4T MRI scans. OMT showed significant increase in overall survival in treated mice. We also observed upregulated immune response indicated by RNA sequencing data obtained from sOMF-treated LN229 cells as well as in treated GBM mouse tumor sections by imaging mass cytometry analysis. The tSNE analysis of various immune clusters suggests significant increase in immune response by activating CD4+, CD8+, murine-macrophages and M1-macrophages located at tumor site in the treated group.

CONCLUSION

The obtained data indicate significant anti-tumor response by inhibiting cancer signaling pathways and an increased immune response. Our findings suggest unique mechanism of action for sOMF stimulation and provide a strong rationale for standalone OMT for GBM.
EXTH-13. ENHANCING INDUCED NEURAL STEM CELL-BASED TRAIL THERAPY FOR GLIOBLASTOMA THROUGH COMBINATION WITH THE NOVEL SENSITIZING AGENT TR-107
Authors: Thang Morrent , Mellows Clara , Mann Breanna , Kass Lauren , Daglish Sabrina , Fennell Emily , Mercer-Smith Alison , Valdivia Alain , Aponte-Collazo Lucas , Graves Lee M , Satterlee Andrew B , Hingtgen Shawn
Published: November 2023

Tumor-homing neural stem cell therapy (tNSC) is emerging as a promising treatment for aggressive cancers of the brain. Despite their success, developing tNSC therapies that maintain durable tumor suppression remains a challenge. Here, we report a new synergistic combination regimen where the novel agent TR107 augments induced NSC-TRAIL therapy (hiNeuroS-TRAIL) in models of the incurable brain cancer glioblastoma (GBM). We found that the combination of hiNeuroS-TRAIL and TR-107 synergistically upregulated caspase markers and restored the sensitivity to the intrinsic apoptotic pathway by significantly downregulating inhibitory pathways associated with chemoresistance and radioresistance in GBM. This combination regimen showed dramatic tumor suppression and enhancement of survival of mice bearing human xenografts of both solid GBM and established invasive GBM. The combination also synergistically suppressed tumor growth in low-passage patient derived GBM cells established with an ex vivo brain slice platform. These findings elucidate a novel combination regimen and suggest combination of these clinically relevant agents may represent a new therapeutic option with increased potency for GBM patients.
EXTH-26. 3D LIVE MICROSCOPY AND SINGLE CELL TRANSCRIPTOMIC TO DECIPHER MOLECULAR ACTORS INVOLVED IN GLIOBLASTOMA CELL INVASION IN HUMAN CEREBRAL ORGANOIDS
Authors: Verreault Maite , Akbar David , Cherchame Emeline , Galet Benjamin , Quissac Emie , Ravassard Philippe , Idbaih Ahmed
Published: November 2023

Glioblastomas are characterized by a highly invasive phenotype involving heterogeneous and dynamic molecular effectors. This process is one of the first causes of relapse following standard treatment. In vitro 2D cell migration assays do not recapitulate the biological and cellular microenvironment present in the human brain. Here, human induced pluripotent stem cells (hiPSC) -derived ventral forebrain organoids (hVFO) were used to assess the invasion phenotype of a panel of glioblastoma patient-derived cell lines (PDCLs) from mesenchymal, proneural and classical molecular subtypes. 3D live confocal microscopy allowed to characterize invasion phenotypes between PDCLs. A wide diversity of invasion phenotypes was observed which could not be explained by molecular subtypes. Single cell transcriptomic analysis was performed on a highly invasive PDCL following hVFO invasion, which permitted the identification of putative molecular candidates involved in invasion processes. Functional validation of druggable candidates is ongoing and will be presented.
EXTH-32. SYNERGISTIC EFFICACY OF Y BOX BINDING PROTEIN 1 (YBX1) INHIBITION COMBINED WITH CHEMOTHERAPY FOR THE TREATMENT OF MYC-AMPLIFIED MEDULLOBLASTOMA
Authors: Carney Stephen , Bonatto Christian , Guadarrama Guadalupe , Tailor Dhanir , Malhotra Sanjay , Evans Myron
Published: November 2023

Medulloblastoma is the most common pediatric brain tumor in children. Patients diagnosed with MYC-amplified group 3 (G3) have a dismal prognosis with a 5 year survival rate of < 50%. Standard of care consists of maximal resection surgery followed by craniospinal irradiation and chemotherapy, but patients experience diminished quality of life from these extensive treatment regimens. Recent observations have shown that Y-box binding protein 1 (YBX1) is upregulated across human medulloblastoma subgroups compared to normal cerebellum. G3 patient tumors have the highest expression of YBX1, possibly due to an oncogenic feedback loop. We utilized an orthogonal pharmacogenetic approach to target YBX1. Knockdown/out of YBX1 significantly inhibits proliferation of G3 MB cells in vitro and in vivo. We next investigated the therapeutic potential of a novel YBX1 inhibitor, which displays single agent efficacy at decreasing the proliferation of medulloblastoma cell line derived xenografts (CDX). Since YBX1 targeting downregulated ABC transporter expression, we hypothesize that inhibition of YBX1 may sensitize medulloblastoma cells to chemotherapeutic agents. We performed drug synergy experiments combining YBX1 inhibition and commonly used standard of care chemotherapy. We identify that combining YBX1 inhibition sensitizes to both gemcitabine and vincristine in vitro and in vivo. We are currently evaluating this YBX1 inhibitor in an “anchor-probe” screen combining with all currently FDA approved drugs. Our findings impart an alluring prospect of targeting YBX1 in combination with chemotherapy, and possibly other compounds could improve patients’ outcomes.
EXTH-37. FUNCTIONAL GENOMICS IDENTIFIES THERAPEUTIC VULNERABILITIES OF GLIOMA SUBTYPES AND YAP/TAZ-ENRICHED TUMORS
Authors: Lin Wan-Hsin , Kosari Farhad , Smadbeck James , Barrett Michael , Feathers Ryan , Penheiter Alan , Lynch Jamie , Sotiriou Sotiris , Sadeghian Dorsay , Maruthi Vijaya Kadam , Johnson Sarah , Karagouga Giannoula , Harris Faye , Berry Taylor , McCune Alexa , Murphy Stephen , Kinsella Lindsey , Moniz-Garcia Diogo , Ensign Shannon Fortin , Yang Lin , Emanuel Angela , Salvatori Rebecca , Klein Janet Schaefer , Ida Cristine , Jentoft Mark , Salomao Marcela , Sherman Wendy , Porter Alyx , Rosenfeld Steven , Kizilbash Sani H , Jaeckle Kurt , Mrugala Maciej , Mansfield Aaron , Borad Mitesh , Bendok Bernard , Burns Terry , Quiñones-Hinojosa Alfredo , Cheville John , Vasmatzis George , Anastasiadis Panos
Published: November 2023

Sequencing efforts have identified key oncogenic drivers and transcriptomic subtypes of high-grade gliomas (HGGs), but this knowledge has not resulted in individualized therapy or improved patient outcomes. Here, we used a functional genomics approach combining integrated genomic/transcriptomic analyses with patient-derived 3D micro-cancers (mCancers) to rapidly identify individualized therapeutic vulnerabilities and determine predictive response biomarkers. 30 primary/recurrent HGGs, including 20 glioblastomas, 5 astrocytomas, and 5 oligodendrogliomas, were included for drug testing. mCancers recapitulated the structural and molecular alterations, cellularity, and heterogeneity, of parental patient tumors. A total of 119 single-agent drugs and 183 drug combinations were tested, while a pre-selected drug panel comprising 25 glioma-relevant treatment strategies was tested across all cases. In general, mCancer efficacy corresponded well to historical responses to previously tested agents (EGFR, HDAC inhibitors, etc.). Combined, strong efficacy (i.e. >70% growth inhibition at Cmax) of single treatments targeting deregulated receptor tyrosine kinase (RTK), p53/apoptosis, cell cycle, DNA damage repair, IDH, or telomere maintainance pathways, was observed in 14 out of 30 cases. Surprisingly, transcriptional signatures, but not specific genetic alterations, were found to stratify drug responses. For example, mCancers enriched for the most aggressive mesenchymal (MES) and glycolytic/plurimetabolic (GPM) transcriptional subtypes exhibited stronger response to the BET inhibitor JQ1 (and other clinical BET inhibitors) and the DNA-PKcs/mTOR dual inhibitor CC-115. This therapeutic vulnerability was associated with enrichment of YAP/TAZ signaling, and the glioblastoma stem cell G-STEM signature. Notably, individual combination strategies were effective across tumors, with strong responses ranging from 38% to 77% of all tumors tested. Overall, this study underscores the value of functional genomics in identifying novel vulnerabilities of HGGs and associated response biomarkers. It also highlights the need for further clinical validation of several novel therapies and especially drug combination strategies with strong efficacy in the ex vivo setting.
EXTH-38. VELCRIN MOLECULAR GLUES INDUCE CELL DEATH IN GLIOBLASTOMAS WITH HIGH PDE3A AND SLFN12 EXPRESSION
Authors: Aquilanti Elisa , Goldoni Silvia , Baker Andrew , Kotynkova Kristina , Andersen Sawyer , Gao Galen , Cherniack Andrew , Lange Martin , Kopitz Charlotte , Lienau Philip , Lewis Timothy , Garrido Marine , Gradl Stefan , Seidel Henrik , Ligon Keith , Wen Patrick , Meyerson Matthew , Greulich Heidi
Published: November 2023

Velcrins are molecular glues that kill cells by inducing the formation of a protein complex between the RNase, SLFN12, and the phosphodiesterase, PDE3A. Formation of the complex activates SLFN12, which cleaves tRNALeu(TAA) and induces apoptosis. Velcrins such as the clinical investigational compound, BAY 2666605, were found to have activity across multiple solid tumor cell lines from the Cancer Cell Line Encyclopedia (CCLE), including glioblastoma cell lines. We therefore aimed to characterize velcrins as novel therapeutic agents in glioblastoma. We measured PDE3A and SLFN12 expression levels in commercially available glioblastoma cells as well as glioblastoma neurospheres from the Center for Patient Derived Models at Dana Farber Cancer Institute. We identified velcrin-sensitive glioblastoma cell lines and neurospheres, and determined that velcrin response is highly correlated with PDE3A expression. We also determined that sensitive cells exhibit a reduction in nascent polypeptide formation upon velcrin treatment, which is rescued by CRISPR-induced knockout of PDE3A. To assess velcrin efficacy in vivo, we measured central nervous system and plasma levels of the velcrin, BAY 2666605, and determined that it freely crosses the blood brain barrier. We also determined that twice daily dosing of BAY 2666605 elicits full tumor regression in an orthotopic glioblastoma xenograft model, with sustained complete responses after treatment withdrawal. Lastly, we demonstrated that the velcrins BAY 2666605 and BAY 2501293 induce tumor regression in biomarker-positive subcutaneous glioblastoma patient-derived xenograft models. In summary, our data demonstrates that velcrins have anti-tumor activity in preclinical models of glioblastoma, warranting further investigation as potential therapeutic agents.
EXTH-39. D2C7-CAR: A NOVEL, DUAL-SPECIFIC CHIMERIC ANTIGEN RECEPTOR T CELL WITH HIGH SPECIFICITY FOR EGFR AND EGFRVIII IMPROVES SURVIVAL IN EGFR/EGFRVIII GLIOBLASTOMA AND EGFR OVER-EXPRESSING MEDULLOBLASTOMA
Authors: Wilson Zach , Wilkinson Daniel , Ryan Katherine , Chandramohan Vidya , Bigner Darrell , Fecci Peter
Published: November 2023

BACKGROUND

GBM is the most common primary malignant brain tumor found in adults. Despite strenuous efforts at improving outcomes, overall survival remains dismal (15-20 months). D2C7-CAR is a dual specific CAR T cell that targets EGFR and EGFRvIII. We performed pre-clinical analysis of D2C7-CAR glioblastoma and other EGFR aberrant tumor models to assessed efficacy and safety.

METHODS

U87 and U87vIII glioblastoma and DAOY medulloblastoma cell lines were characterized by flow cytometry to evaluate for EGFR and EGFRvIII expression. Cytotoxicity assays were performed utilizing flow cytometry on serially diluted effector: target ratios of U87, U87vIII, and DAOY mixed with D2C7 CAR. U87 and U87vIII was orthotopically implanted into the frontal lobe and DAOY was orthotopically implanted into the frontal lobe and posterior fossa of NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. After tumor implantation, D2C7 CAR, vIII CAR, or Mock CAR was introduced within the tumor bed. Survival was measured and analyzed using the Log-rank test. Bioluminescence with IVIS imaging of CT2AVIII with luciferase was utilized to perform time point analysis of IC tumor response to treatment vs control. Toxicity against somatic tissue EGFR expression was assessed by in vitro cytotoxicity assay as described above.

RESULTS

EGFR was detected in U87, U87vIII, and DAOY on flow analysis. EGFRvIII was expressed only on U87vIII. D2C7 CAR demonstrated effective in vitro cytotoxicity against all three cell lines with >90% cytotoxicity achieved at an effector: target ratio of 2.5:1. In vivo, D2C7 CAR significantly prolonged survival compared to treatment with mock and vIII CAR when tumor was implanted intracranially. Bioluminescence imaging demonstrated robust tumor response. D2C7 was not cytotoxic when co-cultured with EGFR expressing human keratinocytes.

CONCLUSION

D2C7-CAR demonstrates effective preclinical results both in vitro and in vivo. D2C7-CAR is not cytotoxic against human keratinocytes, suggesting it will be well tolerated in clinical trials.
EXTH-41. COMBINATION TREATMENT OF CALCIUM CHANNEL ANTAGONIST MIBEFRADIL ENHANCES THE EFFECT OF HYDROXYUREA AT THERAPEUTIC RANGES IN HIGH-GRADE MENINGIOMA IN VITRO
Authors: White Erik , Prabhu Michael , Thakkar Jigisha , Barton Kevin , Prabhu Vikram , Piedras-Renteria Erika
Published: November 2023

High-grade meningiomas (MNs), WHO Grade II- III, are highly aggressive brain tumors that are difficult to treat. Standard chemotherapy agents are, at best, moderately effective in treating high-grade MNs. There is great interest in developing combinatorial drug treatment regimens to enhance the effects of standard chemotherapy. Many cancer types, including brain tumors, have an increase in the expression of voltage-gated calcium channels (VGCCs). These channels are involved in the regulation of cell cycle, proliferation, and apoptosis, among other functions. FDA-approved VGCC antagonists nimodipine (NIMO) and mibefradil (MIB) target two different VGCCs, L- and T-type channels, and have been of great interest for their use in combination therapy in other cancers. We sought to determine the efficacy of chemotherapy agents tested at clinically relevant concentrations for the treatment of high-grade MNs alone or in combination with NIMO or MIB. We cultured CH-157MN and IOMM-Lee MN cells and assessed their cell survival, apoptosis, and proliferation in the presence of temozolomide, octreotide, sunitinib, or hydroxyurea (HU). We confirmed that HU (150 µM) was the most efficacious chemotherapy agent, decreasing cell viability at therapeutic ranges. Monotherapy treatment with 2 or 4 µM MIB significantly decreased cell viability in both cell lines, whereas 1 µM NIMO only affected IOMM-Lee cells. The combination of HU and MIB further decreased cell viability but only in the most aggressive cell line, IOMM-Lee, whereas NIMO did not enhance HU’s ability to decrease cell survival. Remarkably, we detect an enhancement of HU’s effect by MIB when both agents are used within therapeutic ranges, as reported by pharmacokinetic studies. Here we demonstrate for the first time that T-type calcium channels play an important role in MN survival. The combination of HU and MIB suggests their use could be a promising treatment for high-grade MN.
EXTH-48. PROTOPORPHYRIN IX LEVELS IN PATIENTS’ PLASMA, BLOOD, AND BRAIN TUMOR BY A VALIDATED LC-MS/MS METHOD
Authors: Knight William , Margaryan Tigran , Sanai Nader , Tovmasyan Artak
Published: November 2023

BACKGROUND

Protoporphyrin IX (PPIX) is an intermediate molecule in the heme biosynthesis pathway. Cancer cells, having a higher metabolic rate than normal cells, accumulate PPIX when an exogenous dose of its precursor, 5-aminolevulinic acid (5-ALA), is administered. 5-ALA is currently approved by the U.S. FDA for the visualization of high-grade gliomas (HGG) and fluorescence guided surgery. 5-ALA and PPIX are also central to experimental treatments of photodynamic and sonodynamic therapy for HGG patients. Accurate quantitation of PPIX in brain tumor, plasma, and blood is necessary to evaluate its pharmacokinetics and hence optimize its therapeutic benefit in the context of experimental therapies and tumor visualization.

METHODS

Plasma was used as a matrix for PPIX quantitation in plasma and brain homogenate. Brain homogenates (1:7) were prepared in 5 mM ammonium formate containing 0.2% formic acid. A separate plasma curve was used for blood quantitation. Before protein precipitation, blood and corresponding calibrators were diluted five times with water. PPIX was extracted from human plasma, blood, and brain homogenate samples using methanol containing PPIX-d6 (internal standard). Sample preparation was performed under low light conditions (< 5 lux). Chromatographic separation of the analyte was achieved isocratically on Phenomenex Kinetex™ EVO C18 column, with a total run time of 3.5 min. Analyte detection was performed on Sciex QTRAP 6500+ MS/MS detector.

RESULTS

The method was validated for 1-2000 nmol/L range. Using plasma as a surrogate matrix, the maximum coefficient of variation for intra- and inter-day precision and accuracy were within acceptable ranges for all matrices.

CONCLUSIONS

A new rapid and sensitive LC-MS/MS method was successfully validated for the PPIX quantitation in human plasma, blood, and brain. It is currently used in a sonodynamic therapy clinical trial (NCT04559685) to evaluate PPIX pharmacokinetic profile in plasma and blood, and to determine levels in brain tumors of HGG patients.
EXTH-51. IDENTIFYING REGULATORS OF HETEROGENEITY IN DMGS USING SCREGCLUST
Authors: Yildirim Irem , Larsson Ida , Nelander Sven
Published: November 2023

Diffuse Midline Gliomas (DMGs) are pediatric brain tumors that arise in the pons, thalamus or the brainstem. DMGs present a pressing clinical problem since they cannot be surgically removed and respond poorly to radio- and chemotherapies. Like adult gliomas, DMGs present a high degree of intra-tumoral heterogeneity, with cells adopting different levels of differentiation similar to oligodendrocytes, astrocytes, precursor and mesenchymal cells. These different phenotypes possibly play distinct roles in tumor progression. Yet, we lack a good understanding of the underlying mechanisms of DMG heterogeneity. Here, we present a novel strategy to uncover regulator genes of DMG heterogeneity in a comprehensive and unbiased fashion, using an integration of machine learning with Cas9-based Perturb-seq. We first use a new data-driven modeling technique, termed single cell regulatory-driven clustering (scRegClust; Larsson et al., BioRxiv 2023) to uncover transcriptional modules, and their upstream transcriptional and kinase regulators. The goal of this analysis is to identify regulator genes that control cellular processes relevant to the disease, thereby enhancing our understanding of DMGs and uncover potential therapeutic targets. Applied to recently available single-cell data from 90 DMG patients, scRegClust revealed 160 regulators of meta-modules including oligodendrocyte-like, oligodendrocyte-progenitor-like, astrocyte-like and mesenchymal like cells. To validate the importance of these regulators, we are establishing a Perturb-seq experimental pipeline by combining pooled CRISPR knock-out and single cell RNA sequencing in patient-derived DMG cell lines. By perturbing the candidate regulators both in vitro and in vivo we aim to evaluate their impact on DMG tumorigenicity. This comprehensive strategy will ultimately increase our understanding of the molecular processes in DMGs and present the functional significance of these regulators and their involvement in disease progression.
EXTH-66. SINGLE-CELL SPATIOTEMPORAL GENOMICS REVEALS CLONAL EVOLUTION AND THERAPEUTIC TARGET IN RECURRENT DISSEMINATED MEDULLOBLASTOMA
Authors: Liu Hailong , Li Jiankang , Wang Ziwei , Liu Fei , Qiu Xiaoguang , Jiang Tao
Published: November 2023

Despite the cellular heterogeneity observed in single-cell studies of medulloblastoma, limited knowledge exists regarding the genetic features and spatiotemporal states of specific cell populations following tumor relapse and dissemination, leading to a lack of effective treatment strategies. In this study, we conducted single-cell transcriptomic, chromatin accessibility, and spatial transcriptomic analyses on 15 primary and recurrent Group 3 medulloblastomas, along with two PDX models (including a lung metastasis model). Subsequently, we deconvoluted our findings with our RNA-seq cohort to further validate cell cluster-specific gene expression associated with relapse and its prognostic significance. We analyzed malignant cells, including cancer stem cells (MB-CSCs), proliferating cells, and differentiated cell populations, and examined gene expression features closely associated with clinical prognosis. To elucidate the origin and maturation process of these malignant cells accurately, we compared tumor cell profiles with early human cerebellar cell-types. Furthermore, we described the spatiotemporal transitions from MB-CSCs to terminal states, with a particular emphasis on the extensive spatial heterogeneity within the tumor during the processes of primary, local relapse, and dissemination. Through computational non-negative matrix factorization (cNMF) analysis, we identified a group of tumor cells in recurrent Group 3 medulloblastoma with high cellular plasticity (HCP), demonstrating strong stemness and proliferative capabilities, as well as the ability to differentiate into multiple functional tumor cell subgroups. This cell population exhibited elevated expression of PTPRZ1, which phosphorylates downstream molecules to promote tumor progression. Through single-cell transcriptomic and chromatin accessibility analyses, we validated the expression of PTPRZ1 in human samples, PDX samples, and transgenic mouse samples. In vitro and in vivo inhibition of PTPRZ1 function using small molecule inhibitors effectively suppressed tumor proliferation and metastatic activity. By employing single-cell spatiotemporal genomics, we elucidated the evolutionary states and subclonal events of primary and recurrent medulloblastoma, and identified PTPRZ1 as a target for effectively inhibiting tumor progression.
EXTH-72. TARGETED INHIBITION OF THREE MAJOR PROLIFERATION PATHWAYS IN GLIOBLASTOMA INDUCES SENESCENCE THROUGH A MITOCHONDRIA-DEPENDENT MECHANISM
Authors: Baltira Chrysiida , Mayayo-Peralta Isabel , Guillen-Navarro Miriam , Alkan Ferhat , Thijssen Bram , Pello Kimberley , Fedorushkova Daria , Their Anna , Silva Joana , Jochems Fleur , Bleijerveld Onno , Janssen Hans , Faller William , Bernards Rene , de Gooijer Mark , van Tellingen Olaf
Published: November 2023

Glioblastoma (GBM) is a fatal brain tumor with a great unmet need for better therapies. Research on the genomic landscape of GBM has revealed that three major proliferation pathways — the PI3K-mTOR-AKT, the MAPK, and the CDK4/6-RB pathways — are overactive in the majority of GBM patients. Based on that knowledge we have developed a multi-target combination therapy (MTCT) by employing inhibitors of these three pathways. When these inhibitors are used in combination, lower, clinically more relevant concentrations of each drug are sufficient for target inhibition and proliferation arrest than with single agents. Excitingly, we find that MTCT not only shuts down proliferation but also causes permanent growth inhibition by the induction of senescence and the secretion of a senescence-associated secretory phenotype (SASP). MTCT-senescent cells have increased mitochondrial reactive oxygen species (mtROS). However, they do not acquire nuclear DNA damage but only local mitochondrial DNA damage. Addition of antioxidants that deplete mtROS resulted in senescence rescue both in terms of morphology and proliferation arrest. MTCT-senescent cells display an enhancement in total mitochondrial mass, mitochondrial DNA copy numbers, and the transcription of mitochondrial proteins. Despite this enhancement, the basal respiration rate of these cells is comparable to untreated cells, indicating an impaired maximal respiration capacity in MTCT-senescent cells. Concordantly, these cells display striking disturbances of their mitochondrial network. Intriguingly, depletion of functional mitochondria prevents the induction of mtROS and senescence by MTCT but not by classical senescence inducers such as ionizing radiation or high concentrations of CDK4/6 inhibitors. To conclude, MTCT induces senescence in GBM cells through a unique nuclear DNA damage-independent mechanism for which the mitochondria are essential.
QLTI-02. ADVERSE EVENTS IN GLIOMA SURGERY: RESULTS OF A PROSPECTIVELY COMPILED DATABASE OF A SINGLE-CENTER TERTIARY CARE HOSPITAL
Authors: Trong Philip Dao , Kaes Manuel , Jungk Christine , Unterberg Andreas
Published: November 2023

BACKGROUND

Adverse events in glioma surgery can cause severe problems for patients and can be a significant burden to healthcare systems. Therefore, understanding and avoiding adverse events should be essential in centers performing glioma surgery. Nevertheless, it is still uncommon to assess adverse events in a prospective, standardized manner. In this study we want to share the findings of our prospectively compiled database for adverse events in glioma surgery.

METHODS

Every patient treated at our institution received a peer-reviewed, standardized discharge form focused on adverse events. Any event, that led to readmission, worsening of clinical outcome, new neurological deficits, revision surgery, contributed to death or prolonged hospital stay within 30 days of discharge was recorded and classified according to the treatment-related classification system of Clavien-Dindo (Grade 1 requiring to treatment to Grade 5 resulting in death).

RESULTS

In 2022 a total of n = 194 patients received glioma surgery at our institution. Surgery was performed using a common craniotomy in 145 cases (74.7%), an awake craniotomy in 16 cases (8.2%) and in 33 cases (17.0 %) a stereotactic approach for biopsy was chosen. A total of n = 44 (22.7%) adverse events were recorded among these cases. The most common adverse event was a new neurological deficit after surgery in 20 cases (10.3%) followed by non-surgery related adverse events in 10 cases (5.2%). Wound healing disorders and CSF-leaks were recorded in 8 cases (4.1%) and in 6 cases (3.1%), respectively. Clavien Dindo classification showed low-grade complications (grade 1,2) in 15.9% and high-grade complications (grade 3,4,5) in 6.6%. Revision surgery was necessary in 9 cases (4.6%).

CONCLUSION

Adverse events in glioma surgery are not uncommon. Understanding and classifying these events in a prospective, standardized manner may help to reduce the risk of adverse events in glioma surgery in the future.
QOL-09. QUALITY OF LIFE AFTER SURGERY FOR LOWER GRADE GLIOMAS
Authors: Heffernan Anne , Wu Yilun , Benz Luke , Verhaak Roel , Kwan Bethany , Claus Elizabeth
Published: November 2023

BACKGROUND

Limited data exist on long-term quality of life (QOL) for adults diagnosed with lower grade glioma (LGG).

METHODS

QOL was assessed for 320 adults with LGG (World Health Organization grade 2/3) enrolled in the International Low Grade Glioma Registry using the Medical Outcomes Study 36-Item Short Form (SF-36) health survey. Data on symptoms were also collected. QOL outcomes were examined by treatment group and also compared to those from a population-based case/control study of meningioma (the Meningioma Consortium), in which 1722 meningioma cases diagnosed among residents of Connecticut, Massachusetts, California, Texas, and North Carolina from May 1, 2006 through March 14, 2013 were enrolled and frequency matched to 1622 controls by age, sex and geography.

RESULTS

The LGG sample average age is 45 years at time of interview and 53.1% male. Almost 55% of patients had received radiation and chemotherapy (primarily temozolomide); 32.4% had received neither treatment. Almost 2/3 LGG subjects report difficulty with speaking, memory, or thinking and over 1/3 report personality change or difficulty driving. After controlling for age and other co-morbidities, individuals diagnosed with LGG report levels of physical, emotional, and mental health functioning below those reported in a meningioma as well as a general healthy population.

CONCLUSIONS

Despite being relatively young, persons with LGG report significantly reduced QOL compared to persons with non-malignant brain tumors and to a control population, highlighting the need to better acknowledge and manage these symptoms for this group of patients diagnosed in the prime of life.
QOL-11. ADAPTING CALM PSYCHOTHERAPY FOR CAREGIVERS OF PATIENTS WITH MALIGNANT GLIOMA
Authors: Willis Kelcie , Fox Amber , Reid Morgan , Thumma Lillia , Barrett Sarah , Lo Karen , Loughan Ashlee
Published: November 2023

Caregivers of patients with malignant gliomas (PwMG) report significant emotional distress yet are often omitted from supportive psycho-oncology programs. CALM (Managing Cancer and Living Meaningfully), an evidence-based psychotherapy, has shown preliminarily to reduce depressive and existential distress among PwMG. While caregivers are invited to participate in CALM alongside the patient, the benefit of CALM for caregivers has not yet been evaluated. This NIH ORBIT model phase 1a qualitative study sought to assess caregivers’ interest in CALM and their recommendations to adapt the intervention to their emotional needs. Bereaved caregivers (N = 22, Mage = 47.2, 77% female, 73% White) of PwMG participated in 90-minute focus groups (n = 4-7). Caregivers first received psycho-education on CALM and then participated in a semi-structured group interview. Sessions were audio-recorded, transcribed, and coded by five independent coders using thematic content analysis and NVivo software (kappa = .80-.94). Three major themes were explored: 1) CALM’s relevancy to the neuro-oncology caregiving experience; 2) the suitability of CALM for PwMG caregivers; and 3) suggested adaptations to CALM for PwMG caregivers. First, caregivers felt the four domains of CALM mirrored their experience of caregiving. Secondly, they noted both strengths and weaknesses of the intervention. Lastly, caregivers provided valuable recommendations to improve the timing (e.g., introduce CALM early, continuously), content (e.g., include sessions about bereavement and caregiver burden), and format (e.g., both independent and joint sessions) of the CALM intervention. Examples of each theme will be provided. The results suggest that CALM may be a potentially impactful intervention for the emotional needs of caregivers of PwMG. Nevertheless, adjustments to the timing, content, and format of this intervention are warranted, prior to a future feasibility/acceptability trial. This study not only provides the foundational data required to proceed with future CALM trials, but it also provides valuable considerations for those developing interventions for caregivers of PwMG largely.