bluuebunny/crossref_metadata_2025 huggingface dataset:
TMIC-35. CROSSTALK BETWEEN TAMS AND GLIOBLASTOMA STEM-LIKE CELLS IN A HYPOXIC MICROENVIRONMENT INDUCES SENESCENCE ARREST AND ENHANCED RADIORESISTANCE
Authors: Carneiro-Lobo Tatiana , Olson Cheryl , Markwell Steven , Mesci Pinar , Muotri Alysson , Brat Daniel
Published: November 2022

Patients with glioblastoma (GBM) have an overall survival of 15 months. These catastrophic survival rates are correlated with systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after treatments. Our goal was identifying whether radioresistance of GBM is caused by GSCs and how hypoxia and TAMs affect this process. First, we established a glioblastoma-brain cortical organoid (GBM-BCOs) to model human GBM. We co-cultured GFP-labeled GBM neurosphere with BCOs for 14 days and we observed that tumor take rate was 100% for all GBM neurosphere tested. Next, we evaluated whether hypoxia enhanced TAMs migration into GBM-BCOs. We incorporated THP-1 cells into GFP-GBM-BCOS for 14 days and incubated for 24 h under normoxic or hypoxic conditions. Hypoxia increased THP-1 cells influx into GBM-BCOs. Further, we investigated whether TAMs enhanced the enrichment of GSCs in GBM neurosphere and in GBM-BCOs. We found that, co-culture of THP-1 cells with GBM neurosphere or with GBM-BCOs system, enhanced CD133+ population after 72 h hypoxic condition. In addition, IF of GBM human tissue revealed increased of CD133+ and IBA1+ cells in peri-necrotic area compared to non-necrotic area and non-necrotic tumor. To examine whether TAMs enhanced the radioresistant phenotype and the quiescent population, we irradiated GBM neurosphere grown under hypoxic and normoxic conditions with different doses of γ-rays. After irradiation, these cells were co-cultured with TAMs for 72 h under normoxic and hypoxic conditions. MTT assay showed that TAMs enhanced the radioresistant phenotype promoted by hypoxia in GBM neurosphere and an increase in quiescent markers (γ-H2AX and IL-6) were found in our co-culture model after hypoxia exposure. These results indicate, not only hypoxic condition play a key role in the GSCs enrichment and radioresistance, but also crosstalk between TAMs and GSCs promote tumor oncogenesis and contribute to an ineffective anti-tumor response.
TMIC-68. EVALUATING FLASH AND CONVENTIONAL DOSE-RATE RADIATION AND IMMUNE RESPONSE WITH SINGLE-CELL SEQUENCING IN DIFFUSE MIDLINE GLIOMA (DMG)
Authors: Minns Hanna , Padilla Oscar , Wei Hong-Jian , Webster-Carrion Andrea , Tazhibi Masih , McQuillan Nicholas , Zhang Xu , Yeh Rebecca , Zhang Zhiguo , Szalontay Luca , Pavisic Jovana , Garty Guy , Garvin James , Canoll Peter , Vanpouille-Box Claire , Menon Vilas , Olah Marta , Rabadan Raul , Wu Cheng-Chia , Gartrell Robyn
Published: November 2022

Diffuse Midline Glioma – H3K27M mutant (DMG), is a fatal and inoperable pediatric brain tumor with limited treatment options as radiation provides only temporary reprieve, leaving the median survival between 9-15 months. Conventional dose-rate radiation (2Gray/minute, CONV) has been shown in other cancers to recruit an immune component, however, this has not been studied in DMG. Ultra-high dose-rate radiation given at 90 Gray/second (FLASH), is a novel technique associated with decreased toxicity and effective tumor control. Using a syngeneic model of brainstem DMG, we performed single-cell RNA sequencing on CD45+ immune cells isolated from tumors irradiated with 15Gray using FLASH or CONV, and compared to unirradiated tumor and normal brainstem. Isolation of 33,308 immune cells revealed 17 unique clusters, most abundant of which was microglia (73.8%), present in four distinct subtypes representing a spectrum from homeostatic to activated. In the most activated microglia, both FLASH and CONV showed an enrichment in type 1 interferon (IFN1) pathway scores compared to untreated tumors (p< 0.001 and p< 0.001, respectively). The most differential response was found in macrophages (MAC) and dendritic cells (DC) with a robust enrichment of IFN1 pathway scores for CONV compared to FLASH (p< 0.001, MAC and p< 0.001 DC). FLASH showed an increase in anti-inflammatory MAC markers such as Mrc1, Cd163, and Maf and an enrichment of myeloid-derived suppressor cell (MDSC) signature in monocytes, not seen in CONV (p< 0.001). Finally, we correlated our data with publicly available single-cell data taken from the cerebrospinal fluid of DMG patients treated with anti-GD2 CAR T Cell therapy and found similar inflammatory markers characteristic of our unirradiated murine tumors. In summary, our work is the first to study immune alterations comparing different dose-rates of radiation with single-cell resolution in DMG, highlighting the potential for combining radiation and immunotherapy in these tumors.
MODL-26. EVOLUTION OF MULTI-FACETED GLIOBLASTOMA MICROENVIRONMENTS IN 3D
Authors: Senior Jessica , Dalby Amanda , Correia Joao , Pike Jeremy , Jaworska Kayley , Thomas Steve , Smith Alan , Brüning-Richardson Anke
Published: November 2022

Glioblastomas (GBM) account for poor prognosis and dismal survival rates in patients due to their highly aggressive infiltrative nature to rapidly migrate within the brain. Experimental treatments for GBMs using animal models often elicit severe side effects and there are major doubts regarding the usefulness of such in vivo models when undergoing animal to human clinical translation. Here, we describe the development of a series of 3D bioengineered GBM models towards the generation of a more physiologically representative system in which candidate drugs can be tested. Glioma cell lines U87 and U251 derived from human GBM were used along with associated knockdowns of previously described anti-migratory and pro-migratory genes or anti-migratory inhibitors to examine their roles in the actin polymerization pathway in cancer cell migration. GBM models were fabricated by implantation of spheroids within hydrogel microenvironments that were fashioned to exhibit migratory collagen tracts within a non-cell adhesive outer shell. The distribution of collagen was organised to have low, intermediate, and high-density regions within the construct, replicating the complexity of native GBM. 3D models were then cultured under control conditions (media only) or treated with anti-migratory drugs (CCG-1423, rhosin or combination). Using light-sheet and confocal microscopy, migration velocity, cell phenotype and migratory behaviours were analysed in live and fixed tumour mimics. In models where migration is promoted, actin was vastly upregulated and cells assumed a migratory mesenchymal phenotype, whereas under anti-migratory drug treatment, cells were amoeboid in shape with a dramatic reduction in actin expression and consequently limited migration velocity. Here, we have demonstrated that it is possible to develop biologically-relevant GBM models that capture the anisotropic nature of the tumour microenvironment using multi-layer biopolymer engineering. The ultimate goal of this research is to develop technology that can help provide personalised treatments for GBM and subsequently improve patient outcomes.
STEM-02. GENERATION AND CHARACTERISATION OF A LIVING BIOBANK OF POST-SURGICAL RESIDUAL GLIOBLASTOMA TO IDENTIFY NOVEL THERAPEUTIC TARGETS
Authors: McGarrity - Cottrell Connor , Myers Katie , Wang Dennis , Dunning Mark , Bagga Veejay , Al-Tamimi Yahia , Sinha Saurabh , Rominiyi Ola , Collis Spencer
Published: November 2022

Glioblastoma is the most common cancer arising within the brain and contributes to ~190,000 brain tumour related deaths/year globally. Current standard-of-care therapy consists of maximal safe surgical resection, radiotherapy with concomitant then adjuvant chemotherapy (Temozolomide) which triggers the cellular DNA damage response (DDR). However, survival for patients remains poor (median OS ~ 12-15 months). Lack of progress in the development and clinical translation of novel therapeutics is largely attributed to extensive inter- and intra-tumoral heterogeneity and resistant glioma stem cell (GSC) niches. Traditionally, primary ex vivo and in vivo models of glioblastoma have been derived from the resected tumour mass potentially omitting significant genetic, epigenetic and phenotypical characteristics exhibited by post-surgical residual tumour cells that are ultimately responsible for disease recurrence and morbidity. We therefore hypothesise that GSC’s isolated from the invasive edge of the tumour are inherently treatment resistant due to an increased “stemness” and upregulated DDR. Here we display novel methodology for the generation of multiple parallel primary ex vivo GSC cell models from anatomically discrete regions of specific partial lobectomy specimens. Importantly, these samples contain large portions of infiltrated adjacent brain to recapitulate features of resected (tumour core) and typically residual glioblastoma (distal invasive tumour edge). Initial RNA-seq analysis has revealed large divergent transcriptional landscapes of resected vs residual tumour cells and protein expression analyses has identified key differences in DDR proteins and subsequent cellular responses to current standard-of-care radio-chemotherapy regimens. Immunofluorescence analysis of DNA damage markers has also revealed differential capacity & kinetics for repair of DNA damage between resected and residual GSC populations. These data therefore highlight the potential clinical relevance of our novel parallel resected and residual ex vivo glioblastoma models, which will hopefully aid evaluation of novel therapeutics capable of targeting post-surgical GSC subpopulations leading to improved disease outcomes.
STEM-20. ROLE OF CELLULAR PRION PROTEIN IN TEMOZOLOMIDE RESISTANCE OF GLIOBLASTOMA STEM CELLS
Authors: Iglesia Rebeca , Prado Mariana , Alves Rodrigo , Tiek Deanna , Goenka Anshika , Song Xiao , Hu Bo , Hu Bo , Lopes Marilene
Published: November 2022

Glioblastoma (GBM), the most aggressive type of brain tumor, is initiated and maintained by a subpopulation of tumorigenic cells called glioblastoma stem cells (GSCs) that contribute to progression and resistance to therapy. In GBM therapy the alkylating agent temozolomide (TMZ) is the most effective chemotherapist, but resistance is frequent, especially in GSCs located in hypoxia niches. One of the mechanisms of resistance to TMZ involves the modulation of MGMT, which promotes cell survival through the induction of antiapoptotic proteins expression and can be regulated by hypoxia inducible factors (HIFs). Recent data from our group demonstrate that blocking the interaction between the cellular prion protein (PrPC) and one of its main ligands, the heat shock organizing protein (HOP) with a HOP peptide (HOP230-245) can inhibit GSCs self-renewal and glioblastomas growth in vivo. PrPC silencing decreases the expression of stem cells markers, self-renewal, and tumorigenesis of GSCs. Remarkably, a PrPC peptide which mimics HOP binding site (PrPC106-126) can promote HIF1α expression, inducing protection against cell death. Considering these data together, this study aims to identify the participation of PrPC in the TMZ resistance of GSCs mediated by HIF1α. In addition, we will evaluate HOP230-245 peptide potential in sensitizing GSCs to TMZ, since it binds to PrPC at the specific site 106-126 being able to compete with other PrPC ligands by this domain and, consequently, inhibit functions modulated by these interactions. Preliminary trials on stem cell enriched glioblastoma lineage cultures suggest that treatment with TMZ associated HOP230-245 increases cell death compared to TMZ or the peptide alone, sensitizing cells to TMZ treatment and increasing their efficiency. Finally, the search for therapeutic-combined strategies targeting GSCs is imperative to improve the efficacy of treatments against this incurable tumor.
STEM-27. MECHANOSENSITIVE BRAIN TUMOR CELLS CONSTRUCT BLOOD-TUMOR BARRIER TO MASK CHEMOSENSITIVITY
Authors: Chen Xin , Momin Ali , Wanggou Siyi , Wang Xian , Dong Weifan , Fan Jerry , Sun Yu , Li Xuejun , Huang Xi
Published: November 2022

Two major obstacles in brain cancer treatment are the blood-tumor barrier (BTB) and quiescent tumor cells. Here we show that Sox2+ tumor cells directly project cellular processes to ensheathe capillaries in medulloblastoma (MB), a process that depends on the mechanosensitive ion channel Piezo2. MB develops a tissue stiffness gradient as a function of distance to capillaries. Sox2+ tumor cells perceive substrate stiffness to sustain local intracellular calcium, actomyosin tension, and adhesion to promote cellular process growth and cell surface sequestration of β-Catenin. Piezo2 knockout reverses WNT/β-Catenin signaling states between Sox2+ tumor cells and endothelial cells, compromises the BTB, reduces the quiescence of Sox2+ tumor cells, and markedly enhances MB response to chemotherapy. Our study reveals that mechanosensitive tumor cells construct the BTB to mask tumor chemosensitivity. Targeting Piezo2 addresses the BTB and tumor quiescence properties that underlie therapy failures in brain cancer.
RADT-11. CLINICAL OUTCOMES IN THE MANAGEMENT OF MELANOMA BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY AND ANTI-PD-1+CTLA-4
Authors: Tang Joseph , Dohm Ammoren , Kalagotla Hruday , Bhandari Menal , Kim Youngchul , Graham Jasmine , Khushalani Nikhil , Forsyth Peter , Etame Arnold , Liu James , Tran Nam , Vogelbaum Michael , Yu Michael , Ahmed Kamran , Oliver Daniel
Published: November 2022

BACKGROUND

Anti-PD-1+CTLA-4 therapy has revolutionized melanoma brain metastases (MBM) treatment. Prospective trials show higher response in asymptomatic versus symptomatic patients. We evaluated clinical outcomes in MBM treated with stereotactic radiosurgery (SRS) and anti-PD-1+CTLA-4.

METHODS

Patients were included if MBM were diagnosed and treated with SRS within 3 months of anti-PD-1+CTLA-4, and this was their last course of systemic treatment. Endpoints of this study were distant MBM control, MBM local control (LC) defined as less than 20% volume increase on follow-up MRI, and overall survival (OS) from SRS. Adverse advents were evaluated using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

RESULTS

29 patients with 122 MBM treated over 40 SRS sessions between 2015-2020 were identified. Median SRS dose: 24 Gy (range: 15-24). Median MBM diameter: 0.6 cm (range: 0.3-2.9). Median follow-up using reverse Kaplan-Meier (KM) method: 19.3 months (interquartile range: 14.6-38.4).Six-, twelve-, and eighteen-month KM distant MBM control rates were 51%, 42%, 42%, respectively. LC rates: 90%, 86%, 85%. OS rates: 76%, 68%, 56%. 17 patients (59%) were asymptomatic and 12 (41%) symptomatic. KM distant MBM control and OS for asymptomatic and symptomatic patients were not significant; p=0.61 and p=0.67, respectively.On univariate analysis (UVA), Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) 0-1 was associated with increased risk of distant MBM failure versus DS-GPA 3.5-4 (hazard ratio (HR): 9.8, 95% confidence interval (CI) 1.9-51.5, p=0.007). UVA showed decreased OS with increased number of organs with metastases at diagnosis (HR:12, 95% CI 2.0-83.1, p=0.0075).2 lesions (1.6%) developed symptomatic radiation necrosis requiring steroids; 10 lesions developed grade 3 edema (8%); 13 patients experienced grade 1-2 fatigue and/or headache (45%); no patients experienced grade >3 events.

CONCLUSION

Combination SRS and anti-PD-1+CTLA-4 in MBM shows durable intracranial control with similar outcomes between asymptomatic and symptomatic patients with acceptable toxicity. Further study is warranted.
RADT-29. THE IMPACT OF TUMOR LOCATION AT THE SKULL BASE ON RADIATION NECROSIS IN PATIENTS UNDERGOING STEREOTACTIC RADIOSURGERY: AN ANALYSIS OF 205 PATIENTS
Authors: Kerschbaumer Johannes , Demetz Matthias , Krigers Aleksandrs , Nevinny-Stickel Meinhard , Thomé Claudius , Freyschlag Christian
Published: November 2022

Background

Skull base (SB) surgery and radiosurgery (SRS) are an interdisciplinary concept and represent an individualized treatment option for various skull base tumors. Radiation necrosis (RN) is a possible sequela of SRS, but despite few accepted risk factors, there is very limited data on the influence of tumor location. The aim of this study was to assess tumor location in correlation to the development of radiation necrosis for skull-base tumors.

METHODS

All patients treated with radiosurgery for meningioma, vestibular schwannoma and other benign neoplasms between January 2004 and November 2020 were retrospectively evaluated. The clinical, imaging and medication data were gained from the patients’ charts. The diagnosis of RN was established retrospectively using imaging parameters. Patients with tumors located at the skull base were compared to patients with tumors of other location.

RESULTS

A total of 205 patients could be included in this study. 157 neoplasms (76.6%) were localized at the SB, while the remaining 48 (23.4%) were non-SB. 32 (15.6%) of all patients developed RN after median 10 (IqR 5-12) months during a median follow-up of 24 (IqR 6-62) months. SB-tumors showed a significantly lower risk of radiation necrosis with a Hazard Ratio (HR) of 0.252, p < 0.001, independently of the applied radiation dose. Furthermore, higher radiation doses had a significant impact on the occurrence of RN (HR 1.372, p = 0.002). No significant difference could be shown for age, previous resection or previous radiosurgery. Administered dose of dexamethasone did not correlate with the risk of radiation necrosis.

CONCLUSION

The risk for development of RN for SB-tumors appears to be low. No difference between recurrent and newly diagnosed tumors was found, which may underpin the value of radiosurgical treatment for patients with recurrent SB-tumors. For extensive tumors of the SB, combinations of surgery and radiosurgery represents a valuable approach.
CTIM-05. FINAL RESULTS OF 2-THE-TOP: A PILOT PHASE 2 STUDY OF TTFIELDS (OPTUNE) PLUS PEMBROLIZUMAB PLUS MAINTENANCE TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM)
Authors: Tran David , Ghiaseddin Ashley , Chen Dongjiang , Le Son , Rahman Maryam
Published: November 2022

INTRODUCTION

TTFields induce anti-tumor immunity via type-1 interferon (T1IFN) pathways of the STING and AIM2 inflammasomes. Thus, TTFields may synergize with immune checkpoint inhibitors to prolong survival in GBM.

METHODS

We enrolled 26 ndGBM patients in a pilot phase 2 study combining TTFields, pembrolizumab and maintenance TMZ. Primary endpoints were PFS versus case-matched controls of TTFields plus TMZ in the EF-14 study and immune signatures by multiomics of PBMCs and tumors. Secondary endpoints included toxicity and OS.

RESULTS

The median age was 60.5 years. Fourteen (54%) had biopsy only or partial resection. Nineteen (73%) had unmethylated MGMT and 3 (11.5%) had an IDH mutation. As of 2/16/22, 7 (27%) were progression-free and 14 (54%) were alive with median follow-up of 16.8 months. Median PFS was 12.1 months versus 7.9 months in a case-matched control cohort of 26 patients (HR = 0.456; 95% CI: 0.222-0.937; P = 0.015). Twelve-month PFS was 52.4% (95% CI: 31.4-69.6%) versus 20.4% (95% CI: 5.5-41.7%) in controls; P = 0.012. Six of 15 (40%) patients with measurable disease achieved partial or complete response. Median OS was 25.2 months versus 15.9 months in controls (HR = 0.382; 95% CI: 0.168-0.861; P = 0.078). Two-year OS was 57.8% (95% CI: 33.7-75.9%) versus 19.2% (95% CI: 7.0-36.0%) in controls; P = 0.002. In a Cox regression analysis adjusting for key prognostic factors, P-value reached 0.033 for PFS and 0.020 for OS. Molecular analyses confirmed robust T cell activation via the T1IFN trajectory, which highly correlated with TCRαβ clonal expansion (Spearman coefficient = -0.8; P = 0.014), and defined a T cell-based gene signature of TTFields effects. The most common serious adverse events were thromboses, seizures, and metabolic disturbances in 4 (15%), 3 (11.5%), and 2 (8%) patients, respectively.

CONCLUSIONS

The triple combination demonstrated acceptable toxicity and promising efficacy in ndGBM. Survival and molecular data will be updated.
CTNI-11. DEEP PHENOTYPING OF MULTI DRUG RESPONSES IN PATIENTS WITH GLIOMAS USING TUMOR-EMBEDDED MICRODEVICES
Authors: Peruzzi Pierpaolo , Dominas Christine , Blitz Sarah , Chiocca E Antonio , Wen Patrick Y , Jonas Oliver
Published: November 2022

The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle for the advancement of therapy for high grade gliomas (HGG), and particularly glioblastoma (GBM), one of the few cancers whose prognosis has not improved over the past several decades. With this pilot clinical trial we provide first in human evidence that drug-releasing intratumoral microdevices (IMD) can be safely and effectively used to obtain patient-specific, high throughput molecular and histopathological data to inform selection of drugs based on their observed antitumor effect in situ. The use of IMD is seamlessly integrated in standard surgical practice during tumor resection. None of the six enrolled patients experienced adverse events related to the IMD, and the retrieved tissue was usable for downstream analysis for 11 out of 12 retrieved specimens. Molecular analysis of the specimens provided, for the first time in humans, preliminary evidence of the robustness of the readout, with strong correlation between IMD analysis and clinic-radiological responses to temozolomide. From an investigational aspect, the amount of information obtained with IMD allows unprecedented characterization of tissue effects of any drugs of interest, within the physiological context of the intact tumor.
CTNI-19. A TWO-PART, PHASE 1 STUDY OF RHENIUM-186 NANOLIPOSOME (186RNL) DELIVERED BY CONVECTION ENHANCED DELIVERY (CED) FOR RECURRENT OR PROGRESSIVE CHILDHOOD EPENDYMOMA AND HIGH-GRADE GLIOMA (HGG)
Authors: Plant-Fox Ashley , DeCuypere Michael , Lam Sandi , Quijano Carla , Sereno Lisa , Bao Ande , LaFrance Norman , Hedrick Marc , Brenner Andrew
Published: November 2022

Childhood ependymoma and HGG are difficult tumors to treat. Recurrent ependymoma is treated with re-resection and multiple rounds of external beam radiation therapy (EBRT). HGG is treated with chemoradiation followed by clinical trials, if available. While EBRT remains a central component of management, it is limited by tolerance of the surrounding normal brain tissue. Rhenium-186 NanoLiposome (186RNL) permits the selective delivery of beta-emitting radiation with excellent tumor retention. In an adult Phase 1 trial for recurrent glioblastoma (NCT01906385), the mean absorbed dose to the tumor was 392 Gy (CI 306 – 478), markedly higher than absorbed doses typically delivered by EBRT. Despite this, no dose-limiting toxicity was observed and no treatment-related serious adverse events have occurred. Here, we describe the first pediatric trial using a two-part, Phase 1 dose-finding study followed by expansion cohorts to explore efficacy. Enrolling subjects will be 6 to 21 years of age with a diagnosis of recurrent ependymoma or HGG. Subjects will be allowed to enroll either if they have exhausted standard of care options or if they are clinically stable and surgical resection can be deferred by 4 weeks. Part 1 will enroll up to 24 subjects to determine the maximum feasible dose (MFD) of 186RNL administered by CED. Tumor size and concentration of infusate will be escalated in each cohort (A-D) to a maximum tumor diameter of 6 cm (114.1 mL) and a concentration of 2mCi/ml. Up to 4 CED catheters will be used. Part 2 will independently evaluate 186RNL in 2 different expansion cohorts: Cohort 2A: recurrent ependymoma; Cohort B: recurrent HGG. The primary endpoint for Cohort 2A is overall response rate (ORR) by Radiographic Assessment in Pediatric Neuro-Oncology (RAPNO) criteria and the primary endpoint for Cohort 2B is progression free survival. Planned enrollment will begin in early 2023.
CTNI-23. PRELIMINARY SAFETY AND PHARMACOKINETICS DATA FOR A PHASE 1B TRIAL OF TELAGLENASTAT IN COMBINATION WITH RADIATION THERAPY AND TEMOZOLOMIDE IN PATIENTS WITH IDH-MUTANT GRADE 2/3 ASTROCYTOMA (NCI-10218)
Authors: Kizilbash Sani , Piccioni David , Sahebjam Solmaz , Villano John , Jaeckle Kurt , Welch Mary , Kong Xiao-Tang , Holdhoff Matthias , Lammers Anita , Remick Adam , Reid Joel , Allred Jacob , Port John , Lanza Ian , McBrayer Samuel , Kunos Charles , Shapiro Geoffrey , Adjei Alex
Published: November 2022

IDH mutant gliomas depend on glutaminase for glutamate/glutathione generation from glutamine because R-2-hydroxyglutarate inhibits branched chain amino acid transaminase mediated glutamate biosynthesis. Telaglenastat (CB-839 HCl) is a potent glutaminase-1 specific inhibitor which depletes tumor glutamate in orthotopic IDH mutant glioma PDX models and extends survival in these orthotopic models when added to radiation/temozolomide. NCI-10218 (NCT03528642) is a phase I clinical trial investigating the safety and tolerability of telaglenastat administered orally concurrently with standard doses of radiation (50.4 Gy, grade 2; 59.4 Gy, grade 3) and temozolomide (75 mg/m2 orally daily) in patients (age 16+) with previously untreated IDH mutant grade 2/3 astrocytoma. Telaglenastat dose was escalated in cohorts (400-800 mg twice daily) based on a standard 3 + 3 design to determine the recommended phase 2 dose (RP2D). Toxicities were graded per CTCAE v5.0. An expansion cohort additionally incorporated a seven-day run-in of telaglenastat monotherapy at RP2D prior to radiation to evaluate the pharmacodynamic impact of telaglenastat on plasma and tumor metabolites. 23 patients with IDH mutant astrocytoma (WHO grade 2, n = 5; WHO grade 3, n = 18) were accrued between December 2018 and January 2022 (Dose Escalation: 16; Dose Expansion: 7). Median age was 32 years (range 23-69 years). 61% were male and 70% were ECOG 0. No dose-limiting toxicities were observed. Grade 3/4 adverse events (independent of attribution) included: lymphopenia (3), neutropenia (2), leukocytosis (2), alanine transaminase elevation (2), thrombocytopenia (1), leukopenia (1), maculopapular rash (1), hyperglycemia (1), hyponatremia (1). The RP2D of concurrent telaglenastat was defined as 800 mg twice daily. Following peak absorption on Day 15 at RP2D, the mean (%CV) terminal elimination half-life in the plasma was 4.2 (53.5%) hours (range 2.1-7.1 hours). The Cmax, Tmax, oral clearance, and AUC were 1496 ng/mL, 4.0 hr, 93.6 L/hr/m2, and 7430 ng/mL*hr, respectively.
CTNI-30. LOGGIC/FIREFLY-2: A PHASE 3, RANDOMIZED TRIAL OF TOVORAFENIB VS. CHEMOTHERAPY IN PEDIATRIC PATIENTS WITH NEWLY DIAGNOSED LOW-GRADE GLIOMA HARBORING AN ACTIVATING RAF ALTERATION
Authors: van Tilburg Cornelis , Jones David T , Schmidt Rene , Avula Shivaram , van Meeteren Antoinette Schouten- , Sehested Astrid , Opocher Enrico , Driever Pablo Hernáiz , Witt Ruth , Ziegler David , Blackman Samuel , Zhao Xin , Tsao Li-Pen , Cox Michael , Hargrave Darren , Witt Olaf
Published: November 2022

BACKGROUND

Genomic alterations and dysregulation of RAF are the main oncogenic driver in almost all pediatric low-grade gliomas (pLGGs). About 50%‒60% of pLGGs harbor KIAA1549-BRAF fusion and 5%‒15% BRAF V600E mutation. No targeted therapy has received regulatory approval for either relapsed or newly diagnosed pLGG to date. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II panRAF inhibitor. The registrational, phase 2 FIREFLY-1 (NCT04775485) study with tovorafenib in pediatric patients with recurrent/progressive LGG is currently ongoing.

METHODS

LOGGIC/FIREFLY-2 (EudraCT 2022-001363-27) is a registrational, randomized, multicenter, global (~100 sites across Australia, Canada, Egypt, Europe, New Zealand, Singapore, South Korea, Taiwan, and USA), phase 3 trial evaluating the efficacy, safety, and tolerability of tovorafenib vs. standard of care (SoC) chemotherapy in patients < 25 years old with LGG harboring a RAF-alteration and requiring first-line systemic therapy. Approximately 400 patients will be randomized 1:1 to receive oral tovorafenib, 420 mg/m2 ( ≤ 600 mg) weekly (tablet or liquid suspension for 26, 28-day cycles), or an investigator’s choice of SoC chemotherapy: COG-V/C regimen (60 weeks), SIOPe-LGG-V/C (81 weeks) regimen, or single-agent vinblastine (70 weeks). After completing 26 cycles tovorafenib, patients may continue tovorafenib or opt to enter a drug holiday at any point. Patients who progress in the SoC arm may receive tovorafenib. Patients who progress after stopping tovorafenib may be re-challenged. Primary endpoint is ORR based on RANO criteria, as determined by an independent radiology committee. Key secondary endpoints are progression-free survival and duration of response per RANO criteria, and ORR per RAPNO criteria. Other secondary endpoints include changes in neurological and visual function, and safety and tolerability. Exploratory objectives include quality of life and health utilization measures, molecular biomarker evaluation for treatment response and resistance, efficacy of tovorafenib after progression on chemotherapy and retreatment upon progression during drug holiday.
CTNI-44. A PHASE 0 ‘TRIGGER’ TRIAL OF PAMIPARIB IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA PATIENTS
Authors: Sanai Nader , Chang Yu-Wei , Jiang Jun , Molloy Jennifer , Montgomery Chelsea , Harmon Jocelyn , Hong Amy , Wanebo John , Kennedy William , Garcia Michael , Barani Igor , Yoo Wonsuk , Tovmasyan Artak , Tien An-Chi , Li Jing , Mehta Shwetal
Published: November 2022

This study evaluates glioblastoma (GBM) pharmacokinetics (PK) and pharmacodynamics (PD) of pamiparib, a PARP1/2-selective inhibitor, graduating patients to a therapeutic expansion phase of drug plus radiotherapy. Newly-diagnosed (Arm A) and recurrent GBM (Arm B) patients received 4 days of pamiparib (60 mg BID) prior to planned resection at 2-4 or 8-12 hours following the final dose. Arm C included recurrent GBM patients who received 4 days of olaparib (200 mg BID). Tumor tissue cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug > 5-fold biochemical IC50 in nonenhancing tumor determined eligibility for the therapeutic expansion phase. PARP inhibition was assessed via ex vivo radiation and quantification of PAR levels compared to non-radiated control. All patients exceeding the PK threshold were eligible for an expansion phase of study drug plus radiotherapy followed by maintenance regimen. In Arms A (n = 20) and B (n = 15), the mean unbound concentrations of pamiparib in Gd-nonenhancing tumor region were 171.5 nM and 102.9 nM, respectively and in Arm C (n = 4) the mean unbound concentration of olaparib was 11.0 nM. All patients in Arms A and B, but only one in Arm C, exceeded the PK threshold to qualify for the expansion phase of the study. 12/20 (60%), 7/14 (50%), and 1/4 (25%) patients in Arms A, B, and C, respectively progressed to expansion phase. Radiation-induced PAR expression was 2.44 fold in untreated control vs 1.16 in Arm A, 0.82 in Arm B and 1.11 in Arm C patients, respectively. The median progression-free survival was 5.4 (Arm A) (n = 7), 5.0 months (Arm B) (n = 6), and 2.7 months (Arm C) (n = 1), respectively. Pamiparib was generally well-tolerated, achieved pharmacologically-relevant concentrations in nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation.
CTNI-47. TUMOR TREATING FIELDS COMBINE WITH TEMOZOLOMIDE FOR NEWLY DIAGNOSED GLIOBLASTOMA: A RETROSPECTIVE ANALYSIS OF CHINESE PATIENTS
Authors: Qin Zhiyong , Chen Lingchao , Chen Junrui , Yao Yu , Wu Jinsong , Zhuang Dongxiao , Nie Jigntao
Published: November 2022

BACKGROUND

TTFields plus Temozolomide (TTFields/TMZ) extended survival versus TMZ alone in newly diagnosed glioblastoma (GBM) patients in the EF-14 trial. We report a retrospective analysis of Chinese newly diagnosed GBM patients who received TTFields combine with TMZ treatment and traditional TMZ monotherapy from May 2019 to May 2021 in Shanghai Hua Shan hospital.METHOD: Overall survival (OS) and progression-free survival (PFS) curves were constructed using the Kaplan-Meier method. A Cox proportional hazards regression model with inverse probability of treatment weighting (IPTW) based on propensity score was used to assess the effect of TTFields and account for confounding factors. RESULT: In the preliminary analysis, the PFS in the TTFields/TMZ arm was 16 months (95% CI:9.6–24.6) versus 11 (95% CI: 9–12) with TMZ alone (p ＜0.05). Median overall survival was 21.8 months (95% CI 17.4-NA) with TTFields/TMZ versus 15 months (95% CI 13–18; HR 0.43, p ＜0.01) with TMZ alone. In the Multivariate analysis, Surgery type, STUPP scheme, IDH status, and TTFields use were identified as favorable prognostic factors. After PSM adjustment, the groups were similar, except that MGMT promoter methylation remained more in the TMZ group (12 v 32; P = 0.011). Upon IPTW Survival analysis, TTFields was associated with a significantly lower risk of death (hazard ratio [HR], 0.19 in OS (95% CI 0.09–0.41) and progression (HR, 0.35 (95% CI 0.14–0.91) compared with TMZ alone.

CONCLUSION

In the analysis of our single center of patients with glioblastoma, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the outcome of EF-14.
CTNI-53. PNOC014: PHASE IB STUDY RESULTS OF DAY101(TOVORAFENIB) FOR CHILDREN WITH LOW-GRADE GLIOMAS (LGGS) AND OTHER RAS/RAF/MEK/ERK PATHWAY-ACTIVATED TUMORS
Authors: Wright Karen , Kline Cassie , Abdelbaki Mohamed , Ebb David , Sayour Elias , Elster Jennifer , Leary Sarah , Miller Matthew , Margol Ashley , Cohen Kenneth , Kilburn Lindsay , Bendel Anne , Kao Pei-Chi , Ma Clement , London Wendy , Mueller Sabine , Prados Michael , Haas-Kogan Daphne
Published: November 2022

BACKGROUND

Pharmacokinetic modeling for previously reported phase 1A data of pan-RAF inhibitor DAY101 in RAS/RAF/MEK/ERK pathway-altered tumors suggested a correlation between higher doses and improved efficacy without clear safety data. The protocol was amended to explore differential dosing across different body surface areas (BSA).

METHODS

Eligible patients were < 25 years old with radiographically recurrent/progressive RAS/RAF/MEK/ERK pathway-altered tumors. We applied a novel modification of a TITE-BOIN design to determine recommended phase 2 dosing of oral, weekly DAY101 in evaluable patients within two BSA subgroups: ≤ 1.5 m2 or > 1.5 m2. Target toxicity probability was closest to 20%. We tested 420 and 530 mg/m2. Dose limiting toxicities (DLTs) were determined within Cycle 1. Evaluable patients had either ‘complete’ or ‘partial’ information. Complete information meant patient had a DLT or received 3 of 4 planned doses with no DLT. Partial information meant patient received only 1 or 2 doses or did not complete the DLT observation period. Three patients with complete information at a given dose level were required before dose escalation. The primary endpoint driving dose escalation was time from start of Cycle 1 to first DLT or, if no DLT, time from start of Cycle 1 to minimum of date of last contact or end of Cycle 1.

RESULTS

We treated 35 eligible patients: 21 KIAA1549:BRAF-, 9 BRAFV600E-, 4 novel RAF- and one FGFR1-altered tumors. Histologically, cohort included 30 LGGs, 4 high grade gliomas and 1 soft tissue sarcoma. There were 6 DLTs: 3 in each BSA subgroup, all at 530 mg/m2/dose, all grade 3, and 5 known side effects ( 2 fatigue, 3 rash, 1 menorrhagia).

CONCLUSIONS

Oral weekly DAY101 is well tolerated. The TITE model recommends 530 mg/m2/dose PO weekly for patients with BSA < 1.5m2 and 420 mg/m2/dose PO weekly for patients with BSA >1.5m2.
DNAR-01. CHROMOTHRIPSIS, ONE MAJOR GENETIC INSTABILITY FACTOR IN GLIOBLASTOMA, IS RARE IN IDH-MUTANT GLIOMAS
Authors: Sourty Baptiste , La Basset ëtitia , Garcion Emmanuel , Rousseau Audrey
Published: November 2022

INTRODUCTION

Adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas, and IDH-wildtype glioblastomas (GBM). GBM display genomic instability, which is favored by two genetic events leading to massive chromosomal alterations: chromothripsis (CT) and whole-genome duplication (WGD). Those events are scarcely described in IDH-mutant gliomas. The better prognosis of IDH-mutant gliomas may be in part related to their greater genomic stability compared to GBM.

METHODS

Pangenomic profiles of 301 adult diffuse gliomas were analyzed at initial diagnosis by SNP arrays, including 196 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 oligodendrogliomas). We further analyzed 16 IDH-mutant recurrent gliomas (11 astrocytomas and 5 oligodendrogliomas). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening. Survival data were compared using Kaplan-Meier method and categorical variables using Chi2 test.

RESULTS

At initial diagnosis, 37 GBM (18.8%) displayed CT (mainly affecting chromosomes 12, 9 and 7) versus five IDH-mutant gliomas (4.8%) (p = 0.0007). The latter were all high-grade astrocytomas. No oligodendroglioma or grade 2 astrocytoma displayed CT. There was a trend towards higher occurrence of CT in GBM versus high-grade IDH-mutant astrocytomas (p = 0.0589). WGD was detected at initial diagnosis in 18 GBM (9.2%) and 9 IDH-mutant gliomas (of any subtype and grade; 8.6%). Over 75% of chromosomal losses occurred after WGD. Neither CT nor WGD was associated with overall survival in GBM. At recurrence, one grade 4 IDH-mutant astrocytoma displayed CT and another one, WGD with CT.

CONCLUSION

CT is rare in IDH-mutant gliomas compared to GBM. The absence of CT in oligodendrogliomas and grade 2 astrocytomas may contribute to their greater genomic stability and better prognosis. CT occurrence in high-grade IDH-mutant astrocytomas may underlie aggressive biological behavior. WGD is a rare early event occurring equally in IDH-mutant gliomas and GBM.
DNAR-04. BOTH P53 CODON 72 ARG/ARG AND PRO/ARG GENOTYPES IN GLIOBLASTOMA MULTIFORME PATIENTS HAVE A BETTER PROGNOSIS IN BEVACIZUMAB TREATMENT
Authors: Shen Chiung-Chyi
Published: November 2022

BACKGROUND

In glioblastoma multiforme (GBM), bevacizumab increased progression-free survival but it has failed to improve overall survival (OS) in controlled trials. This study, therefore, aimed to retrospectively analyze the polymorphisms of p53 codon 72 and the clinical characteristics of GBM specimens from Taiwanese patients.

METHODS

The polymorphisms of p53 codon 72 in 99 patients with GBM treated at Taichung Veterans General Hospital in Taiwan from 2007 to 2017 were analyzed using direct DNA sequencing and PCR-RFLP analysis.

RESULTS

We found that among these GBM patients, the polymorphisms of p53 codon 72 were not directly associated with the overall survival of GBM, both the Arg/Arg and Arg/Pro genotypes were associated with significant benefits in terms of overall survival in patients treated with CCRT plus bevacizumab compared to patients treated with CCRT alone.

CONCLUSIONS

This pilot study suggests that both the Arg/Arg and Arg/Pro genotypes of p53 codon 72 polymorphism may have value as independent prognostic or predictive parameters for bevacizumab treatment response and failure. Relatedly, the results of the study further demonstrate the utility of stratifying GBM patientsaccording to bevacizumab sensitivity.
DNAR-07. BET PROTEIN INHIBITION SENSITIZES GLIOBLASTOMA CELLS TO TEMOZOLOMIDE TREATMENT BY ATTENUATING MGMT EXPRESSION
Authors: Tancredi Alessandro , Gusyatiner Olga , Bady Pierre , Buri Michelle , Lomazzi Rémy , Chiesi Davide , Hegi Monika
Published: November 2022

Bromodomain and extra-terminal tail (BET) proteins have been identified as potential epigenetic targets in cancer, including glioblastoma. These epigenetic modifiers link the histone code to gene transcription that can be disrupted with small molecule BET inhibitors (BETi). With the aim of identifying rational combination treatments for glioblastoma, we analyzed BETi-induced differential gene expression in glioblastoma derived-spheres. This identified 6 distinct expression patterns. To uncover emerging actionable vulnerabilities that can be targeted with a second drug, we extracted the significantly disturbed DNA Damage Response genes. Among the constantly downregulated candidates was the O-6-methylguanine-DNA methyltransferase (MGMT) gene, a known resistance factor for alkylating agent therapy in glioblastoma. BETi not only reduced MGMT expression in GBM cell lines, but also inhibited its induction, typically observed upon temozolomide treatment. To determine the potential clinical relevance, we evaluated the specificity of the effect on MGMT expression and MGMT mediated treatment resistance to temozolomide. BETi-mediated attenuation of MGMT expression was associated with reduction of BRD4- and Pol II-binding at the MGMT promoter. On the functional level, we demonstrated that ectopic expression of MGMT under an unrelated promoter was not affected by BETi, while under the same conditions, pharmacologic inhibition of MGMT restored the sensitivity to temozolomide, reflected in an increased level of gammaH2AX. Importantly, members of the mismatch repair pathway, required for sensitivity to unrepaired O6G-lesions, namely MSH6 and MSH2, were only transiently affected by BETi. Taken together, the addition of BET-inhibitors to the current standard of care, comprising temozolomide treatment, may improve the outcome of the 50% of patients whose GBM exert an unmethylated MGMT promoter.
DNAR-09. THE IMPACT OF MISMATCH REPAIR DEFICIENCY ON HIGH GRADE GLIOMAS IN CHILDREN, ADOLESCENTS AND YOUNG ADULTS; A REPORT FROM THE IRRDC AND THE GLIOMA TASKFORCE
Authors: Negm Logine , Nobre Liana , Bennett Julie , Chung Jiil , Fernandez Nick , Johnson Monique , Aronson Melyssa , Zhang Cindy , Komosa Martin , Bianchi Vanessa , Stengs Lucie , Lim-Fat Mary Jane , Keith Julia , Tsang Derek , Gao Andrew , Munoz David , Nguyen Lananh , Das Sunit , Levine Adrian , Das Anirban , Hawkins Cynthia , Tabori Uri
Published: November 2022

Mismatch repair deficiency (MMRD) is a pan-cancer mechanism resulting in universal hypermutation and aggressive cancers that are resistant to chemoradiation yet sensitive to immunotherapy. MMRD mutations can occur somatically or be inherited as a part of Lynch Syndrome or Constitutional Mismatch Repair Deficiency (CMMRD). Although MMRD affects children, adolescents and young adults (CAYA, ages 0-40) with gliomas, its prevalence and impact of germline inheritance is unknown. Given that high microsatellite instability (MSI) is a key characteristic of MMRD, we previously developed a robust low-coverage whole genome-based tool to quantify MSI, which allows for accurate MMRD detection. We are therefore performing a large-scale MMRD screen of CAYA high grade gliomas (HGGs) and utilizing data from the International Replication Repair Deficiency Consortium (IRRDC) to determine the impact of germline mutations in MMRD gliomas. Ongoing data on 346 HGGs from CAYA patients reveals that MMRD is identified in 6% of HGGs and is not present in tumors with pediatric type alterations. Moreover, of MMRD tumors with IDH1 mutations, none harbor 1p/19q co-deletions. Of patients with available information, all are diagnosed with Lynch Syndrome (69%) or CMMRD (31%), with all Lynch Syndrome diagnoses occurring in patients above 18 years of age. Complementary data from the IRRDC on 113 MMRD patients with gliomas reveal that the median age of glioma is 9.7 and 17.5 years in CMMRD and Lynch Syndrome, respectively (p < 0.001). Strikingly, CMMRD gliomas are enriched for secondary polymerase mutations (60%, p < 0.001) and exhibit ultra-hypermutation, while MMRD gliomas with Lynch Syndrome are enriched for IDH1 mutations (32%, p < 0.025) and harbor a lower mutational burden. Our data reveal a high prevalence of MMRD in CAYA HGGs with alarming impact of germline predisposition. These data can support universal screening for MMRD in high grade glioma diagnostics and identify patients for precision therapeutics.
DNAR-12. COMBINING TUMOUR TREATING FIELDS WITH THERAPEUTIC DNA DAMAGE RESPONSE INHIBITORS TO INCREASE POTENCY IN HIGH-GRADE GLIOBLASTOMAS USING CLINICALLY RELEVANT EX-VIVO GLIOMA STEM CELL MODELS
Authors: Vanderlinden Aurelie , Rominiyi Ola , Collis Spencer , Jones Callum , Myers Katie , McGarrity - Cottrell Connor
Published: November 2022

High-grade gliomas are the most common and aggressive type of primary brain cancer. Despite maximal surgical resection, followed by chemotherapy and radiotherapy, overall survival for patients remains between 10-16 months, with limited improvement in survival rates over the last 40 years. This highlights an urgent unmet clinical need to develop more effective therapeutic interventions for these devastating tumours.Tumour-Treating Fields (TTFields), which deliver low-intensity (1–3V/cm) intermediate-frequency (100–300kHz) alternating electric fields to localised tumour sites, represents an exciting new clinically-approved fourth modality for the treatment of high-grade gliomas, with randomised clinical trial evidence supporting improved overall survival (20.9 vs 16.0 months). Whilst TTFields are primarily thought to mediate their anti-cancer effects by disrupting mitotic tubulin dimer alignment leading to abnormal chromosomal segregation and mitotic cell death, recent data suggests that TTFields may also attenuate DNA damage repair efficiency and replication fork dynamics. We therefore hypothesised that combining TTFields with therapeutic DNA damage response inhibitors (DDRi), to develop next generation multimodal therapy regimes, would enhance TTFields potency in glioma cells either alone, or in combination with current standard-of-care chemoradiotherapy. To assess this, we employed clinically-relevant patient-derived primary glioma stem cell (GSC) models that represent both inter-patient and intra-tumoural heterogeneity, including unique ex-vivo models of post-surgical residual disease. We show that combining TTFields with radiation and clinically approved PARP inhibitor therapy leads to significantly increased amounts of DNA damage with concurrent decreased clonogenic survival in GSCs. Furthermore, we have shown similar impressive potency when TTFields treatments are combined with ATR inhibitors that are currently being assessed in various global clinical trials for other cancers. Overall, these exciting findings support further assessment of TTFields and DDRi combinations to underpin future clinical trials combining TTFields with clinically approved DDRi to improve outcomes for patients with currently incurable high-grade gliomas.
DDEL-12. QUADRUPLE CARBON DOT NANO MODEL FOR ENHANCED TUMOR TARGETING AND DUAL DRUG DELIVERY FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMAS
Authors: Graham Regina , Cilinger Emel Kirbas , Hettiarachchi Sajini , Zhou Yiqun , Ferreira Braulio , Leblanc Roger , Vanni Steven
Published: November 2022

High-grade gliomas remain among the most lethal neoplasms. Nanotechnology aims to Improve drug targeting and efficacy. Here we developed a quadruple nano-model (QNM) that specifically targets pediatric high-grade glioma cells and delivers chemotherapies to the cell nucleus. This carbon dot based QNM were fabricated by covalently attaching two drugs (epirubicin and temozolomide) and two targeting peptides. ShPep-1 peptide binds to the IL-13Rα2 receptors allowing for cellular import while lnPep-1h peptide delivers the DNA damaging drugs to the nucleus. Despite demonstrating the lowest measurable drug content (23.3%), the dual peptide linked QNM induced significantly greater cell death than single peptide linked conjugates suggesting enhanced cell uptake. Greatest effect was observed in glioblastoma (SJ-GBM2) and diffuse intrinsic pontine glioma (NP53) cells with IC50s of approximately 60 nM, 3-6-fold lower than single peptide conjugates. Imaging studies using FITC-conjugated carbon dots confirmed the dual peptide conjugate demonstrated greatest cellular uptake and nuclear localization.