bluuebunny/crossref_metadata_2025 huggingface dataset:
CTNI-22. DABRAFENIB (D) AND TRAMETINIB (T) EITHER IN COMBINATION OR AS MONOTHERAPY IN PEDIATRIC PATIENTS HARBORINGBRAF ALTERATIONS IN GLIOMAS OR OTHER RARE TUMORS: FINDINGS FROM AN EARLY ACCESS PROGRAM (EAP)
Authors: Russo Mark , Ferreira AnaRita , Roughton Michael , Rizk Sviatlana , Aoun Manar
Published: November 2024

BACKGROUND

In 2022, dabrafenib and trametinib (D+T) combination received an accelerated US FDA approval for use in adult and pediatric patients with BRAF V600E–mutated unresectable or metastatic solid tumors with no viable alternative therapy. However, to provide global access to therapy in countries where the suitable formulations and/or indications are not yet approved, EAPs are established. We report on patient data from an EAP for pediatric patients with BRAF V600-mutated gliomas or other rare tumors with BRAF alterations such as BRAF fusions, seeking clinical benefit from therapy with dabrafenib and/or trametinib.

METHODS

We analyzed data from the global EAP, where pediatric patients with BRAF alterations in solid tumors including gliomas or other rare tumors received D+T combination or monotherapy. Key eligibility criteria included: age <18 years, absence of approved indications, presence of BRAF V600E/K mutation or other BRAF alterations, and exhaustion of standard therapies. Requests were processed through a global system from November 2016 to December 12, 2022 (cutoff date). Key data on patient characteristics and median treatment duration (mDoT) were collected and will be presented.

RESULTS

Overall, 482 patients with solid or hematological malignancies were included, of which 35.1%, 31.7%, and 33.2% received combination therapy and dabrafenib and trametinib monotherapies, respectively. Across the treatment cohorts, median age was 4.2-6.6 years, and 49.4%-52.9% were males. Most patients had low-grade (72%) or high-grade (4.6%) gliomas, followed by Langerhans cell histiocytosis (17.8%) and other tumors (5.6%). The estimated mDoT for liquid and solid formulations were, respectively, 14.6 months and 10.1 months in combination therapy, 16.5 months and 12.8 months in dabrafenib monotherapy, and 8.8 months and 7.4 months in trametinib monotherapy.

CONCLUSIONS

EAP data represent a valuable real-world resource in understanding patient characteristics in rare tumors (pediatric gliomas). A significant number of treatment requests indicate substantial unmet need, and significant mDoT across age categories was suggestive of benefit to pediatric patients on therapy.
CTNI-41. LONG-TERM SURVIVAL AND PATTERNS OF PROGRESSION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA TREATED WITH OR WITHOUT TUMOR TREATING FIELDS (TTFIELDS) IN A REAL-WORLD SETTING
Authors: Riegel Devon , Bureau Britta , Conlon Patrick , Chavez Gordon , Connelly Jennifer
Published: November 2024

BACKGROUND

Tumor Treating Fields therapy (TTFields) is an FDA-approved locoregional treatment for patients with newly diagnosed glioblastoma (ndGBM). Previous trial data showed the addition of TTFields to standard TMZ-based therapy to significantly improve overall survival (OS), but real-world data is lacking, particularly with long follow-up duration. Here, we report real-world survival and patterns of progression for patients with ndGBM treated with or without TTFields.

METHODS

Patients diagnosed with GBM and treated with standard of care therapy at the Medical College of Wisconsin between March 2015–March 2023 were included. Progression-free survival (PFS) and OS outcomes were assessed, and compared across groups who received or did not receive TTFields therapy during maintenance treatment. Patterns of disease progression were analyzed via anatomic assessment. Patients were followed through March 1, 2024.

RESULTS

A total of 210 patients (TTFields: n=110/52.4%; No-TTFields: n=100/47.6%) were included for analysis. Median age was 60 and 63 years for the TTFields and No-TTFields groups, respectively, with each group 43% female. Other baseline characteristics were consistent across groups. Median TTFields duration was 6.8 months (range: 1–94). OS was significantly improved for the TTFields group vs No-TTFields group (median OS: 21.6 months [18.4–24.8] vs 17.7 months [15.0–20.8]; HR 0.73 [95% CI: 0.54–0.99, P=0.042]). Median PFS was 12.1 months (10.3–14.4) vs 9.6 months (8.5–12.8) with HR 0.77 (95% CI: 0.58–1.02; P=0.071). 5-year OS was 17% (10–28) for the TTFields group, and 11% (5–22) for No-TTFields group. Patients treated with TTFields exhibited a higher rate of non-local progression compared with the No-TTFields group (28% vs 15%, [P=0.044]).

CONCLUSIONS

Analysis of patients from a large institutional dataset reveals an association between TTFields use and long-term survival benefit. Higher incidence of non-local patterns of progression among TTFields users is consistent with pivotal trial findings.
CTNI-42. A BIOMARKER-GUIDED PHASE 2 STUDY OF DB107-RRV (A RETROVIRAL REPLICATING VECTOR) COMBINED WITH DB107-FC (FLUCYTOSINE EXTENDED-RELEASE TABLETS) IN PATIENTS WITH RECURRENT GLIOBLASTOMA OR ANAPLASTIC ASTROCYTOMA: A CLINICAL PROTOCOL
Authors: Shah Ashish , Ramsoomair Christian , Seetharam Deepa , Hudson Anna , Lu Victor , Nasany Ruham , Kushnirsky Marina , Hill Colin , Komotar Ricardo , Ivan Michael , Wright Leonela , Andrews David , Carattini Yamina , Valiathan Ranjini , Koru-Sengul Tulay , De La Fuente Macarena
Published: November 2024

INTRODUCTION

Despite significant advances in understanding the basic pathogenesis of glioblastoma, the median survival of patients has minimally changed in the past 25 years with a 5-year survival rate of <7%. Because of the dismal prognosis, attention has shifted to alternative adjuvant treatment modalities including gene/viral-based therapy. The first clinically tested replicating retroviral vector DB107-RRV (vocimagene amiretrorepvec, formerly Toca511) was assessed in a randomized Phase 3 study (NCT02414165) to evaluate the intracranial administration of DB107-RRV with subsequent oral administration of DB107-FC (5-fluocytosine extended-release tablets) in patients with recurrent HGG. Although the primary endpoint of overall survival (OS) in the intent-to-treat population was not met (median OS=11.07 months, DB107-RRV+ DB107-FC arm and 12.22 months for the SOC arm (HR=1.06; 95% CI:[0.83, 1.35], p=0.6154)), post-hoc analysis identified a subgroup of patients (responders) who demonstrated a marked survival benefit from the Phase III clinical trial (Toca 5, NCT02414165). Using a non-invasive genotyping pipeline, a novel biomarker, DGM7, was identified among responders that confers an improved prognosis: (DB107-RRV+DB107-FC is 18.3 months vs. 12.0 months in the SOC group (HR=0.50; 95% CI:[0.28, 0.89], p= 0.0167)). DGM7 is present in the blood of approximately 20-30% of HGG patients.

METHODS

This is a Phase 2, single-site, open-label, single-arm study to assess the oral administration of DB107-FC in combination with DB107-RRV in DGM7+ patients with recurrent/progressive HGG. Key inclusion criteria include presence of the DGM7 biomarker in blood, patient age 18–75 with histologically proven, measurable (MRI) recurrent/progressive HGG, and no radiation therapy for at least 12 weeks without histopathologic/MRI progression confirmation. The primary endpoint of this study will be progression-free survival at 6 months (PFS6) and OS of DB107-RRV+DB107-FC in DGM7+ patients with recurrent/progressive HGG compared to the historical study arm SOC/DGM7+ from NCT02414165.
CTNI-44. NCT03643549 PHASE IB/II TRIAL: EFFICACY, SAFETY, AND BIOLOGICAL MECHANISMS OF OBJECTIVE RESPONSES IN RECURRENT GBM PATIENTS WITH UNMETHYLATED MGMT PROMOTER TREATED WITH SEQUENTIAL BORTEZOMIB AND TEMOZOLOMIDE
Authors: Goplen Dorota , Rahman Mohummad Aminur , Brekke Jorunn , Kumar Surendra , Arnesen Victoria , Birkeland Even , Simonsen Anne , Waha Andreas , Marienhagen Kirstin , Oltedal Leif , Haasz Judit , Miletic Hrvoje , Selheim Frode , Solheim Tora Skeidsvoll , Brandal Petter , Lie Stein Atle , Chekenya Martha
Published: November 2024

BACKGROUND

Glioblastoma (GBM) is amongst the deadliest malignancies in adults, but especially for patients with unmethylated MGMT promoter (uMGMT) who gain limited benefit from the standard treatment. We previously demonstrated that proteosome inhibitor bortezomib (BTZ), inhibited NFkB activation,depleted MGMT protein and sensitized uMGMT GBM cells to Temozolomide (TMZ). Thus, a phase I/II trial testing sequential combination BTZ+TMZ was launched to investigate safety and clinical benefit.

METHODS

Recurrent GBM patients with uMGMT promoter, progressing ≥12 weeks after radiotherapy, KPS≥70 and radiologically measurable lesions were enrolled. The trial was powered for n=63 patients compared with n=102 historical controls. Patients received BTZ 1.3mg/m² IV on days 1, 4, and 7 of each 4-week cycle, starting on day 3 with oral 200mg/m² TMZ for 5 days/week. Whole exome sequencing (WES) of tumor DNA was conducted to identify genetic changes and LC-MS/MS used to asses proteomic changes in plasma collected during treatment.

RESULTS

As of January 2024, 54 patients (median 55y (25-70); 38 males, 16 females) were treated. The median KPS 90 (range 70-100) and NANO score was 1 (range 0-7). QoL was preserved, with mild /moderate adverse events. Adjusted analyses showed overall survival (OS) of 16.2 months compared to 8.4 months for uMGMT control patients, HR0.48, 95%CI[1.057-2.74],P=0.028. Objective radiological responses stable disease or better were observed in 22% (12/54) patients. Survival from recruitment was 10.5 months for responders vs. 4.8 months for rest of cohort, P=0.054 HR2.55, 95%CI[0.984-5.94]. Preliminary data indicate 78% (7/9) of responders harboured amplified EGFR vs. 38% in rest-of-the patients. The responders differentially expressed proteins critical for cellular processes, including ADAMTSL4, NCAM1, AZGP1, MMP2, CD163, and IL6ST.

CONCLUSION

Sequential BTZ+TMZ therapy is safe, effective and showed clinical benefit. EGFR amplification may be a predictive biomarker for response through NFκB activation, that is targeted by BTZ thereby depleting MGMT protein and enhancing treatment efficacy. Sequential BTZ+TMZ treamtment may represent additional treatment option at recurrence.
CTNI-49. PRECISION MEDICINE CLINICAL TRIAL FOR ADULT PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Chen Jiaying , Solomon David A , Bush Nancy Ann Oberheim , Grabowsky Jennifer A , Kline Cassie , Kroetz Deanna L , Taylor Jennie W , Villanueva-Meyer Javier , Molinaro Annette M , de Groot John F , Butowski Nicholas A , Tedesco Meghan , Rabbitt Jane , Hervey-Jumper Shawn L , Aghi Manish , Berger Mitchel , Chang Edward F , Chang Susan M , Clarke Jennifer L
Published: November 2024

Salvage therapies for recurrent glioblastoma (rGBM) have limited efficacy, with median overall survival of 9 months (OS-9) and 6-month progression-free survival (PFS-6) of 10-25%. Given GBM’s molecular heterogeneity, targeting a single molecular abnormality in isolation has consistently failed as a strategy, and precision combination approaches are needed. An initial 15-patient cohort evaluated the feasibility and safety of treating patients with rGBM with an individualized treatment regimen; we added a second 15-patient expansion cohort to improve the power of preliminary efficacy assessment. Patients underwent clinically indicated surgery with genomic profiling using the UCSF500 targeted DNA sequencing panel. Each personalized treatment regimen combined up to 4 FDA-approved drugs, including one cytotoxic agent, as determined by consensus discussion at an individualized molecular tumor board for each patient. Bevacizumab was not utilized in these combinations. The primary objective of the combined 30-patient cohort was efficacy of individualized treatment regimens by OS-9; secondary objectives included safety and additional efficacy measures including PFS-6. Median age was 53 years (range 32-71). Of 30 patients, 18 were male, 23 were enrolled at first recurrence, 29 had IDH-wildtype glioblastoma, 1 had IDH-mutant astrocytoma, and 10 had MGMT promoter methylation. A total of 12 FDA-approved drugs were used in 18 combinations; the most common regimen prescribed was lomustine, afatinib, and abemaciclib (7; 23%,); second-most common was temozolomide, olaparib, and afatinib (4; 13%). OS-9 of the combined cohort was 70% (95% CI 0.55 – 0.89) and PFS-6 was 27% (95% CI 0.15 – 0.48), with median OS of 11.6 months (95% CI 9.7 – 16.7) and median PFS of 3.7 months (95% CI 2.0 – 5.5).While overall efficacy was modest, implementation of individualized treatment regimens in a timely fashion was safe and feasible for patients with surgically resectable rGBM. Analysis is ongoing to assess whether specific genomic profiles or treatment regimens were particularly efficacious.
CTNI-54. RESPONSE BY RANO2.0 CRITERIA IN ONC201 (DORDAVIPRONE)-TREATED PATIENTS WITH RECURRENT H3 K27M-MUTANT DIFFUSE MIDLINE GLIOMA
Authors: Cloughesy Timothy , Allen Joshua E , Arrillaga-Romany Isabel , Barbaro Marissa , Batchelor Tracey T , Butowski Nicholas , Cluster Andrew , de Groot John , Graber Jerome , Haggiagi Aya M , Kilburn Lindsay B , Kurz Sylvia C , Melemed Allen S , Ramage Samuel C , Salacz Michael E , Shonka Nicole , Sumrall Ashley , Tarapore Rohinton , Taylor Lynne , Wen Patrick
Published: November 2024

PURPOSE

Response assessment in neuro-oncology (RANO) 2.0 is a recently established response assessment for glial tumors that is agnostic to WHO grade. This updated response assessment includes quantitative evaluation of enhancing and non-enhancing disease and recommendations to account for pseudoprogression. This analysis evaluated response to ONC201 by RANO2.0 in recurrent, H3K27M-mutant diffuse midline glioma (DMG), which was previously assessed by RANO-HGG/RANO-LGG (Arrillaga-Romany, JCO, 2024).

METHODS

Fifty patients with recurrent H3 K27M-mutant DMG were selected based on criteria designed with input from regulators to evaluate objective response to ONC201 monotherapy. Patients had contrast-enhancing, measurable, progressive disease, and were ≥90 days from radiation, with adequate washout from other anti-cancer therapies. Diffuse intrinsic pontine glioma, primary spinal tumors, leptomeningeal spread, or CSF-disseminating tumors were ineligible. Response was assessed using RANO2.0 criteria by two-party blinded independent central review.

RESULTS

Best response by RANO2.0 included one complete response (CR, 2.0%), nine partial responses (PR, 18.0%), and four minor responses (MR, 8.0%). Overall response rate (CR+PR+MR) by RANO2.0 criteria was 28.0% (n=14; 95%CI, 16-42). Disease control rate (CR+PR+MR+SD) was 40.0% (n=20; 26-55). Median duration of response was 10.4 months (95%CI, 7.4-15.4). Median time to response was 4.6 months (range, 1.6-15.9). 6- and 12-month progression free survival rates were 32.0% (95%CI, 19-47) and 27.0% (15-41), respectively. RANO2.0 response as a time-varying covariate was significantly associated with overall survival in a multivariate analysis considering baseline performance score, multiple enhancing target lesions, enhancing tumor size, and number of prior recurrences (HR [95%CI], 0.22 [0.08–0.58]; p=0.0023). Patients with an objective response by RANO2.0 were more likely to be alive at 12 (100%) and 24 (86%) months, have reduced corticosteroid usage, and have improved performance status. Responses occurred at a higher rate among patients with a higher performance score and fewer target lesions.

CONCLUSIONS

RANO2.0 assessment of ONC201-treated patients suggests durable and clinically meaningful efficacy in recurrent H3K27M-mutant DMG.
CTNI-67. AI BASED PREDICTION OF CLINICAL TTFIELDS RESPONSE IN GLIOBLASTOMA PATIENTS (RETROSPECTIVE ANALYSIS)
Authors: Kebir Sied , Wilms Sarah , Wenger Katharina , Kessler Almuth F , Pröscholdt Martin , Harapan Biyan N , Quach Stefanie , Hottinger Andreas F , Suchorska Bogdana , Schmidt Teresa , Oster Christoph , Sure Ulrich , Kleinschnitz Christoph , Scheffler Björn , Glas Martin
Published: November 2024

RESEARCH QUESTION

Accurate and individualized prediction of response to therapies is central to precision medicine and a major goal in neuro-oncology. An extension of overall survival (OS) and progression-free survival (PFS) was observed in patients treated with tumor treating fields (TTFields) plus maintenance temozolomide compared to those treated with maintenance temozolomide alone and TTFields have become an integral part of the treatment of glioblastoma. To identify patients who benefit most from TTFields, we aim to implement a state-of-the-art machine learning approach to create a model capable of identifying responding patients early in treatment.

METHODOLOGY

In this retrospective analysis, patients with IDH-wildtype glioblastoma treated with TTFields, in addition to RT and temozolomide, as first-line therapy are included. Clinical data and MRI raw data (in DICOM format) are collected. The preprocessing of the MRI data includes reorientation, bias field correction, registration, segmentation, and intensity normalization. This is followed by the extraction of a Radiomics signature. The latter, along with the clinical data, is trained using various machine learning models. The model validation occurs on an independent test cohort. Data collection from various neuro-oncological centers across Europe is ongoing.

RESULTS

So far, data from 134 TTFields patients and 131 control patients have been collected. Initial results, providing detailed insights into the model architecture and performance, will be presented at the time of the SNO meeting.

CONCLUSION

This study has the potential to optimize the treatment of glioblastoma patients by using machine learning to allow the early identification of patients that respond to first line therapy.
CTNI-72. VAL-083 IN PATIENTS WITH RECURRENT GLIOBLASTOMA TREATED UNDER EXPANDED ACCESS PROGRAM
Authors: Kamiya-Matsuoka Carlos , Weathers Shaio-Pei , Harrison Rebecca , Majd Nazanin , Aaroe Ashley , Knight Stephanie , Hanna Teresa , Patel Chirag , Langlands john , Brown Dennis , Puduvalli Vinay
Published: November 2024

BACKGROUND

Current standard-of-care for glioblastoma (GBM) includes surgery followed by chemoradiation with temozolomide (TMZ) followed by adjuvant TMZ. Almost all GBM patients experience disease progression despite upfront standard-of-care treatment, with a median overall survival of 3-9 months after first recurrence. There are limited treatment options at the time of disease progression, apart from participation in clinical trials. VAL-083 is a bi-functional DNA damaging agent that induces inter-strand DNA cross-links at N7-guanine in a manner independent of O6-methylguanine-DNA-methyltransferase (MGMT).

METHODS

Under an Expanded Access program (NCT03138629), we used VAL-083 to treat 30 patients with recurrent GBM who were not eligible to participate in clinical trials. Here we report safety and efficacy results.

RESULTS

Four patients (13.3%) with leptomeningeal disease were excluded from efficacy evaluation. All patients received chemoradiation with TMZ. Twelve (12/26; 46.2%) patients had ≥2 recurrences and 9/26 (34.6%) had prior lomustine. All tumors had ≥1 mutation, with 14/26 (53.8%) having ≥5 mutations; one patient had a hypermutator phenotype. The most common mutations were TERT (57.7%), PTEN (38.5%), TP53 (26.9%), and NF1 (26.9%). All patients started treatment with VAL-083 at 30 mg/m2/day administered on 3 consecutive days every 21 days. Eight (8/26; 30.8%) patients received bevacizumab concurrently with VAL-083. Eight (8/26; 30.8%) patients had a VAL-083 dose reduction. Patients received a median of 3.0 (5-95pth 1-10) VAL-083 treatment cycles. Median progression free survival (mPFS) and median overall survival (mOS) from last disease progression was 5.1 (95%CI: 2.7-7.2) and 9.8 (95%CI: 5.3-16.4) months, respectively. VAL-083 was well-tolerated and the most frequent adverse events were consistent with prior experience, i.e., thrombocytopenia and neutropenia.

CONCLUSIONS

Use of VAL-083 continues to show benefit in the treatment of GBM patients who have had multiple recurrences and have limited therapeutic options.
CTNI-82. BELZUTIFAN TREATMENT OF VHL-ASSOCIATED CENTRAL NERVOUS SYSTEM HEMANGIOBLASTOMA
Authors: Thomsen Anna , Valerius Allison , Uhm Joon , Ruff Michael , Baykal Duru , Caron Samantha , White Jessica , Webb Mason , Pichurin Pavel , Neth Bryan , Sener Ugur
Published: November 2024

Von Hippel-Lindau (VHL) disease is caused by pathogenic variants in the VHL gene. Abnormal function of VHL protein leads to accumulation of HIF-α and the engagement of hypoxia-sensitive genes with oncogenic effects. VHL is associated with tumors in multiple organs. Belzutifan is an oral selective inhibitor of hypoxia-inducible factor 2 alpha. Belzutifan was approved in 2021 as a targeted therapy for VHL-associated CNS hemangioblastomas, renal cell carcinomas, and pancreatic neuroendocrine tumors. Here, we report on our institutional clinical experience with belzutifan for VHL-associated CNS hemangioblastomas. From October 2021 to May 2024, thirteen adults (9 female, 4 male, median age 40) were treated. Median duration of therapy was 24 months. Seven had a partial radiographic response after median of 3 months; one patient had a partial response; 1 patient had progressive disease on belzutifan. Four patients have been taking belzutifan for less than 3 months, and do not have follow-up imaging to assess response. The most common adverse effect was fatigue (7 patients). Four patients experienced anemia and 2 experienced hypoxia. Three patients discontinued belzutifan due to adverse effects. One patient had to take multiple medication pauses, due to seizure and kidney injury, but resumed treatment with dose reduction. Nine patients remain on therapy. Based on this data, belzutifan is often well-tolerated and associated with durable radiographic responses. Toxicity profile among our patients was similar to that encountered in the clinical trial leading to approval of the agent. These findings provide real-world data supporting continued use of belzutifan in this patient population, with an awareness of potential adverse reactions. Future studies should assess continued radiographic response, sex differences, and effects after long-term use.
DNAR-01. THERAPEUTIC APPLICATIONS OF MESENCHYMAL STEM CELL LOADED WITH GOLD NANOPARTICLES FOR REGENERATIVE MEDICINE
Authors: Cheng Wen-Yu , Yang Meng-Yin , Yeh Chun-An , Yang Yi-Chin , Shen Chiung-Chyi , Hung Huey-Shan
Published: November 2024

In the present study, the various concentrations of AuNP (1.25, 2.5, 5, 10 ppm) were prepared to investigate the biocompatibility, biological performances and cell uptake efficiency via Wharton’s jelly mesenchymal stem cells and rat model. The pure AuNP, AuNP combined with Col (AuNP-Col) and FITC conjugated AuNP-Col (AuNP-Col-FITC) were characterized by Ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR) and Dynamic Light Scattering (DLS) assays. For in vitro examinations, we explored whether the Wharton’s jelly MSCs had better viability, higher CXCR4 expression, greater migration distance and lower apoptotic-related proteins expression with AuNP 1.25 and 2.5 ppm treatments. Furthermore, we considered whether the treatments of 1.25 and 2.5 ppm AuNP could induce the CXCR4 knocked down Wharton’s jelly MSCs to express CXCR4 and reduce the expression level of apoptotic proteins. We also treated the Wharton’s jelly MSCs with AuNP-Col to investigate the intracellular uptake mechanisms. The evidence demonstrated the cells uptake AuNP-Col through clathrin-mediated endocytosis and the vacuolar-type H+-ATPase pathway with good stability inside the cells to avoid lysosomal degradation as well as better uptake efficiency. Additionally, the results from in vivo examinations elucidated the 2.5 ppm of AuNP attenuated foreign body responses and had better retention efficacy with tissue integrity in animal model. In conclusion, the evidence demonstrates that AuNP shows promise as a biosafe nanodrug delivery system for development of regenerative medicine coupled with Wharton’s jelly MSCs.
DNAR-08. THY1 MEDIATES TREATMENT RESISTANCE IN GLIOBLASTOMA THROUGH RAPID REPAIR OF DNA DAMAGE
Authors: Basha Syed Safiulla , Tripathy Arushi , Ravikumar Visweswaran , Awadia Sahezeel , Palavalasa Sravya , Huang Dah-Luen , Rao Arvind , Wahl Daniel R , Rehemtulla Alnawaz , Al-Holou Wajd N
Published: November 2024

Glioblastoma (GBM) is a uniformly lethal primary intracranial neoplasm that inevitably recurs despite treatment by DNA damaging agents radiation (RT) and temozolomide (TMZ). Recurrence may be driven by inherently resistant glioma stem-like cells (GSCs). GSCs have been shown to have constitutive upregulation of DNA damage response (DDR) pathways, resulting from elevated DNA replication stress. This baseline elevated DDR has consequently been shown to confer inherent resistance to DNA damaging agents, TMZ/RT. However, factors mediating elevated replication stress and upregulated DDR in GSCs are poorly defined. Previously, we identified the cell-surface protein, THY1, as a mediator of GSC phenotype and treatment resistance in GBM. To determine mechanisms mediating treatment resistance in THY1+ cells, we engineered patient-derived neurosphere and organoid models, to either overexpress or silence THY1 expression. These models were treated with RT and collected at various time points to measure DNA repair efficiency by assessing the formation and resolution of yH2AX foci and ATM/ATR activation. In parallel, patient-derived GBM tissue from over 20 patients was analyzed using single cell RNA sequencing and spatial transcriptomics to assess pathways associated with THY1 expression. Interestingly, spatial transcriptomics and single cell RNA sequencing data demonstrates significant upregulation of GSC pathways, as well as constitutive upregulation of DDR pathways (p<2e-16) in THY1-high cells. Exploiting our patient-derived lines we determined that DNA repair activation was upregulated at baseline, measured using yH2AX foci and immunoblotting. We then measured DDR in response to radiation and found that high THY1 expression mediated rapid repair of DNA. Overall, we demonstrate that THY1 mediates therapy resistance by constitutively upregulating DDR, likely by upregulating DNA replication stress. We are now working to determine the mechanisms mediating the GSC phenotype and DNA replication stress in THY1 cells in hopes of future translation.
DNAR-15. GROUP 3 MEDULLOBLASTOMAS EXPLOIT A TRANSIENT MECHANISM OF TELOMERE REPAIR MEDIATED BY ZSCAN4 WHICH IS TARGETABLE FOR THERAPEUTIC BENEFIT WITH BRAIN-PENETRANT DRUGS
Authors: Jung Jangham , Yu Bohyeon , Diaz Aaron
Published: November 2024

All cancers need some mechanism of telomere repair. However, it is unknown how Group 3 (G3) medulloblastomas (MB) repair their telomeres, even though MB is the most common malignant brain tumor in kids and G3 is its most aggressive subtype. With rare exceptions, G3 MBs lack telomerase gain-of-function alterations or evidence of constitutive alternative-lengthening-of-telomeres pathway activation. We profiled tumors from N=38 MB patients from UCSF via single-nucleus RNA sequencing; 13 cases were also subjected to single-cell assay for transposase-accessible chromatin by sequencing, and 4 were subjected to single-cell cleavage under targets and tagmentation for H3K27ac. These data identified a network of gene enhancers that were specifically active in rhombic-lip progenitor-like MB cells, the putative G3 MB cell of origin. This program was driven by zinc finger and SCAN domain containing 4 (ZSCAN4), a gene reported to drive transient telomere repair during zygotic genome activation in early embryos. CRISPR inhibition of ZSCAN4 led to significant telomere shortening, telomeric DNA damage, telomere fusions, decreased proliferation, and increased survival of orthotopic xenografts. Conversely, ZSCAN4 over-expression induced significant telomere elongation, increased proliferation, and decreased survival in vivo. Analysis of endogenous-reporter cells indicated that ZSCAN4 is transiently expressed in response to telomere shortening and increases global histone acetylation by inducing chromatin-remodeling factors. Rebastinib targeted ZSCAN4, histone acetylation, and telomere repair, was brain penetrant, and significantly enhanced orthotopic-xenograft survival with no toxicity. Acetyltransferase inhibitor CPI-1612 was brain penetrant and extended xenograft survival with no toxicity. Our data support the hypothesis that G3 MBs exploit a transient mechanism of telomere repair mediated by ZSCAN4. Targeting ZSCAN4 or downstream histone acetylation is therapeutically viable. Pan-cancer whole-genome sequencing data showed that MBs have lower telomeric content than most other cancers. Thus, MBs may be particularly vulnerable to therapeutic strategies that inhibit telomere repair.
DDEL-01. ENGINEERING MRNA THERAPIES FOR BRAIN TUMORS
Authors: Yerneni Saigopalakrishna , Azambuja Juliana Hofstatter , Strelkova-Petersen Daria , Gallagher Brendan , Kim Julie Shin , Chaudhary Namit , Zhao Yongxin , Lucas Peter , McAllister-Lucas Linda , Pardi Norbert , Weissman Drew , Whitehead Kathryn
Published: November 2024

Safe delivery of mRNA to the brain will revolutionize the treatment of brain tumors. While lipid nanoparticles (LNPs) are clinically most advanced non-viral delivery vehicles for therapeutic mRNA, LNP-mediated mRNA delivery to the brain remains challenging. We hypothesized that rationally designed LNPs based on extracellular vesicle mimicry would enable efficient delivery of RNA therapeutics to brain cells without undue toxicity. We engineered LNPs consisting of four components similar to the formulation used in the mRNA COVID-19 vaccines (Moderna and Pfizer-BioNTech): ionizable lipid, cholesterol, helper lipid and polyethylene glycol (PEG)-lipid. We screened ten classes of helper lipids based on lipids enriched in extracellular vesicles to engineer biomimetic LNPs and tested their GFP mRNA delivery efficacy in SIM-A9 mouse microglia cell line. Several unique LNP formulations with potent delivery efficacy (>90% cells transfected) and stable GFP expression kinetics (5 days) were identified. LNP formulations with high transfection efficacy were then tested in vivo for luciferase mRNA delivery via intrathecal injection in C57BL/6 mice. Luciferase expression in vivo confirmed widespread mRNA delivery in the brain. We then tested Cre recombinase mRNA delivery in Ai9 mouse to identify LNP-targeted cells via flow cytometry and histology. Flow cytometry and expansion microscopy confirmed Cre recombinase mRNA delivery to a variety of brain cells, including microglia (75-90%), neurons (31-40%), neural stem cells (39-62%), oligodendrocytes (70-90%), and astrocytes (44-76%). LNPs were further evaluated for Cas9 mRNA and CD81 sgRNA delivery in C57BL/6 mouse brains to assess brain-targeted gene editing. Sanger sequencing showed that CRISPR-Cas9 editing was successful in ~40% of cells in the mouse brain. In summary, we engineered extracellular vesicle-based LNP library that can deliver RNA therapeutics to a variety of brain cells in vivo. With further development, this technology could potentially enable genetic and epigenetic therapies targeting drivers of brain tumors.
DDEL-03. INTRANASAL DELIVERY OF PDGFRA-TARGETED NANOTHERAPEUTICS FOR THE TREATMENT OF PEDIATRIC HIGH-GRADE GLIOMA
Authors: Mineji Kentaro , Watanabe Jun , Uchida Eita , Kaur Savneet , Zhang Peng , Hashizume Rintaro
Published: November 2024

Pediatric high-grade glioma (pHGG) is the most common cause of cancer-related death in children, of which the most malignant and devastating tumors include diffuse midline glioma (DMG). Its anatomical location in the brainstem, infiltrative nature, and blood-brain barrier (BBB) limit surgical resection and the distribution of systemically administered drugs. Intranasal delivery (IND) is a noninvasive method that bypasses the BBB, by leveraging the unique anatomic connections of the olfactory and trigeminal nerve pathways with the nasal cavity. We previously demonstrated the efficacy of IND of nanoliposomal (LS) formulation of the active metabolite of the DNA topoisomerase I inhibitor, irinotecan, LS-SN-38, in orthotopic human brainstem xenograft models. The specificity of liposomes can be enhanced by using immunoliposome (iLS) formulation, which are coated with antibodies specific to the tumor cells leading to targeted drug delivery and reduced toxicity to normal cells. Platelet-derived growth factor receptor alpha (PDGFRA) plays a role in DMG oncogenesis and is expressed in as much as 70% of DMG by immunohistochemistry. In this study, we evaluated the effect of anti-PDGFRA monoclonal antibody-conjugated immunoliposome encapsulated SN-38 (PDGFRA-iLS-SN-38) in pHGG cell lines. PDGFRA signals were assessed in pHGG cells using western blotting. Cells were treated with rhodamine (Rho)-labeled PDGFRA-iLS and cellular uptake was confirmed with a fluorescent microscope. PDGFRA-iLS-SN38 had the additive effect on the LS-SN-38 in DIPG007 cells (PDGFRA positive), but not in SF8628 cells (PDGFRA negative) in vitro. We treated mice bearing human DMG xenografts with IND of PDGFRA-iLS-SN38. Tumor growth and response to therapy are quantitatively measured by bioluminescence imaging, and efficacy is assessed by survival analysis. Results of survival analysis will be reported at the meeting. PDGFRA-targeted nanotherapeutics represented a specific effect on glioma cells expressing PDGFRA, providing a promising therapeutic approach for targeting pHGG.
DDEL-07. EFFICACY OF TEMOZOLOMIDE IN MEDULLOBLASTOMA PATIENTS: REVIEW OF SERIES OF TWO ADULT PATIENTS WITH RECENT UPDATES IN LITERATURE
Authors: Raval Ruchi , Desai Khushi , Raval Aarya , Behl Jaspreet , Raval Om , Gor4ty Aishwarya , Parikh Sakshi , Parikh Krishna , Gupta Meher , Raval Sumul
Published: November 2024

Medulloblastoma is a primary malignant CNS tumor commonly seen in children and rarely in adults (20% vs 1% of all primary brain tumors). Maximal safe resection and craniospinal irradiation followed by adjuvant chemotherapy have proven to be an effective treatment in children. Due to insufficient data available in adult patients, it is also the usual approach in them despite unclear long-term outcomes. Standard chemotherapeutic regimens consisting of vincristine, cisplatin, and lomustine are known to cause greater toxicity in adults making adequate dose titration a challenge. Temozolomide is a second-generation cytotoxic alkylating agent with favorable CNS penetration. It is a potential alternative that has yielded superior results in treating gliomas and preventing recurrence along with minimal toxicity. We discuss a series of two adult medulloblastoma cases which were given 24 cycles of Temozolomide monotherapy over two years following surgical resection and craniospinal irradiation. Serial MRIs did not report any signs of recurrence rendering one case cancer-free for seventeen years and the other for ten. Minimal toxicity in the form of nausea, vomiting, headache, and reversible, temporary pancytopenia was seen in contrast to other agents. Improved survival with minimal toxicity was demonstrated in both cases proving the efficacy of Temozolomide as adjuvant chemotherapy for adult Medulloblastoma. While a regimen of Temozolomide is recommended for recurrent Medulloblastoma, there is no optimal regimen available for initially diagnosed, localized tumors, especially in adults. Multi-institutional clinical trials are required to study its role as a monotherapy during an early yet critical phase of management.
DDEL-08. MEGADOSE BOSWELLIA SERRATA CAUSES SIGNIFICANT DECREASE IN CEREBRAL EDEMA WITH MINIMAL TOXICITY IN BRAIN TUMOR PATIENTS
Authors: Carrillo Jose , Wagle Naveed , Sharma Akanksha , Nguyen Minhdan , Truong Judy , Mauritson Emmaline , Kong Janet , Katz Samuel , Carrillo Cole , Carrillo-Singh Yash , Kesari Santosh
Published: November 2024

Boswellia serrata has been shown to reduce cerebral edema following radiation in brain tumors by Kirste et al in a prospective, randomized, placebo-controlled, double-blind pilot trial. In the study dose of Boswellia used was 4200mg/day, and was well tolerated. We report 2 patients who took doses 10x that which was recommended, after inadvertently buying much higher doses online. Both patients obtained significant reduction in cerebral edema and enhancing disease on MRI. The daily dose of 42000mg/day was tolerated well, with only mild dysphonia in one patient. The optimal dosing of Boswellia serrata to treat cerebral edema is not known, and should be studied further.
DDEL-15. PHARMACOKINETIC ANALYSIS OF CARBOPLATIN AND FLUORESCEIN BRAIN PENETRATION AND PERMANENCE FOLLOWING ULTRASOUND-BASED BLOOD-BRAIN BARRIER OPENING ON GLIOBLASTOMA CLINICAL TRIAL
Authors: Habashy Karl J , Synold Tim , Feng Ye , Kim Kwang-Soo , Gomez Cristal , Amidei Christina , Ward Rachel , VanderMolen Sarah , Zarrieneh Ashkan , Arrieta Victor A , Fares Jawad , Burdett Kirsten B , Zhang Hui , Dmello Crismita , Chen Li , Bebawy John F , Canney Michael , Stupp Roger , Portnow Jana , Sonabend Adam M
Published: November 2024

The blood-brain barrier (BBB) impedes the passage of most circulating drugs into the brain. Low-intensity pulsed ultrasound with microbubbles (LIPU/MB) transiently opens the BBB, improving drug delivery to the brain. The implication of this transient BBB opening on parenchymal drug permanence is unknown. We compared the parenchymal levels and permanence/retention of temozolomide, carboplatin, and fluorescein, and investigated in a clinical trial (NCT04528680) the effect of LIPU/MB on the permanence of carboplatin and fluorescein in the human brain. Four patients underwent intraoperative LIPU/MB (SonoCloud-9, Carthera) with intravenous carboplatin and fluorescein infusion. Microdialysis catheters were implanted into sonicated and non-sonicated brain for continuous drug measurement over 24 hours. Published data from a microdialysis study of temozolomide were used for comparison. Temozolomide and carboplatin exhibited similar brain-to-plasma AUC ratios (17.8 ± 13.3%; 16.3 ± 8.2%, respectively) which were higher than that of fluorescein (10.4 ± 6.9%). Parenchymal half-life was the longest for fluorescein (13.6 ± 11.0 hours), followed by carboplatin (5.1 ± 1.9 hours) and temozolomide (2.9 ± 1.6 hours). LIPU/MB led to sustained elevated parenchymal drug concentrations, achieving a 3.1-fold increase in AUC for both carboplatin (P = 0.02), and fluorescein (P = 0.04), and higher parenchymal than systemic drug levels starting at 21 hours and 7 hours for these drugs respectively (P < 0.05), timepoints where these drugs had mostly cleared from the plasma. Fluorescein exhibits prolonged permanence in the brain parenchyma and may be “trapped” by the BBB. In the context of transient BBB opening by LIPU/MB, parenchymal carboplatin and fluorescein concentrations remain elevated over time, supporting the notion that the BBB exhibits a bi-directional restriction of drug passage. Future studies are warranted to explore the efficacy of drug trapping to achieve prolonged/sustained exposure of cytotoxic drugs for brain tumor therapy.
DDEL-16. MICROMESH FOR REVAMPING THE ‘COLD’ TUMOR MICROENVIRONMENT IN GLIOBLASTOMA IMMUNOTHERAPY
Authors: Palange AnnaLisa , Guerriero Irene , Estevez Ana Maria Lopez , Pesce Cristiano , Spano’ Raffaele , Mascolo Daniele Di , Decuzzi Paolo
Published: November 2024

High-grade gliomas have poor prognoses with limited treatment options, typically maximal safe resection and adjuvant radiochemotherapy. Novel therapies often face challenges due to low brain penetrance and poor bioavailability. To address these issues, a conformable, compartmentalized polymeric implant called microMESH has been developed. microMESH provides localized, sustained release of drugs, small inhibitors, antibodies, and nanomedicines, enabling novel therapeutic combinations. When applied to the tumor margins, microMESH adheres to the tissue, releasing its therapeutic cargo over weeks and reducing systemic toxicity. Its biocompatibility, cytotoxicity, and anti-tumor efficacy were tested on murine cancer cells (CT-2A) and orthotopic glioblastoma syngeneic models. Exposing primary bone marrow-derived monocytes (BMDM) to CT-2A conditioned medium increased the expression of anti-inflammatory cytokines (IL-10 and IL-4) by 2 times without significantly affecting the pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), indicating that CT-2A cells tend to establish an immunosuppressive ‘cold’ tumor microenvironment. Next, the co-incubation of CT-2A cells with BMDM followed by the administration of the immune checkpoint inhibitor aCD47 resulted in a cancer cell viability drop by 50% already at 50 μg/ml aCD47 after 1 day. Additionally, pre-treatment with docetaxel (DTXL) further decreased cell viability, suggesting a synergism between aCD47 and the chemotherapeutic drug. Flow cytometry showed that 50 nM DTXL at 3 days post-incubation was responsible for a strong translocation of the ‘immunogenic dell death’ protein calreticulin on the cell membrane, potentially explaining the synergism. Over 2 months, the intracranially deployed microMESH biodegraded without inducing any toxic effect. In orthotopic CT-2A tumors, aCD47/DTXL–microMESH (0.75 mg/kg, single intracranial application) showed a 40-day survival compared to 22 days for iv DTXL (3 mg/kg qod), 24 days for ip aCD47 (5 mg/kg qod), and 18 days for untreated mice. microMESH helped identify and enabled novel combination therapies directly at the tumor bed, demonstrating superior efficacy over systemic therapies.
DDDR-03. DEVELOPMENT OF ANTI-TUMOR AROMA THERAPY FOR GLIOBLASTOMA WITH LEMONGRASS ESSENTIAL OIL
Authors: Saito Norihiko , Hirai Nozomi , Koyahara Yuki , Hiramoto Yu , Fujita Satoshi , Nakayama Haruo , Hayashi Morito , Ito Keisuke , Iwabuchi Satoshi
Published: November 2024

INTRODUCTION

Aroma essential oils apply to cancer therapy because of their immune-enhancing and sedative effects, and their ability to reduce the side effects of chemotherapy. Recently, aroma essential oils have also been reported to have anti-tumor effects. We investigate the anti-tumor effects of aromatic compounds contained in essential oils as a novel treatment for glioblastoma. In this study, we analyzed the antitumor effect of lemongrass essential oil and investigated its antitumor aroma therapy for glioblastoma. methods and

RESULTS

Human glioblastoma cells (U87, T98G) and mouse brain tumor cells (RSV-M) were used in the study. Tumor cells were cultured in the presence of lemongrass essential oil for 72 hours, and the growth inhibitory effect was observed, suggesting that the evaporated lemongrass essential oil components acted on tumor cells in the vicinity. In addition, a similar effect was observed with citral alone, which is the main component of lemongrass. Analysis of the effects of citral revealed that citral strongly binds to MARK4 and inhibits its enzyme activity, and that citral decreases the phosphorylation of tau protein. Next, a mouse brain tumor model with RSV-M was established, and the anti-tumor effect of lemongrass essential oil was studied. The results showed that the mice that inhaled lemongrass essential oil for 12 h/day had a significantly prolonged survival period compared to the control group.

DISCUSSION

Citral is the main component of lemongrass essential oil, which contains 70-80% of lemongrass essential oil. This study suggests a mechanism of inhibition of tumor cell proliferation by citral in malignant gliomas. Citral is a volatile monoterpene, and its anti-tumor effect was demonstrated by diffusion through evaporation.

CONCLUSION

Citral in lemongrass essential oil shows anti-tumor effects and is expected to be applied to a new glioblastoma therapy using “aroma”
DDDR-16. SORTING TO ENRICH FOR CHEMOTHERAPEUTIC-RESISTANT GLIOMA CELLS BASED ON UNIQUE MEMBRANE PROPERTIES
Authors: Dang Vi , Jiang Alan , Hanamoto J Nicole , Lav Nicole , Bota Daniela , Flanagan Lisa
Published: November 2024

Glioblastoma, astrocytoma, and oligodendroglioma comprise a class of aggressive and deadly brain tumors called diffuse gliomas. Around 20,000 glioma cases are diagnosed yearly in the US alone. The current standard chemotherapy treatment, temozolomide (TMZ), is insufficient as the 5-year survival rate of glioblastoma patients is as low as 8%. This is due to the presence of TMZ-resistant cells within tumors that lead to chemoresistance and tumor recurrence. Thus, studying the molecular properties of TMZ-resistant cells would enable more effective means of targeting them and thus improve patient outcomes. We leveraged dielectrophoresis (DEP), a phenomenon by which non-uniform electric fields induce differential movement of cells, as a novel label-free technique to sort glioma cells based on their membrane electrophysiological properties. We were able to successfully use DEP to sort cells from glioblastoma and oligodendroglioma established cell lines, which yielded fractions that differed in membrane capacitance, the membrane’s ability to store charge. Interestingly, the DEP-sorted cell fractions also exhibited significant differences in TMZ resistance, indicating that we were able to use DEP to enrich for TMZ-resistant cells. Further, the differences in TMZ resistance were coupled with their membrane capacitance differences. Because we previously found that changes in membrane capacitance were linked to differences in glycosylation, we utilized lectin analysis to assess glycan expression of DEP-sorted oligodendroglioma cells. Our data show that TMZ-resistant oligodendroglioma cells enriched from DEP sorting had reduced levels of mannose glycans compared to less TMZ-resistant fractions. Collectively, our novel findings demonstrate (a) TMZ-resistant glioma cells can be enriched by DEP, and (b) TMZ resistance is correlated with membrane capacitance and cell surface glycosylation. These findings could enable further characterization of TMZ-resistant cells to better understand molecular mechanisms of TMZ resistance and the development of more effective treatment strategies for gliomas through targeting membrane properties such as glycosylation.
DDDR-19. PHARMACOSCOPY FOR BRAIN METASTASES FROM NON-SMALL CELL LUNG CANCER (NSCLC)
Authors: Le Rhun Emilie , Mena Julien , Lee Sohyon , Festl Yasmin , Buck Alicia , Voglis Stefanos , Zeitlberger Anna Maria , Weiss Tobias , Serra Carlo , Neidert Marian , Regli Luca , Weller Michael , Snijder Berend
Published: November 2024

Brain metastases remain a common and important complication in the course of disease in patients with non-small cell lung cancer (NSCLC). While targeted therapies and immunotherapies have led to prolonged disease control in subsets of patients with brain metastases from NSCLC, there is still an urgent need for novel treatments after failure of these standards and after exhaustion of local therapies including surgery and radiotherapy. Here we performed an explorative feasibility study to profile ex vivo drug sensitivities across a large panel of classical anti-cancer as well as neuroactive drugs, using an automated imaging platform called “pharmacoscopy”. The anti-cancer drug panel included chemotherapies and targeted therapies such as receptor tyrosine kinase, cyclin dependent kinase, and BCL2 inhibitors. The neuroactive drug panel included antidepressants and antipsychotics. A total of 19 samples from 17 patients were dissociated after surgery and incubated with drugs for 48 hours ex vivo to measure drug sensitivities. Patient cancer cells were identified by immunofluorescence using EpCAM, TTF-1, or CK7 as markers whereas immune cells were identified by CD45. On-target drug activity (pharmacoscopy score) was measured by quantifying the specific reduction of cancer cells upon drug treatment. Among the top ranking drugs ex vivo, several patient samples displayed on-target responses to candidate targeted therapies such as the CDK4/6 inhibitor abemaciclib, the BCL2 inhibitor venetoclax, and the MEK inhibitor cobimetinib as well as unexpected sensitivies to certain neuroactive drugs. Integration of pharmacoscopy results with molecular data from next generation sequencing in the respective brain metastases tissues is ongoing. Overall, this study demonstrates the feasibility of pharmacoscopy-based functional drug testing in NSCLC brain metastases, and highlights novel opportunities of personalized treatment for future exploratory clinical studies in patients with brain metastases from NSCLC.