bluuebunny/crossref_metadata_2025_split huggingface dataset:
CTNI-56. A PHASE II CLINICAL TRIAL USING ACCELERATOR-BASED BNCT SYSTEM FOR REFRACTORY RECURRENT HIGH-GRADE MENINGIOMA
Authors: Miyatake Shin-Ichi , Wanibuchi Masahiko , Kawabata Shinji , Ko Naonori , Ono Koji 
Published: December 2020

Abstract

BACKGROUND
Boron neutron capture therapy (BNCT) is tumor-selective particle radiation. Recently accelerator-based neutron sources (ABNS) have been developed for clinical trials to obtain on-label use, i.e. new drug approval for malignant gliomas. Recently Japanese regulatory authority has just given this permission for H&N cancers. Recurrent high-grade meningiomas (HGM) are difficult to control. We have applied reactor-based BNCT for 46 cases of refractory HGM. All cases showed good tumor shrinkage with good local control.

PURPOSES
Based on these situations, we proposed “A phase II clinical trial using accelerator-based BNCT system for refractory recurrent HGM” for AMED in Japan which is similar to NIH in USA. This proposal was successfully accepted.

DESIGN
We prepared 2 study groups, BNCT test treatment group and control best supportive care group, for RCT. PFS and OS were set-up as primary and secondary endpoints, respectively. Rescue BNCT is allowed for control group patients, if they showed PD during observation. Modified Macdonald criteria is adopted for assessment. Hypothesized PFS of treatment group and control group was 5 months and 24 months, respectively. The trial started in August 2019.

METHODS
Twelve BNCT and 6 control subjects will be included. Patients’ eligibility criteria is recurrent HGM after some radiotherapy. Cyclotron-based ABNS system is used for neutron source. Neutron-irradiation time is determined not to exceed to 7.5 Gy-Eq for scalp dose which was referencing preceding phase I trial for malignant gliomas.

PROGRESS
As of April 2020, 4 subjects were included, 3 for BNCT treatment group, 1 for control best supportive care group. The control subject showed PD during one month observation and rescue treatment showed PR. Treatment group 3 cases showed more than SD.

CONCLUSION
We started this RCT and will introduce the interim report of this clinical trial in the meeting.
CTNI-67. EFFICACY AND SAFETY OF LAROTRECTINIB IN PATIENTS WITH TROPOMYOSIN RECEPTOR KINASE (TRK) FUSION PRIMARY CENTRAL NERVOUS SYSTEM (CNS) TUMORS: AN EXPANDED DATASET
Authors: Perreault Sébastien , Doz François , Drilon Alexander , Geoerger Birgit , Boni Valentina , Chisholm Julia , Dubois Steven G , Grilley-Olson Juneko E , Hong David S , Italiano Antoine , Kang HyoungJin , Nysom Karsten , Øra Ingrid , Owens Cormac , Schulte Johannes H , Tahara Makoto , Ziegler David , Ellezam Benjamin , Reeves John A , Fellous Marc , De La Cuesta Esther , Laetsch Theodore W , van Tilburg Cornelis M 
Published: December 2020

Abstract

BACKGROUND
TRK fusion proteins are oncogenic drivers of various CNS and non-CNS tumors. Larotrectinib, a highly selective FDA- and EMA-approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% across various non-CNS cancers (Hong et al. Lancet Oncol. 2020). We report data in an expanded set of TRK fusion primary CNS tumors treated with larotrectinib.

METHODS
Patients with primary CNS tumors harboring an NTRK gene fusion treated with larotrectinib in two clinical trials (NCT02637687, NCT02576431) were identified. Disease status was investigator-assessed (RANO). Data cutoff: July 15, 2019.

RESULTS
Twenty-four patients with TRK fusion primary CNS tumors were identified. Eighteen patients had gliomas (13 high-grade and five low-grade). Median age was 8.0 years (range 1.3–79.0), with 20 patients &lt; 18 years old. ORR was 29% (95% CI 13–51%); best responses were two complete responses, five partial responses (two pending confirmation), 15 stable disease, and two progressive disease. The 24-week disease control rate was 63% (95% CI 41–81%). For the five confirmed responders, median time to best response was 1.8 months and median duration of response was 4.9 months (range 1.7+ to 10.1+). Median progression-free survival was 11.0 months (range 1.1 to 19.8+) and median overall survival was not reached (range 1.9+ to 21.4+) at a median follow-up of 6.0 months. Treatment duration ranged from 1.2 to 21.4+ months; three patients continued treatment beyond progression. Treatment-emergent adverse events (TEAEs) were mainly Grade 1 and 2. Grade 3–4 TEAEs occurred in 10 patients, with two deemed related to larotrectinib. The most common neurological TEAE was headache in three patients (Grade 1–2). No patients discontinued larotrectinib due to AEs.

CONCLUSIONS
Larotrectinib was active and well tolerated in patients with TRK fusion primary CNS tumors. These results support testing for NTRK gene fusions in patients with primary CNS tumors.
CTNI-73. OVERALL SURVIVAL OF NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS TREATED BY STANDARD THERAPY IN COMPARISON TO STANDARD THERAPY PLUS TUMOR TREATING FIELDS
Authors: Rulseh Aaron , Derner Adam , Sroubek Jan , Klener Jan , Vymazal Josef 
Published: December 2020

Abstract

BACKGROUND
Tumor treating fields (TTFields; 200 kHz) have shown significant prolonged survival in newly diagnosed (ndGBM). TTFields are anti-mitotic, low intensity, intermediate frequency alternating electric fields. The applied fields disrupt the mitotic spindle, microtubule assembly and the segregation of intracellular organelles during cell division, leading to apoptosis or mitotic arrest. We compared overall survival (OS) between patients recently treated with standard therapy and standard therapy plus TTFields at our institution.

METHODS
Subjects (N=25) with ndGBM treated with standard therapy plus TTFields (STDTh-TTF) at our institution were included. Standard therapy (STDTh) consisted of surgical resection, followed by combined radiotherapy and chemotherapy (Temozolomide). In 3 cases, biopsies were performed instead of resection. The date of resection or biopsy was considered the entry date and was used in calculating survival. The study took place from July 2015 to April 2019. A matching control group of 25 subjects with ndGBM were treated with STDTh alone at our institution and were assembled from our database based primarily on date of resection or biopsy, and secondarily by age (2 subjects underwent biopsy in place of resection). When assembling the control group, the investigators were blinded to survival outcome.

RESULTS
Significantly greater overall survival was observed for the group treated by TTFields in addition to standard therapy (p &lt; 0.001; Hazard ratio [HR] 0.21; 95% confidence interval [CI] 0.1–0.45; median survival time STDTh-TTF 31.7 months, STDTh 7.1 months). The groups were balanced with respect to sex, and no differences with respect to age (p = 0.13; STDTh-TTF mean 51.58 years, SD 8.8; STDTh mean 52.42 years, SD 8.7) or inclusion date (p = 0.22) by paired t-test were detected.

CONCLUSIONS
Our initial results appear promising with respect to overall survival benefit in patients undergoing TTFields treatment in addition to standard therapy.
DDRE-04. miR-149-3p INHIBITS THE GSC PHENOTYPE AND RE-SENSITIZES THERAPY-RESISTANT GBM CELLS
Authors: Lopez-Bertoni Hernando 
Published: December 2020

Abstract

BACKGROUND
Intra-tumor heterogeneity presents one of the biggest challenges in the development of solid cancer therapeutics. Cells within the same tumor display distinct phenotypes that affect their growth rate, survival, migration, therapy-response, and tumor-propagating capacity. We now understand cancer stem cells (CSCs) play critical roles in driving intra-tumor cellular heterogeneity by establishing dynamic cellular transitions within tumors. GBM are highly aggressive tumors that display a poorly differentiated cell phenotype. Lineage-tracing experiments show that stem-like cells are responsible for GBM re-growth after therapy and this process is in part mediated by known drivers of stemness (e.g. Sox2).

PURPOSE
Understand the contribution of stem-cell driving mechanisms to the therapy-resistant phenotype of GBM.

METHODS
We used human GBM-derived neurosphere lines as cell models. miRNA expression was performed using commercially available mimics. Change in self-renewal capacity were measured via neurosphere formation assays, and levels of miRNA and stem cell markers were quantified by qRT-PCR.

RESULTS
We show that GBM cells expressing transgenic Oct4 and Sox2 are more resistant to ionizing radiation (IR) treatment and exposing GBM neurospheres to temozolomide (TMZ) and IR gives rise to a cell sub-set with higher gene expression levels of Oct4 and Sox2 compared to untreated cells. The clinical relevance of this phenotype is supported by multi-dimensional transcriptome analyses that identifies a group of genes induced by Oct4 and Sox2 enriched in recurrent GBM. We identified miR-149-3p as a high-priority candidate capable of simultaneously inhibiting several transcripts induced by Oct4/Sox2 in recurrent GBM. Transient expression of miR-149-3p decreases the capacity of GSCs to self-renew as spheres and re-sensitized therapy-resistant GSCs to TMZ treatment.

CONCLUSION
These results show that GSC-driving mechanisms induce a subset of genes that give rise to therapy-resistant GBM cells and suggests that miR-149-3p can be developed as a therapeutic for recurrent GBM.
DDRE-17. INITIAL CLINICAL EXPERIENCE USING OSIMERTINIB IN PATIENTS WITH RECURRENT MALIGNANT GLIOMAS WITH EGFR ALTERATIONS
Authors: Abousaud Marin , Faroqui Naqeeb , Hsu Fang-Chi , Lesser Glenn , Strowd Roy , Ramkissoon Shakti , Kwatra Madan , Houston Kristin Strickland , Carter Annette , DeTroye Alisha 
Published: December 2020

Abstract
EGFR alterations are commonly observed in malignant gliomas (MG), especially glioblastomas, making this pathway an appealing therapeutic target. Unlike other EGFR tyrosine kinase inhibitors (TKIs), osimertinib (osi), a third-generation, irreversible EGFR-TKI commonly used to treat EGFR-mutant lung cancer, is able to effectively penetrate the blood brain barrier (BBB) and achieve therapeutic concentrations in brain tissue. METHODS: A retrospective chart review identified six patients (pts) aged 46–74 years with recurrent MG and known EGFR alterations identified by next generation sequencing who received at least one dose of osi between 1/1/2018 and 5/26/2020. Patients received osi 80 mg by mouth once daily and continued treatment until disease progression, the development of unacceptable side effects, medical complications, or death. RESULTS: All patients had EGFR amplification. Other EGFR alterations identified included EGFRvIII (1 pt), deletion of introns 1–7 (3 pts) and deletion of introns 13–15 (2 pts). Four of the six patients were evaluable for response. Three patients (75.0%) had stable disease (SD) as best response and one patient (25.0%) was refractory to treatment. One patient with an EGFRvIII mutation achieved stable disease on osi and remained on treatment for 236 days. Thrombocytopenia developed in 2 patients (grade 2 (1), grade 3 (1) in patient also on concurrent bevacizumab) and 1 patient developed grade 1 diarrhea and pneumonia. Overall, this heavily pretreated patient population tolerated osi therapy and half of the patients had a best response of SD which lasted from 77 to 236 days. CONCLUSIONS: Osi has a tolerable safety profile in this heavily pretreated brain tumor population, and it may benefit selected patients with recurrent MG containing EGFR alterations. Further clinical investigations are needed, particularly in patients whose tumors express an EGFRvIII mutation, to identify which EGFR alterations may sensitize tumors to this BBB penetrant EGFR-TKI.
DDRE-18. DEVELOPMENT OF EGFRvIII AND EGFR DIRECTED CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY FOR THE TREATMENT OF GLIOBLASTOMA MULTIFORME
Authors: Ruff Michael , Sakemura Reona , Manriquez-Roman Claudia , Hefazi-Torghabeh Mehrdad , Schick Kendall , Michelle Cox , Can Ismail , Horvei Paulina , Siegler Elizabeth , Tapper Erin , Kenderian Saad 
Published: December 2020

Abstract

BACKGROUND
Chimeric antigen receptor T cell (CART) therapy has revolutionized the treatment landscape for hematological malignancies, its efficacy remains limited in solid tumors. EGFRvIII is a truncated version of the wild type EGFR in which deletion of exons 2–7 of the extracellular domain leads the variant (EGFRvIII) that is strongly antigenic and is mostly expressed on tumor cells. EGFR amplification (tEGFR) almost uniformly precedes the presence of EGFRvIII on tumor cells. The heterogeneity of surface receptor expression and immunosuppressive stromal microenvironment underscore the need to develop CART strategies to target multiple tumor antigens simultaneously.

METHODS
we generated tEGFR/EGFRvIII directed CAR construct by cloning a clinically relevant tEGFR and EGFRvIII specific scFv into a second generation CAR construct (41BB stimulated) in a third generation lentivirus backbone. This was used to transfect 293T cells and the generated lentivirus particles were used to transduce T cells and generate EGFRvIII/tEGFR CART cells. GBM primary patient derived cell lines were used in these experiments. These cells were passaged and maintained in patient derived xenograft models.

RESULTS
EGFRvIII/tEGFR directed CART cells exhibited potent antitumor activity against EGFRvIII/tEGFR + GBM cell lines: with 100% killing at 1.25:1, 2.5:1, 5:1 and 10:1 E:T ratio on multiple PDX cell lines with EGFRvIII expression and EGFR over-expression (greater than five copies of EGFR gene) at 24 hours of incubation. Conclusion: We demonstrate that targeting EGFRvIII and over-expressed EGFR with CART cells is feasible, efficacious and represents a promising therapeutic strategy to target GMB. Data from in vivo and combinatorial CART experiments will be reported at the meeting.
DDRE-28. EGFR INHIBITION DOWNREGULATES MGMT AND SENSITIZES GBM CELLS TO TMZ
Authors: Guo Gao , Gong Ke , Sarkaria Jann , Habib Amyn 
Published: December 2020

Abstract
Glioblastoma (GBM) is a highly malignant type of adult brain tumor with a poor prognosis. Temozolomide (TMZ), a DNA alkylating agent, has been widely used as an effective first-line chemotherapeutic agent for the treatment of GBM patients. The efficacy of TMZ in GBM depends on the absence of the DNA repair protein MGMT which reverses the DNA damage induced by TMZ. The MGMT promoter is hypermethylated in about 45% of GBMs, resulting in lack of MGMT expression and increased responsiveness to TMZ. TMZ is less effective in MGMT unmethylated GBMs. We propose that EGFR inhibition downregulates MGMT and sensitizes glioma cells to TMZ and a combination of pretreatment with erlotinib followed by TMZ could be a useful therapeutic approach in MGMT expressing GBMs. As our experimental model we used multiple MGMT unmethylated lines from the Mayo Clinic patient derived xenografts (PDXs) panel. Our data demonstrate that exposure of cells to EGFR tyrosine kinase inhibitor erlotinib for 48h results in downregulation of MGMT at the mRNA and protein level. Additionally, EGFR inhibition activates the AP-1 transcription factor and overexpression of AP-1 components Fos and Jun results in decreased MGMT expression in TMZ resistant PDXs, suggesting that AP-1 acts as a transcriptional repressor of MGMT. We further identified that the mice implanted with TMZ resistant PDXs pretreated with afatinib followed by TMZ treatment survived longer compared to those treated with TMZ alone. Thus, the use of EGFR inhibition may enhance the sensitivity of MGMT unmethylated GBMs to TMZ.
DDRE-33. MOLECULAR DIFFERENTIATION OF IMIPRIDONES ONC201 AND ONC206
Authors: Prabhu Varun , Cuoco Caroline , Jung Jinkyu , Morrow Sara , Kawakibi Abed Rahman , Willette Blair , Day Marilyn , Anantharaman Lakshmi , Charter Neil , Rucker Joseph , Doranz Benjamin , Basken Joel , Stogniew Martin , Gilbert Mark , Free R , Sibley David , Allen Joshua 
Published: December 2020

Abstract
ONC201 is the first bitopic antagonist of dopamine receptor D2 (DRD2) and agonist of ClpP in oncology. In clinical trials, the small molecule has induced durable tumor regressions and clinical benefit in H3 K27M-mutant glioma patients while being well tolerated. ONC206 is a chemical derivative of ONC201 with nanomolar anti-cancer potency. In this study, we describe receptor pharmacology, gene expression profiling, acquired resistance and biodistribution studies that suggest ONC206 exhibits distinct therapeutic properties relative to ONC201. ONC206 exhibited a nanomolar Ki for DRD2 with complete specificity across human GPCRs and complete DRD2 antagonism. Schild analyses of ONC206 in cAMP and β-Arrestin recruitment assays revealed hallmarks of non-competitive DRD2 antagonism, unlike antipsychotics but similar to ONC201. Shotgun mutagenesis across DRD2 identified 7 residues critical for ONC206-mediated antagonism at orthosteric and allosteric sites. Six residues were critical for ONC201 and ONC206, however the impact varied between the two compounds and one allosteric residue was exclusive to ONC206. Structural mapping revealed that some ONC206-critical allosteric residue interactions are located at the interface of TM-IV and –V that mediates the DRD2 homodimer interface. Gene expression profiling revealed ONC206 and ONC201 induce distinct signatures in U87 glioblastoma cells, further supporting distinct functional effects. Similarly, T98G glioblastoma cells with acquired resistance to ONC201 or ONC206 reveal partial cross resistance. Finally, rat biodistribution studies revealed nanomolar CSF concentrations that exceed therapeutic thresholds, unlike ONC201. In summary, ONC206 exhibits increased non-competitive DRD2 antagonism, nanomolar potency, distinct biodistribution, differentiated gene expression and disruption of DRD2 dimers relative to ONC201. Thus, ONC206 may be uniquely poised to address tumors that are not addressed by ONC201 or have developed acquired resistance.
DDRE-34. TRIBBLES-1 (TRIB1) PSEUDOKINASE PROMOTES SURVIVAL OF GBM CELLS BY DECREASING RT/TMZ INDUCED APOPTOSIS
Authors: Singh Karnika , Han Chunhua , Fleming Jessica , McElroy Joseph , Bell Erica , Robe Pierre , Haque S Jaharul , Chakravarti Arnab 
Published: December 2020

Abstract

INTRODUCTION
Glioblastoma (GBM) is the most aggressive form of glioma with a mean survival of 12 to 15 months after diagnosis. The current therapy involves administration of radiation therapy and temozolomide (TMZ). Due to poor survival outcome, new druggable therapeutic targets need to be identified for drug development. TRIB1 is a Ser/Thr pseudokinase that acts as a scaffold protein to mediate proteasomal degradation of its substrate proteins in the cell. TRIB1 has been associated with tumorigenesis and therapy resistance of several cancers, including HCC, NSCLC among others. In the present study we show that TRIB1 can promote GBM by increasing survival of GBM cells and reducing RT/TMZ-induced cell death.

MATERIALS AND METHODS
We identified TRIB1 by statistical association (Cox regression analysis) of the patient-derived methylation data generated using 450K and EPIC methylation array. Functional validation of TRIB1 was done in vitro by overexpression and knockdown approaches. Doxycycline inducible system was used for TRIB1 knockdown. Stable cell lines were generated by puromycin selection. Western blotting was utilized to detect protein levels.

RESULTS
The global methylation analysis on a Utrecht GBM cohort showed that TRIB1 promoter methylation was associated with better OS of GBM patients (HR = 0.81 (0.62–1.05); p = 0.11). We also observed that TRIB1 overexpression caused a decrease in apoptosis of patient-derived GBM cell lines after RT/TMZ treatment. Additionally, an increase in the phosphorylation of ERK and Akt was also noted. However, TRIB1 knockdown only led to decreased Akt phosphorylation.

CONCLUSION
TRIB1 promotes GBM cell survival by upregulating survival signaling pathways like ERK and Akt, which leads to decreased effects of RT/TMZ therapy. Targeting TRIB1 would reduce oncogenic signaling in these cells and therefore may sensitize them towards RT/TMZ therapy.
EPCO-10. CHANGES IN ALTERNATIVE SPLICING AND ASSOCIATED NEOANTIGENS DUE TO THERAPY
Authors: Wang Lin , Shamardani Karin , Babikir Husam , Catalan Francisca , Nejo Takahide , Chang Susan , Philips Joanna , Okada Hideho , Diaz Aaron 
Published: December 2020

Abstract
Recent studies have identified alternative splicing (AS) as a novel source of neoantigens for immunotherapy. Surprisingly little is known about the AS milieu in recurrent glioblastoma (GBM), despite this being the venue for most clinical trials. We profiled 29 primary-recurrent paired human GBM specimens via RNA sequencing and re-analyzed RNA-sequencing data from non-malignant human brain tissues. From these data, we reconstructed the landscape of AS in GBM through recurrence and contrasted that to isoforms observed in non-malignant brain. The AS events we identified were cross-referenced with single-cell GBM atlases to determine cell-type specific splicing patterns. From this we identified novel splicing events in cell-surface proteins that are suitable targets for engineered T-cell therapies. We found recurrent-specific isoforms of mitogen-activated kinase pathway genes which are expressed exclusively by GBM stem-like cells that enhance invasiveness. These studies shed light on the effect of therapy on AS and identify novel targets for emerging immunotherapies.
EPCO-25. AN IMMUNOMETHYLOMIC PLATFORM INTEGRATING SYSTEMIC IMMUNE PROFILES AND EPIGENETIC AGE IN NEURO-ONCOLOGY
Authors: Molinaro Annette , Wiencke John , Warrier Gayathri , Lee JiYoon , Koestler Devin , Hansen Helen , Rice Terri , Bracci Paige , McCoy Lucie , Salas Lucas , Christensen Brock , Wrensch Margaret , Kelsey Karl , Taylor Jennie , Clarke Jennifer 
Published: December 2020

Abstract
Lineage-specific DNA methylation marks differentiate leukocyte cell types while individual biological aging mechanisms impact other methylation alterations. Human glioma incidence and survival times have been shown to be associated with aberrant immune profiles and have a strong dependency on age. Here we developed a single epigenetic analysis framework to evaluate both immune cell fractions and epigenetic age in peripheral blood. We examined these measures in archived blood from 197 triple-negative glioma patients (TNG; IDH wildtype, 1p19q intact and TERT wildtype) and 312 frequency-matched controls from the SF Bay Area Adult Glioma Study (AGS). Significant differences were observed with TNG cases having lower CD4 and CD8 T cell, natural killer, and B cell fractions, and higher neutrophil fractions than controls. TNG cases were significantly older than controls in two of three epigenetic age estimates; however, there was no difference in epigenetic age acceleration once immune cell proportions were considered. For the TNG cases, we augmented results from several machine learning methods to delineate risk groups of TNG patients with significantly different overall survival. We compared survival models built by recursive partitioning, random forest, and elastic net methods. The final model was chosen by repeated bootstrap sampling via the Brier score loss function and validated in an independent set of 72 IDH-mutant only or TERT-mutant only glioma patients also from the AGS. The final model indicated important interactions between immune cell fractions (including CD4 and CD8 T cells and neutrophils) and treatment, age, and dexamethasone status when adjusted for the main effects of epigenetic age, glioblastoma status, and the neutrophil-to-lymphocyte ratio. The capacity of immunomethylomics to capture diverse, clinically relevant information and the simplicity of its implementation make this a powerful tool for personalized patient evaluation in the neuro-oncology clinic.