bluuebunny/crossref_metadata_2025 huggingface dataset:
CTNI-45. A PHASE 1B/2 CLINICAL STUDY OF NAPABUCASIN IN COMBINATION WITH TEMOZOLOMIDE FOR ADULT PATIENTS WITH RECURRENT OR PROGRESSED GLIOBLASTOMA MULTIFORME (GBM)
Authors: Chi Andrew , DeRobles Paula , Foos Emma , Hitron Matthew , Mason Warren
Published: December 2020

Napabucasin is an orally-administered NQO1–bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including STAT3. This open-label, multicenter, phase 1b/2 study assessed napabucasin plus temozolomide for recurrent/progressive GBM. Phase 1b objectives were safety/tolerability, recommended phase 2 dose (primary), preliminary antitumor activity, and pharmacokinetics/pharmacodynamics (secondary). Phase 2 objectives were preliminary antitumor activity via 6-month progression-free survival (PFS-6 [20% projected]) (primary); disease control rate; median PFS; objective response rate (ORR); and overall survival (OS) (secondary). Arm A enrolled repeat surgical resection candidates; arm B enrolled patients ineligible for further resection. Patients received napabucasin (oral, 480 mg twice-daily) plus temozolomide (150 mg/m2, days 1–5, 28-day cycles). Arm A closed after 4 patients enrolled to prioritize Arm B enrollment. Arm B data are reported. Arm B enrolled/treated 30 patients (median age=56.5 [range=19–83] years; median napabucasin duration=55.0 [range=1–743] days; previous temozolomide=22 [73.3%] patients); all stopped therapy (radiologic progressive disease [PD], n=20; clinically unacceptable toxicities, n=7; follow-up loss, n=2; clinical PD, n=1). Mean relative dose intensity was 67.2% for napabucasin and 90.9% for temozolomide; 14/30 (46.7%) and 25/30 (83.3%) patients received ≥ 90% intended napabucasin and temozolomide doses, respectively. All patients reported ≥ 1 treatment-emergent adverse event (TEAE, grade ≤4); grade 3 TEAEs (≥ 10% patients) were diarrhea (23.3%, 7/30) and abdominal pain (16.7%, 5/30). One patient reported a grade 4 TEAE (seizure, treatment unrelated). PFS-6 was 28.1% (80% CI=16.8%-40.5%). Median PFS was 1.9 months (95% CI=1.8–3.3), with PFS-12 and PFS-18 both 16.8% (80% CI=7.8%-28.8%). ORR was 10% (95% CI=2.1%-26.5%), with 3 partial responses, 6 stable disease, 14 PD, and 7 patients not evaluated. OS-12 was 28.3%. The napabucasin-plus-temozolomide safety profile was consistent with that anticipated for each agent. Napabucasin (480 mg twice-daily) was associated with grade 3 diarrhea and suboptimal compliance. Antitumor effects were observed per the primary endpoint in this patient population.
CTNI-53. SINGLE ARM, OPEN-LABEL, MULTICENTER PHASE II STUDY OF THE RADIONUCLIDE 177LU-DOTATATE (LUTATHERA) IN ADULTS WITH ADVANCED INTRACRANIAL MENINGIOMA
Authors: Kurz Sylvia , Zan Elcin , Gurewitz Jasone , Cordova Christine , Troxel Andrea B , Sawaged Zacharia , Sevillano-Torres Hector , Silverman Joshua S , Snuderl Matija , Zagzag David , Golfinos John , Kondziolka Douglas , Sulman Erik
Published: December 2020

BACKGROUND

Meningiomas are the most common primary intracranial neoplasm. Once surgical and radiotherapeutic options are exhausted, there are no effective medical treatments available. A majority of meningiomas express somatostatin receptor 2 (SSTR2), representing a promising treatment target. 177Lu-DOTATATE is a SSTR2-targeting radionuclide that has been successful in SSTR2-expressing neuroendocrine tumors. Here we hypothesize that 177Lu-DOTATATE is effective in treating progressive intracranial meningiomas.

METHODS

In this ongoing phase II study (NCT03971461), adults with advanced intracranial meningiomas received 177Lu-DOTATATE 7.4 GBq (200 mCi) every 8 weeks for 4 doses. 68Ga-DOTATATE PET-MRI was obtained before and at the end of treatment (EOT). The primary endpoint was progression-free survival at 6 months (PFS-6). Correlative studies evaluated the association of PFS-6, objective response rate, progression-free survival, overall survival with radiographic tumor measurements, 68Ga-DOTATATE uptake on PET-MRI, SSTR2 expression in tumor, and meningioma methylation subclass.

RESULTS

Nine patients (F = 7, M = 2) with progressive meningiomas (WHO I = 2, II = 6, III = 1) have been enrolled. Median age was 63 (range 49–78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated, although CTCAE grade 3/4 electrolyte derangements and cytopenias were observed. Six patients reached PFS-6, three patients experienced progressive disease. Four patients had EOT 68Ga-DOTATATE PET-MRI evaluations in which anatomic measurements and 68Ga-DOTATATE standardized uptake values (SUV) pre- and post-treatment were assessed: one patient had reduced SUV measurements in all target lesions indicating altered SSTR2 expression and functional treatment response, one patient had stable disease, one patient had a mixed treatment response, and one patient experienced progressive disease.

CONCLUSIONS

SSTR2-targeting 177Lu-DOTATATE represents a promising treatment option for patients with progressive intracranial meningiomas. Treatment is well tolerated and can lead to functional alteration of tumoral SSTR2 expression by 68Ga-DOTATATE PET-MR imaging.
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

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

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 < 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

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 < 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

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

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

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

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

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

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

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

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.
EPCO-39. DICER1 SYNDROME WITH PRIMITIVE NEUROECTODERMAL TUMOR FROM SCREENING MUTATIONS OF DICER1 GENE
Authors: Wu Anhua , Jing Zhitao , Cheng Wen , Zhu Chen , Song Chao , Qin Huijuan , Zhang Xing , Ji Yuhang , Tian Minqi , Li Xiaomin , Ren Yong
Published: December 2020

BACKGROUND

DICER1 syndrome is a rare disorder of tumor predisposition. The DICER1 gene encodes the Dicer protein of the ribonuclease Ⅲ family and plays a critical role in miRNA creation. Patients with DICER1 syndrome-related cancer commonly harbor an additional somatic variant in exon24 or 25 of DICER1 involving one of the hotspots including p.E1705, p.D1709, p.G1809, p.D1810, or p.E1813. Herein, we firstly report the presence of hotspot missence mutation in a patient with primitive neuroectodermal tumor (PNET).

METHODS

The mutations in DIRCER1 were searched in the tumor tissue or peripheral blood from 4,349 patients with different types of cancer via next generation sequencing. Among them, comprehensive genomic profiling (CGP) with 131 CNS cancer-related genes and 4 brain tumor-related chromosome structure variations was performed in 230 cases, and CGP with 539 cancer-related genes was administrated in 4,119 cases. The histopathology diagnosis of each case was confirmed via hematoxylin and eosin staining.

RESULTS

A number of 99 mutations in the exon and intron regions of DICER1 gene were observed from 88 patients in 4,349 cases. The ratio of somatic variants located on exon 24 and 25 where both encoded the RNase Ⅲb cleavage domain to all mutations was 9.09% (9/99). There were 3 and 6 somatic variants in the exon 24 and 25, respectively. Among the 9 mutations, 4 of them were p.E1813, one class of hotspots located on exon 25 leading to DICER1 syndrome, and the other 4 hotspots were not observed. Among 4 cases of DICER1 syndrom, pleuropulmenary blastoma was common, rhabdomyosarcomas arisen in two cases were also reported before, and the last one was patient with PNET.

CONCLUSIONS

In this study, we analyze the mutation distribution of DICER1 in cancer patients, report firstly a patient with PNET harbors a hotspot, and widen and deepen the understanding of DICER1 syndrome.
EPID-06. QUANTIFYING THE POTENTIAL PUBLIC HEALTH IMPACT OF VARICELLA ZOSTER VIRUS (VZV) VACCINATION ON GLIOMA INCIDENCE
Authors: Shen Erica , Wallace Alexander , Zhang Chenan , Shannon Callie , Ashley David , Walsh Kyle
Published: December 2020

BACKGROUND

Varicella zoster virus (VZV) is a neurotropic a-herpesvirus that causes chickenpox and establishes latency in the dorsal root ganglion. Live attenuated VZV vaccine was approved for use in 1995, with the CDC estimating 95% of teens had been vaccinated in 2014. Prior epidemiological literature suggests an association between VZV infection and glioma risk.

METHODS

We conducted a systematic review and meta-analysis of prior studies on the association between VZV infection and glioma risk. We also identified genetic instruments for VZV infection from prior GWAS and tested these for association with glioma risk in TCGA and GliomaScan (2244 cases, 4914 controls).

RESULTS

In six previous studies, individuals with positive chickenpox history or anti-VZV IgG seropositivity had 1.8-fold lower odds of glioma (ORmeta=0.55, 95%Cl=0.39–0.77), with similar effects by grade. GWAS hits for personal history of chickenpox (HLA-A Gly107 and rs9266089) and shingles (HLA-AArg97, HLA-DRB1 PheSerHis13, rs2523591, rs41316748 and rs7047299) were not associated with glioma risk, nor were polygenic scores (P >0.05).

DISCUSSION

Prior VZV infection is associated with reduced glioma risk and, based on analysis of genetic instruments, this appears to be an acquired protection caused by VZV infection rather than innate immunologic differences. VZV infection in known to elicit a broader antibody response than vaccination, but it is unknown whether VZV vaccination provides comparable protection against glioma. Because 89% of U.S. adults have had chickenpox, the “prevented fraction” of glioma due to chickenpox is ~29% of annual incidence. If VZV vaccination confers an equivalent 1.8-fold reduction in glioma risk, this prevented fraction could increase to 32%. However, if VZV vaccination is less protective, it could decrease to just 2%. This potentially drastic increase in glioma incidence in coming decades merits mechanistic studies comparing the neuro-immunologic consequences of VZV vaccination versus chickenpox infection and warrants early public health attention.
EPID-17. THE RELATIONSHIP OF HORMONE EXPOSURE IN BREAST CANCER AND SUBSEQUENT RISK OF HIGH GRADE GLIOMAS
Authors: Lopez-Garcia Carlos , Lopez-Rivera Victor , Dono Antonio , Ballester Leomar Y , Esquenazi Yoshua
Published: December 2020

BACKGROUND

Women have a lower incidence of high grade gliomas (HGGs), which is thought to be related to sex differences and hormone exposure. The association between hormone dependent tumors in women and HGGs remains poorly investigated.

METHODS

The Surveillance, Epidemiology, and End Results (SEER) database of 18 Registries (2000–2017) was used to assess age-adjusted incidence rates and temporal trends of breast cancer (BC) and HGG. Female BC patients 18 years of age or older and with ductal or lobular BC were then assessed for the risk of subsequent HGG, calculated as the standardized incidence ratio (SIR).

RESULTS

A total of 976,134 patients diagnosed with BC between 2000–2017 were identified. The temporal trend of BC and HGG incidence rates remained comparable throughout the study, with a higher incidence of BC and lower incidence of HGGs in females. Female BC patients had a 22% lower risk of developing a HGG (SIR 0.78 [0.69–0.87], p< 0.05) compared to general population. HGG risk by age groups in BC females was significant, with a lower risk found in pre-menopausal women (Ages 18–50, SIR 0.66 [0.45–0.94] vs Ages 50+ SIR 0.79 [0.70–0.89], p< 0.05 for both). Among HGG tumors, a decreased risk of developing glioblastoma (SIR 0.83 [0.75–0.93], p< 0.05) and anaplastic astrocytoma (SIR 0.58 [0.35–90, p< 0.05), was found, but not for anaplastic oligodendrogliomas.

CONCLUSIONS

The findings of our study allude to the protective effect of hormone exposure in the development of HGGs, as shown by the lower risk in female patients with BC compared to the general population.
EPID-32. SURVIVAL OF INTRACRANIAL TUMOR IN CIPTO MANGUNKUSUMO GENERAL HOSPITAL
Authors: Aninditha Tiara , Pratama Putra , Odilo Jonathan , Sofyan Henry , Imran Darma , Aman Renindra , Werdhani Retno , Ranakusuma Teguh
Published: December 2020

INTRODUCTION

Intracranial tumor is a debilitating health burden that cause sever disability. The incidence rate for intracranial tumor is 4.63 per 100,000 populations. Through the development of diagnostic and therapeutic modalities, the survival of intracranial tumor improved although modest. There were several factors such as demographic, clinical, and histopathological affect intracranial tumor survival. However, there were no study about intracranial tumors and factors affecting it survival in Indonesia. This study provides insight of intracranial tumor patients and factor affecting 1-year survival in Cipto Mangunkusumo General Hospital from 2014–2016.

METHODS

The design of this study is retrospective cohort. The subjects were followed-up 1 year after diagnosis. The data retrieved from Dept. of Neurosurgery and Dept. of Neurology Cipto Mangunkusumo General Hospital neuro-oncology registry. Subjects with intracranial tumors underwent surgery/biopsy were included in this study. The factors analyzed in this study were demography, clinical characteristics, histopathology, and treatment types. Analysis of survival were done with Kaplan-Meier curve and cox regression.

RESULTS

There were 317 subjects in this study. Overall 1-year survival of intracranial tumors were 75.4%. There was increased risk of death (HR 1.88; CI95% 1.2–2.94; p = 0.005) in subjects >46 years old. There was no different of risk of death (HR 0.66; CI95% 0.92–1.03; p = 0.067) between men and women. There was no different of risk of death (HR 1.39; CI95% 0.72–2.70; p = 0.333) between supratentorial and infratentorial tumor. There was difference of survival among histopathology (p < 0.001) and therapeutic approaches (p < 0.001).

DISCUSSION

This is the first study in Indonesia that analyze survival of intracranial tumor. Several factors such as age, histopathology, and therapeutic approaches were found to affect 1-year survival of intracranial tumor. To get a representative insight of intracranial tumor in Indonesia, a larger cohort study should be conducted.
EXTH-55. PET, IMAGE-GUIDED HDAC INHIBITION OF PEDIATRIC DIFFUSE MIDLINE GLIOMA IMPROVES SURVIVAL IN MURINE MODELS
Authors: Tosi Umberto , Kommidi Harikrishna , Adeuyan Oluwaseyi , Guo Hua , Maachani Uday Bhanu , Chen Nandi , Su Taojunfeng , Zhang Guoan , Pisapia David , Dahmane Nadia , Ting Richard , Souweidane Mark
Published: December 2020

Efforts at altering the dismal prognosis of pediatric midline gliomas focus on direct-delivery strategies like convection-enhanced delivery (CED), where a cannula is implanted into tumor. Successful CED treatments require confirmation of tumor coverage, dosimetry, and longitudinal in vivo pharmacokinetics monitoring. These properties would be best determined clinically with image guided dosimetry using theranostic compounds, agents with both therapeutic and imaging properties. In this study, we combine CED with novel, molecular-grade positron emission tomography (PET) imaging. We synthesized PETobinostat, a novel PET-imageable HDAC inhibitor, and showed its effectiveness against DIPG models in vitro and in vivo. Cell studies against a library of DIPG cells show nanomolar IC50, allowing for rapid in vivo translation. When injected in mice, PET shows the need of CED to achieve high brain concentrations, as systemic delivery yields inferior brain permeation. PET also shows that CED has significant mouse-to-mouse variability: imaging is used to modulate CED infusions to maximize tumor saturation over time. By determining condition-specific clearance half-life (ranging between 60 and 120 minutes), we maximized tumor permeation above therapeutic concentrations for at least 12 hours. This PET-guided approach resulted in decrease tumor cellularity (p= 0.001), increased apoptosis (p= 0.034), decreased dividing cells (p= 0.003), and recovery of histone-3 acetylation (p < 0.0001) when compared against vehicle and systemic-treated controls in tumor-bearing mice. Further, the PET-guided CED of PETobinostat resulted in survival prolongation (67.5 vs. 35 days, p = 0.0001) when compared to systemic administration of another potent HDAC inhibitor (Panobinostat). CED without PET guidance failed at improving survival (37.5 vs. 35 days, p = 0.74). No significant toxicity was observed following CED of PETobinostat. This work demonstrates how personalized image-guided drug delivery of a novel HDAC inhibitor may be useful in potentiating CED-based treatment platforms, and supports a foundation for the clinical translation of PETobinostat.
EXTH-57. INVESTIGATION OF THE TUMORICIDAL EFFECTS OF SONODYNAMIC THERAPY IN MALIGNANT GLIOBLASTOMA BRAIN TUMORS
Authors: Sheehan Kimball , Sheehan Darrah , Sulaiman Mohanad , Padilla Frederic , Sheehan Jason , Xu Zhiyuan
Published: December 2020

OBJECTIVE

Glioblastoma is the most common primary brain tumor; survival is typically 12–18 months after diagnosis. We sought to study the effects of sonodynamic therapy (SDT) using 5-Aminolevulinic acid hydrochloride (5-ALA) and high frequency focused ultrasound (FUS) on 2 glioblastoma cell lines.

PROCEDURE

Rat C6 and human U87 glioblastoma cells were studied under the following conditions: 1mM 5-ALA (5-ALA); Focused ultrasound (FUS); 5-ALA and focused ultrasound (SDT); control. Studied responses included cell viability using an MTT assay, microscopic changes using phase contract microscopy, apoptotic induction through a caspase-3 assay, and apoptosis staining to quantify cell death.

RESULTS

SDT led to a marked decrease in cell extension and reduction in cell size. For C6, the MTT assay showed reductions in cell viability for 5-ALA, FUS, and SDT groups of 5%, 16%, and 47%, respectively compared to control (p< 0.05). Caspase 3 induction in C6 cells relative to control showed increases of 109%, 110%, and 278% for 5-ALA, FUS, and SDT groups, respectively (p< 0.05). For the C6 cells, caspase 3 staining positivity was 2.1%, 6.7%, 11.2%, and 39.8% for control, 5-ALA, FUS, and SDT groups, respectively. C6 Parp-1 staining positivity was 1.9%, 6.5%, 9.0%, and 37.8% for control, 5-ALA, FUS, and SDT groups, respectively. U87 cells showed similar responses to the treatments.

CONCLUSIONS

Sonodynamic therapy resulted in appreciable glioblastoma cell death as compared to 5-ALA or FUS alone. The approach couples two already FDA approved techniques in a novel way to treat the most aggressive and malignant of brain tumors. Further study of this promising technique is planned using glioma and also brain metastasis models.
EXTH-69. INCREASED CANCER CELL PERMEABILITY FOLLOWING TUMOR TREATING FIELDS (TTFIELDS) APPLICATION IN VITRO
Authors: Voloshin Tali , Porat Yaara , Kaynan Noa , Klein-Goldberg Anat , Paz Rom , Volodin Alexandra , Giladi Moshe , Weinberg Uri , Palti Yoram
Published: December 2020

INTRODUCTION

Tumor Treating Fields (TTFields), encompassing alternating electric fields within the intermediate frequency range, is an anticancer treatment delivered to the tumor region through transducer arrays placed non-invasively on the skin. This novel loco-regional treatment has demonstrated efficacy and safety and is FDA-approved in patients with glioblastoma (GBM) and malignant pleural mesothelioma. TTFields are currently being investigated in other solid tumors in ongoing trials. Recently, TTFields were reported to alter the cellular membrane structure of GBM cells, rendering them more permeable. The objective of this study was to characterize TTFields-induced cellular permeability in cancerous cell lines.

METHODS

TTFields were applied to uterine sarcoma, glioblastoma, and breast adenocarcinoma cell lines across a range of frequencies (50–500 kHz). Cellular permeability was assessed by quantifying the percentages of cells with accumulated 7-aminoactinomycin D (7-AAD) using flow cytometry and cytotoxicity was assessed based on cell counts. Kinetics were determined using different 7-AAD exposure times relative to TTFields treatment end. Changes in intracellular accumulation of anthracycline chemotherapeutics were evaluated in chemotherapy-sensitive and chemotherapy-resistant cells.

RESULTS

TTFields induced cellular permeability to 7-AAD in all 4 cancer cell lines tested. The optimal frequency for TTFields-induced cellular permeability was different from the optimal cytotoxic frequency. Kinetics measurements demonstrated that TTFields-induced permeability is transient and is effective only during application of TTFields. In combination experiments, TTFields improved intracellular accumulation of chemotherapeutic agents. Furthermore, combining chemotherapy with TTFields treatment facilitated accumulation of chemotherapeutics in chemotherapy-resistant cells to levels comparable with accumulation in chemotherapy-sensitive cancer cells.

CONCLUSIONS

This study demonstrates that TTFields can transiently increase cancer cell permeability in vitro with an optimal frequency that is variable from the frequency that is used to induce cancer cell cytotoxicity. Moreover, this effect is reversible and cellular permeability is restored to a normal state upon TTFields treatment cessation.
IMMU-55. GD2 IS A MACROPHAGE CHECKPOINT MOLECULE AND COMBINED GD2/CD47 BLOCKADE RESULTS IN SYNERGISTIC EFFECTS AGAINST GD2 POSITIVE MALIGNANCIES
Authors: Theruvath Johanna , Mount Christopher , Monje Michelle , Mackall Crystal , Majzner Robbie
Published: December 2020

GD2 is a disialoganglioside expressed on a variety of tumors including DIPG, neuroblastoma and osteosarcoma. Anti-GD2 antibodies have demonstrated some success in neuroblastoma and they have either not proven to be effective or have not been evaluated in other GD2 positive malignancies. CD47 is the dominant “Don’t Eat Me” signal expressed by cancer cells to inhibit macrophages and blocking CD47 leads to phagocytosis of tumor cells. We hypothesized that CD47 blockade synergizes with anti-GD2. We measured in vitro phagocytosis of DIPG and NBL cells and observed a synergy of anti-GD2/CD47 compared to the single agents. In vivo, this combination led to the complete clearance of both orthotopic and metastatic models of NBL. Additionally, the combination significantly enhanced survival of OS xenografts. Finally, in a murine model of metastatic pulmonary OS, the combination led to a near elimination of all metastatic burden. To understand the underlying biologic basis, we studied the effects of GD2 crosslinking on tumor cells and the effects of GD2 blockade on macrophages. A portion of DIPG or NBL cells die when treated with dinutuximab, and those that survive upregulate surface calreticulin, an important pro-phagocytic (“Eat Me”) signal. Additionally, we have identified the ligand for GD2, a molecule expressed on macrophages known to inhibit phagocytosis. In summary, we have identified a novel combination of anti-GD2 and anti-CD47 antibodies that is highly effective in preclinical models and will soon be tested in children. Furthermore, we have shown that GD2 itself is a macrophage checkpoint or “Don’t Eat Me” signal.
NCMP-16. THE ROLE OF p38 AND JNK MAPK PATHWAYS IN CISPLATIN CHEMOTHERAPY-RELATED COGNITIVE IMPAIRMENT
Authors: Lomeli Naomi , Di Kaijun , Bota Daniela
Published: December 2020

OBJECTIVES

Chemotherapy-related cognitive impairment (CRCI) is an adverse sequela of cancer treatment commonly reported in cancer survivors. Cisplatin is used for the treatment of various malignancies including ovarian, testicular, head and neck cancers, and pediatric brain tumors. More than 30% of advanced ovarian cancer patients develop CRCI during and after platinum-based chemotherapy. We examined the role of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) activation in cisplatin-induced CRCI, and whether the small molecule p38 MAPK inhibitor Neflamapimod and JNK inhibitor SP600125, can prevent cisplatin-induced neuronal damage. The p38 and JNK MAPK signaling pathways are involved in various stress response pathways in the CNS including oxidative stress.

METHODS

The effect of cisplatin on cognition in an ovarian cancer female rat model was assessed by novel object recognition (NOR). Hippocampal glutathione levels were measured post-behavioral testing. P38 and JNK MAPK signaling activation were assessed in the neural cell lines PC12 and SH-SY5Y by Western blot. Cultured hippocampal neurons were pretreated with Neflamapimod or SP600125 followed by cisplatin for 24 hours, and dendritic spine density and branch length were quantified.

RESULTS

Cisplatin increased phospho-p38 and phospho-JNK MAPK protein levels in PC12 and SH-SY5Y cells. Cisplatin reduced dendritic branching and spine density, which was prevented by Neflamapimod and SP600125 pre-treatment in hippocampal neurons, in vitro. Chronic cisplatin treatment decreased hippocampal glutathione levels and impaired cognitive function in the ovarian cancer rat model.

DISCUSSION

The cognitive deficits caused by cisplatin results in part from dendritic damage and neural apoptosis, which is mediated by oxidative stress and the p38 and JNK MAPK pathways. P38 and JNK MAPK inhibition mitigated cisplatin-induced dendritic spine loss and branching in vitro. Next, we will examine whether Neflamapimod and SP600125 administration in an ovarian cancer rat model is safe and if they can prevent cognitive impairment.