bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXTH-45. MICROGLIA-SPECIFIC DISRUPTION OF SIALIC ACID-SIGLEC-9/E INTERACTIONS: A NOVEL IMMUNOTHERAPY AGAINST GLIOBLASTOMA?
Authors: Schmassmann Philip , Martins Tomás A , Stanczak Michal , Ritz Marie-Françoise , Shekarian Tala , McDaid Marta , Läubli Heinz , Hutter Gregor 
Published: November 2021

Abstract
Recently, ‘don’t eat me’-signals like CD47 have emerged as novel innate immune checkpoints, enabling cancer cells to evade clearance by phagocytes such as monocyte-derived macrophages (MDM) or microglia (MG). Here, we aim at defining the role of inhibitory Siglec-9 in human and its mouse homologue Siglec-E in MG-centered immunotherapy against GBM. TCGA RNA-sequencing data revealed a significant correlation between high expression of immunoinhibitory SIGLEC9 and poor survival in GBM patients (log-rank p = 0.02). Siglec-E blockade increased murine MG mediated GBM cell in vitro phagocytosis (normalized phagocytosis of 1.00 in isotype vs. 1.76 in anti-Siglec-E antibody, p &lt; 0.001). By employing a CT-2A orthotopic GBM mouse model with MG-specific spatio-temporal deletion of Siglece (Sall1 CreERT2 x Siglece flox ), we observed high MG-proliferation upon Siglec-E knockdown (Ki-67+ MG 14.8% in Cre- vs. 34.9% in Cre+, p &lt; 0.0001) accompanied by an enhanced microglial GBM-cell uptake (5.6% in Cre- vs. 12.3% in Cre+, p &lt; 0.001). This beneficial response was counteracted by an accentuated influx of pro-tumorigenic MDM in the Cre+ group (CD163high CD86low MDM of total MDM 47.1% in Cre- vs. 65.3% in Cre+, p = 0.002), which prevented an efficient adaptive anti-tumor immune response and survival benefit. Currently, we are investigating the cross-talk between GBM-associated MG and MDM upon Siglec-E knockdown by scRNAseq of the tumor-infiltrating immune compartment, including TCR-clonotype tracking. By genetically targeting sialic acids, the ligand for Siglec receptors, on CT-2A cells (GNE-KO), we observed a strong innate and adaptive immune response with less exhausted tumor-infiltrating CD8+ T-cells (14.8% in WT vs. 5.9% in GNE-KO, p = 0.003), which resulted in a prolonged survival (30d in WT vs. 41d post-tumor-injection in GNE-KO, p = 0.03). These data identify the sialic-acid-Siglec-E pathway as an anti-phagocytic signal in a pre-clinical GBM model, and demonstrate its therapeutic potential in GBM immunotherapy.
EXTH-51. DEVELOPMENT OF A NOVEL GENE THERAPY APPROACH TARGETING GLIOBLASTOMA FOLLOWING ARTIFICIAL INTELLIGENCE (AI)-DIRECTED IDENTIFICATION OF THE GBM STATE
Authors: Tran David , Le Son , Ma Bo , Falk Darin , Zolotukhin Serge 
Published: November 2021

Abstract

BACKGROUND
Profound heterogeneity has severely hampered therapeutic advancements in GBM. Remarkably, however, GBM exhibits broad clinical and histopathologic overlaps suggesting the presence of a common state. The GBM state embodies network restructuring forced by founding mutations and perpetuated in subclones of GBM stem-like cells (GSCs). Successful targeting of the GBM state promises to circumvent the heterogeneity.

METHODS
To decipher the GBM state, we applied NETZEN, an AI suite integrating a deep neural network with gene network-based ranking, to first generate the reference GBM gene network from TCGA’s entire GBM RNAseq collection, and then identify the altered master regulatory gene subnetwork in GBM using a dataset containing &gt;30 diverse patient-derived GSC lines and their paired differentiated cells, 6 astrocyte and 3 neuronal precursor cell lines. To develop a gene therapy against the GBM state, we screened a rAAV capsid library through GBM patient-derived xenografts (PDX) to identify variants with specific tropism for GBM cells that can deliver targeting constructs intratumorally.

RESULTS
We discovered a putative GBM state anchored by developmentally restricted master regulators. To validate its critical role, we deconstructed it using shRNA in a panel of PDX and uniformly observed improved tumor control and survival compared to controls (p&lt; 0.05 in all lines). More notably, when the core GBM state was forcibly reconstructed in astrocytes, transformation into GSC-like cells occurred, as measured by single-cell analysis, neurosphere formation, and most importantly, development of lethal infiltrating brain tumors in 15/15 mice. Finally, selected novel rAAV capsids with 10-40-fold higher specificity for GBM cells were utilized in a shRNA-based rAAV platform to target key master regulators of the validated GBM state.

CONCLUSIONS
The GBM state is established by a developmental master regulator subnetwork permitting the creation of a first-of-its-kind, heterogeneity-agnostic GBM therapy. This AI-directed R&D program can be expanded to target other tumors.
EXTH-55. TARGETING RECURRENT IDH MUTANT GLIOMA WITH CDK4/6 INHIBITION
Authors: Miller Julie , Cahill Daniel , Melamed Lisa , Nagashima Hiroaki 
Published: November 2021

Abstract
Despite initial responsiveness to standard treatments like radiation and chemotherapy, IDH mutant gliomas inevitably recur, become more clinically aggressively and lead to untimely death. Recurrent IDH mutant tumors are less responsive to conventional treatments, highlighting the need for improved therapeutic strategies at this stage of the disease. At least 20% of recurrent IDH mutant gliomas exhibit homozygous loss of CDKN2A, which results in aberrant signaling through the CDK-RB pathway. We hypothesized that CDKN2A loss leads to enhanced sensitivity to CDK4/6 inhibitors, which are approved for use in a variety of other cancer types. We examined the relationship between CDK4/6 inhibitor sensitivity and CDKN2A loss using patient-derived models of IDH mutant glioma with endogenous CDKN2A homozygous deletion as well as with CRIPSR-mediated gene deletion. We observed enhanced cytotoxicity in glioma models with CDKN2A loss in vitro. Studies to examine the efficacy of CDK4/6 inhibitor treatment on slowing tumor growth in patient-derived xenograft models are ongoing. These preclinical results provide foundational data for design of a biomarker-driven clinical trial of CDK4/6 inhibitors in patients with recurrent IDH mutant glioma.
EXTH-62. COMBINATORIAL THERAPY TARGETING TRANSCIPTION AND IMMUNO-METABOLISM IN RECURRENT GLIOBLASTOMA
Authors: Dighe Pratiksha , Woo Rinette , Salomonis Nathan , Bhattacharjee Anu , Nosrati Mehdi , Desprez Pierre , Dickinson Larry , McAllister Sean , Soroceanu Liliana 
Published: November 2021

Abstract
Recurrent glioblastomas (GBM) are notoriously difficult to treat, and in spite of aggressive chemo- and radiation therapy they inevitably recur in almost all GBM patients within 14 months following initial diagnosis. To interrogate pathways driving therapeutic resistance, we compared matched primary and recurrent IDH wild type glioblastoma samples from a cohort of patients, using RNA-Seq. Our analyses showed that pathways involved with tumor immune and metabolic reprogramming were up-regulated in recurrent GBMs compared to untreated, primary samples. Based on these findings, we tested the anti-tumor efficacy of over 20 rationally selected targeted therapeutic agents alone and in combination in a high-throughput drug screen assay designed to measure long term cell viability of primary tumorspheres from patients who underwent surgery for recurrent GBM. Top performing drug combinations from these screens were validated in vivo using patient-derived intracranial mouse models of glioma. Our data demonstrated that the combination of the transcriptional/metabolic inhibitor TG02 and the dual PI3K/mTOR inhibitor GDC-0084 significantly prolonged in vivo survival of tumor bearing mice, performing better than either drug alone. Notably, both inhibitors are undergoing human clinical trials as single agents with positive initial safety profiles and superior blood brain barrier penetrance. RNA Seq and functional assays of tumor samples from treated mice showed that only the combination treatment (TG02 + GDC-0084) significantly inhibited expression of immunomodulatory cytokines driving tumor progression, including those identified by us to be overexpressed in recurrent human GBM samples. Overall, these data suggest that combining TG02 and GDC-0084 is an effective treatment for recurrent GBMs. Furthermore, our results support the use of a translational research platform consisting of a personalized pharmaco-genomics testing, using patient-derived tumor samples towards designing more effective treatment for recurrent GBM patients.
EXTH-73. PROTEASOME INHIBITION EXPOSES SELECTIVE VULNERABILITY IN CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Miyake Yohei , Kawazu Masahito , Wakimoto Hiroaki , Tateishi kensuke , Yamamoto Tetsuya 
Published: November 2021

Abstract
Central nervous system lymphoma (CNSL), including primary and secondary CNSL, has a poor prognosis despite standard intensive chemotherapy. Since the majority of CNSL tumors are highly dependent on NF-κB signaling pathway for survival, Bruton’s kinase inhibitors, which target upstream in the NF-κB pathway, have demonstrated favorable clinical response in PCNSL patients. However, early recurrence is frequently observed. Therefore, novel therapeutic strategies are required in this progressive CNS disease. To understand the underlying tumor biology and explore a novel therapeutic strategy of CNSL, we previously established a panel of patient-derived xenograft (PDX) models, from both immunocompetent and Epstein-Barr virus (EBV)-positive CNSL patients. We confirmed that these PDX models highly recapitulated the phenotypic and genetic features of patient tumors. Using 19 PDX models, including 17 originally established PDXs, we found that NF-κB pathway related genomic alterations and AKT/mTOR signaling did not correlate with sensitivity to BTK inhibitors. We also found that RelA/p65 dephosphorylation as a biomarker of CNSL cells, which are responding to ibrutinib. Through high-throughput and NF-κB pathway-targeted drug screenings, we discovered that proteasome inhibitors suppressed cell viability across all CNSL models. The therapeutic effect, observed at a lower nanomolar range, was mediated by inhibition of the canonical NF-κB and AKT/mTOR pathways and was reversed by silencing of MYD88/CD79B in immunocompetent CNSL or LMP1 in EBV-positive CNSL. The second-generation proteasome inhibitor marizomib prolonged overall survival in CNSL orthotopic xenograft models through simultaneous suppression of RelA/p65 and AKT/mTOR signaling. Proteasome inhibition deregulated Mcl-1 and mediated caspase-dependent apoptosis, which was further enhanced by Bcl-2 family inhibition. Our results demonstrate the potential of proteasome inhibition as a novel therapeutic strategy in patients with immunocompetent and EBV-positive CNSL.
EXTH-80. PBI-200: IN VIVO EFFICACY OF A NOVEL, HIGHLY CNS-PENETRANT NEXT GENERATION TRK INHIBITOR
Authors: Pal Kollol , Regina Anthony , Elagoz Aram , Albert Vincent , Boudreault Johnathan , Ouellet Marc , Pilote Louise , Bruneau-Latour Nicolas , Wang Hong , Tao Limei , Bellavance Edith , White Peter , Ciblat Stephane , Leef Jordan , Bishop Robert 
Published: November 2021

Abstract
TRK kinases (TRK) are clinically validated targets for cancers harboring NTRK gene fusions. However, approved TRK inhibitors (TRKi) give rise to mutations reducing long-term clinical efficacy, and display limited CNS penetration that may impact their ability to address primary brain tumors (PBT), including high-grade gliomas. Second generation compounds in development address some resistance mutations, but are not sufficiently CNS penetrant. PBI-200 is a novel, orally active TRK inhibitor designed to overcome resistance, with high CNS penetration. In vitro assays demonstrate picomolar- to nanomolar potency against both wild-type TRK and the major acquired resistance mutations. A BaF3 xenograft model encoding the LMNA-NTRK1 gene fusion and G595R solvent front mutation showed superior efficacy with PBI-200 relative to first-generation compounds larotrectinib and entrectinib, and equivalent efficacy to the second-generation compound selitrectinib, in terms of tumor growth inhibition. Importantly, drug concentrations in the brains of PBI-200 treated mice showed an approximately 4-fold brain/plasma ratio (BPR). In contrast, BPR of other TRKi were &lt; 0.17, indicating that only PBI-200 achieved sustained drug levels in brain. PBI-200 demonstrated statistically superior CNS efficacy and survival in a KM12-Luc intracranial murine model, as compared to other TRKi (chi-squared 45.6, p &lt; 0.0001). By day 41, 50% of mice in the PBI-200 group remained alive, whereas mice in the other treatment groups had died on or before day 32. Of note, no gross or histopathological CNS adverse effects were observed in a 14d CNS Field Observation Battery study. Finally, PBI-200 was the most selective TRKi in a 125 kinase panel (ThermoFisher) with only 1 off-target kinase inhibited &gt; 60% at 1 micromolar. Together, these data suggest that PBI-200 has potential as a best-in-class, highly CNS-penetrant next generation TRKi. A Phase 1/2 clinical trial evaluating PBI-200 in NTRK fusion-positive patients, including patients with PBT, is ongoing (NCT04901806).
QOLP-06. THE CHALLENGE OF FACING A NEW MALIGNANT GLIOMA DIAGNOSIS: PATIENT EXPERIENCES LEARNING ABOUT THEIR ILLNESS AND COMMUNICATING WITH THEIR PROVIDERS IN THE NEURO-ONCOLOGY CLINIC
Authors: Mesa Michelle , Kaslow-Zieve Emilia , Traeger Lara , Temel Jennifer , Forst Deborah 
Published: November 2021

Abstract

BACKGROUND
Patients with newly diagnosed malignant gliomas (MG) face the sudden and unexpected news that they have a terminal neurological illness. However, little is known about these patients’ experiences learning about their illness and communicating with their oncology providers.

METHODS
We conducted semi-structured interviews with patients with MG who had recently completed chemoradiation, to explore patient-clinician communication and evaluate how patients process information about their diagnosis. We excluded patients with marked cognitive dysfunction, with eligible patients required to have a Mini-Mental Status Exam score of 24/30 or greater. We terminated enrollment once we reached thematic saturation, after a total of 9 patient interviews. We thematically analyzed qualitative data to describe patterns common to the patients’ experiences.

RESULTS
Most patients were male (6/9, 66.7%), with median age of 55 years (range 26-72) and had a diagnosis of glioblastoma (6/9, 66.7%). The majority of patients described a positive experience communicating with their providers, noting that information was delivered clearly, and visits were not rushed. Despite this, patients found it difficult to absorb and process the large volume of new information, particularly in the setting of their shock and dismay about the diagnosis and their ongoing neurological deficits. Emergent themes included concerns about the impact of the disease on their loved ones, struggles in coping with uncertainty, and worries about preserving their quality of life and functioning. Additionally, patients described their efforts to balance their knowledge about their poor prognosis with their desire to maintain hope, with many patients expressing a goal to “beat the odds” or exceed expectations with respect to their survival.

CONCLUSION
Although patients with newly diagnosed MG describe effective communication with their providers, they face many challenges coping with their terminal diagnosis. Supportive interventions aimed at this population are needed.
QOLP-13. RETROSPECTIVE REVIEW OF HOSPICE CARE UTILIZATION IN GLIOBLASTOMA PATIENTS IN A TERTIARY CARE CENTER
Authors: Puri Sushant , Heron David , NIcholas Martin , Huber Michael , Tuite Jason , Puri Sushant 
Published: November 2021

Abstract

BACKGROUND
Glioblastoma is a highly aggressive grade IV tumor of the brain. Standard of care is maximal safe resection followed by radiation therapy and chemotherapy. Despite optimal management, majority recur, and the median survival is 2-3 years. Hospice is a philosophy of care to alleviate end-of-life suffering, and it can also relieve caregiver fatigue.

METHODS
This is a retrospective chart review in a tertiary care center. IRB approval was obtained from the Office for the Protection of Research Subjects. ICD-10 code for malignant gliomas C71.9 was used to query EMR at UIC from 2015-2020. Patients with primary glioblastoma that had their entire neuro-oncologic care at UIC were included in the data analysis. Patient’s age &lt; 18 years, unknown date of death, or those who transitioned to a different facility were excluded. Data included were demographic (including marital status as a proxy for social support), insurance, ethnicity, tumor characteristics, and treatments provided. End-of life quality measure assessed were (1)no chemotherapy &lt; 2w, (2)hospice status &lt; 7 days, (3)no hospital admission &gt; 30 days (4)no ICU admission &lt; 14 days.

RESULTS
48 patients with primary glioblastoma were identified and out of those, a total of 35 patients received entirety of neurooncological care at our center. Date of death was available for 13 patients. 9 patients had been referred to hospice and 4 were not. Demographic variables were similar except social support – patients referred to hospice were more likely to be married. End-of-life quality measures were met in all patients in hospice group (9/9) but only in half of those not referred to hospice (2/4).

DISCUSSION
Social support has an impact on enrollment of hospice care. Including goals of care discussion earlier in the treatment would require a multi-disciplinary team with additional involvement of supportive care, nurses, and social workers.
QOLP-18. QUALITY OF LIFE IN GLIOMAS WHO UNDERWENT AWAKE SURGERY DEPENDS ON RETURN TO SOCIAL LIFE, ABILITY OF MOVEMENT AND VERBAL FLUENCY
Authors: Nakajima Riho , Kinoshita Masashi , Okita Hirokazu , Nakada Mitsutoshi 
Published: November 2021

Abstract
Awake surgery is performed aiming for maintaining postoperative quality of life (QOL) by preserving brain function. Nowadays, it is not known whether QOL is certainly maintained in gliomas who underwent awake surgery, and which brain functions contribute to maintain their postoperative QOL. Here we investigated QOL following awake surgery, and to determine their background and functional factors influencing on QOL. Totally 80 patients with gliomas were matched our inclusion criteria. SF-36 was performed for assessment of QOL. Three component scores including physical component summary (PCS), mental component summary (MCS), and role/social component summary (RCS) were calculated, and were compared them with that of normal healthy controls. Additionally, neurological/neuropsychological functions were evaluated at pre- and post-operative six months. Multiple regression analyses were used to investigate functional and sociodemographic/clinical factors influencing on SF-36. RCS but not PCS and MCS in patient group was significantly lower than that of normal controls (p&lt; .0001). Then, we investigated sociodemographic/clinical factors influencing on RCS, and found two significant factors, returning to social life and malignancy grade (p=0.011 and 0.022, respectively). The primary reasons for difficulty in returning to social life were functional deficits including aphasia and paresis. Among functional factors, RCS significantly related to motor function and verbal fluency (p= 0.0042 and 0.040, respectively). To support the results, RCS in deficit group for movement and verbal fluency was significantly low than in non-deficit group (Wilcoxon test, p=0.037 and 0.044, respectively). Among factors influencing on RCS, sociodemographic/clinical factors were returning to social life and malignancy grade, while functional factors were motor function and verbal fluency.
QOLP-20. DIETARY, ACTIVITY, AND QUALITY OF LIFE METRICS IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA IMPLEMENTING A KETOGENIC DIET: RESULTS OF A PHASE 1 CLINICAL TRIAL
Authors: Nelson Thomas , Gresham Gillian , Welborn Amelia , Amaral L J , Noorvash Brandon , Lockshon Laura , Tighiouart Mourad , Kim Sungjin , Mack Alexandra , Rudnick Jeremy , Irwin Scott , Freedland Stephen , Hu Jethro 
Published: November 2021

Abstract

BACKGROUND
Emerging evidence suggests that a ketogenic diet (KD) may limit neoplastic growth, but limited data exist regarding the effect of KD on daily activity, cognition, and health-related quality-of-life (HRQOL) for patients with glioblastoma.

METHODS
Newly diagnosed GBM patients participating in a single-arm phase 1 trial of a 16-week KD plus standard-of-care measured BID blood glucose and ketone levels (Keto-Mojo), captured continuous activity data (Fitbit), and completed quality-of-life (QLQ30) surveys and Montreal Cognitive Assessments (MoCA) at baseline, Week 8, and study end (up to 16 weeks). NCT03451799.

RESULTS
All patients (n = 14; 57% female; median age 55 years) maintained blood ketones above 0.3 mM &gt; 50% of study duration (mean per-patient days in ketosis = 87%). Mean glucose (mg/dl) and ketone levels decreased through the study – Weeks 1/2: glucose 94.9 (SD:16.5), ketones 1.44 (SD:5.82); Weeks 3/4: glucose 94.1 (SD:12.9), ketones 1.34 (SD:0.9); Final two weeks: glucose 92.3 (SD:13.3), ketones 1.13 (SD:0.7). On average, patients walked 6,836 steps/day (SD:5,129), spending 14.3 hours sedentary (SD:6.45) and 43.6 minutes (SD:60.4) in high-intensity activity. Sleep duration was 6.8 hours (SD:2.26). Patients (n = 9) with OS &gt; 14.6 mo from diagnosis demonstrated greater minutes of high-intensity activity (58.2 vs 20.7, p = 0.001), downtrending glucose (p = 0.001), and higher ketone levels (1.40 vs 1.11, p = 0.026). Activity data corroborated the tolerability of KD with stable-to-increased activity by study end. MoCA scores were stable from baseline (mean 23.4/30, SD:4.16) to study end (mean 24.8/30, SD:7.12; p = 0.38). When viewed as a composite score, HRQOL was stable-to-improving in 10/14 patients at Week 8 and EOS.

CONCLUSION
The use of wearable technology and at-home testing allowed for remote monitoring of activity and diet adherence. Good adherence and stable HRQOL and activity levels were observed in this phase 1 trial.