tbuckley/cabot-search huggingface dataset:
PDTM-43. THE ROLE OF TUMOR ASSOCIATED MACROPHAGES IN PEDIATRIC HIGH-GRADE GLIOMA
Authors: James Ross, Zhihong Chen, Frank Szulzewsky, Matthew Schniederjan, Oren Becher, Dolores Hambardzumyan
Journal: Neuro-Oncology (2018)

Pediatric high-grade gliomas (pHGG) account for the most cancer-related deaths in children under the age of 19 years old. Recent advances have demonstrated that pHGGs drastically differ from their adult counterparts in terms of genetic and epigenetic alterations, suggesting they may also differ in the constituency of their tumor microenvironment. It is now known tumor associated macrophages (TAMs) can make up 30–40% of the total tumor cell mass in adult high-grade gliomas and play important roles in immune suppression and tumor promotion. This raises the question of whether pHGGs possess a distinct constituency of TAMs due to their unique genetic and epigenetic landscapes. To uncover the composition and behavior of TAMs in pHGG we utilize RCAS/tva, a somatic cell-type specific gene transfer system in which we administer RCAS-PDGFA or RCAS-PDGFB to simulate PDGF receptor activation in immune-competent new-born mice. We found that PDGFB-driven tumors have a significantly lower median survival compared to PDGFA-driven tumors. PDGFB-driven tumors also have increased infiltration of TAMs, made evident by immunohistochemical staining for IBA1. Flow cytometry analysis indicates the increased number of TAMs is due to an increased inflammatory monocyte population, but not due to the microglial population. We hypothesize these findings are attributable to the additional activation of the stromal population by PDGFB, as it can activate both PDGFRα and PDGFRβ while PDGFA only activates PDGFRα. Gene expression analysis indicates that several chemokines, chemokine receptors, macrophage, and immune markers are differentially expressed between PDGFB and -A tumor types. To establish correlations between PDGF signaling and TAM infiltration in human pediatric tumor samples, we stained 37 tumors for IBA1, PDGF-receptors, and PDGF-ligands. A positive correlation exists between high PDGFRb and PDGFB staining with high IBA1. Further studies will be done to discern the effects of increased TAM infiltration and the mechanisms driving enhanced tumor malignancy.
STEM-09. CANCER STEM CELL IMMUNOEDITING
Authors: Elias Sayour, Changlin Yang, Adam Grippin, Hector Mendez-Gomez, Mariana Dajac, Brian Nazareth, Michael Andrews, Tyler Loche, Aida Karachi, Brian Stover, Ginger Moore, Jesse Kresak, Jianping Huang, Duane Mitchell, Loic Deleyrolle
Journal: Neuro-Oncology (2018)

Conventional therapies most effectively eliminate highly proliferative tumor cells but leave behind residual slow-cycling cancer stem cells (SCCs) that evade treatment and ultimately seed disease recurrence. We reported the existence of SCCs that exhibit enhanced invasiveness, tumorigenicity and resistance to therapy in glioblastoma (GBM). The increased tumorigenicity of these GBM SCC suggests they may have enhanced immunoediting capacity. OBJECTIVES: We speculate that GBM SCCs drive disease progression and recurrence through immune escape. The objective of this study is to characterize the GBM SCC interface with the immune system and identify immunosuppressive mechanisms employed by these cells. SCCs were isolated from mouse and human models of malignant glioma and separated by flow cytometry based on their ability to retain CellTrace labeling. Draining lymph nodes from animals bearing SCC-derived malignant gliomas showed decreased CD8+ and increased CD4+/Foxp3+ cells. Immune gene signature analysis of tumor infiltrates uncovered enhanced recruitment of macrophages to SCC-derived tumors, with ApoE being the most over-expressed. ApoE promotes macrophage polarization toward the immunosuppressive M2 phenotype and inhibits T cell interferon-(IFN)-γ secretion. Using the IFN-γ reporter (GREAT) mice, we found that tumors derived from SCCs repressed IFN-γ secretion/expression by in vivo imaging, ELISA and RNA sequencing. This correlated with the up-regulation of gene networks in SCCs involved in immunosuppression, specifically CSF1 a prominent survival factor for macrophages. The immune surveillance hypothesis suggests that oncogenesis, driven by cancer cell immunoediting, shapes the immune system toward a pro-tumorigenic phenotype. Our study indicates that SCCs play a pivotal role in shifting the GBM immune milieu toward a regulatory phenotype characterized by M2 macrophages polarized by ApoE signaling.
CADD-19. PAM-OBG: A MAOB-SPECIFIC PRODRUG INHIBITOR OF O6-METHYLGUANINE DNA METHYLTRANSFERASE (MGMT) THAT SENSITIZES GMB TO BCNU/CCNU
Authors: Martyn Sharpe, David Baskin
Journal: Neuro-Oncology (2018)

MGMT gene methylation status indicate the levels of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) in glioma. MGMT repairs the DNA lesions caused by classical alkylating agents TMZ, BCNU and CCNU. Systemic inhibition of MGMT using the inhibitor O6-methylguanine (OBG) in GBM patients, prior to chemotherapy with TMZ or BCNU has failed due to toxicity toward bone marrow. We have shown that the enzyme monoamine oxidase B (MAOB) is upregulated in GBM. We have designed, synthesized and tested in vitro and in vivo, a MAOB-specific prodrug version of OBG. The prodrug, PAM-OBG, does not inhibit MGMT but is converted to OBG by MAOB. This prodrug should therefore only generate high levels of OBG in tissues with high levels of MAOB; i.e. Glioma, and only these tissues will become hyper-sensitive to DNA-alkylating agents. PAM-OBG was synthesized by conventional chemistry. Enzyme kinetics, activity in vitro and in an in vivo intracranial primary GMB nude mouse model studies were performed in a manner similar to our previously reported work on MAOB prodrugs. PAM-OBG is a highly specific MAOB substrate, with a Km of only 200 microMolar. In tissue culture it is highly effective at inhibiting MGMT in cells with high MAOB activity, but not in cells where MAOB is inhibited. In an intracranial model of primary GBM we find that PAM-OBG is not toxic. It does however sensitize the brain tumors to the DNA-alkylating agents BCNU and CCNU. The efficacy of PAM-OBG with BCNU and CCNU, based on animal survival time, is six-fold. No increased toxicity of these chemotherapeutics is observed in off-target mouse tissues. We have developed a drug candidate prodrug to complement existing GBM therapy. We hope that PAM-OBG can be used to sensitize a patient’s GBM to DNA-alkylating agents, during and following, radiotherapy.
CBMT-06. LOWER GRADE ISOCITRATE DEHYDROGENASE (IDH) MUTANT GLIOMAS METABOLICALLY MIMICKING GLIOBLASTOMA (GBM) EXPRESS HIGHER R:S 2-HYDROXYGLUTARATE RATIOS RELATIVE TO NON-GBM-MIMICKING IDH MUTANT GLIOMAS
Authors: Romina Nejad, Farshad Nassiri, Yasin Mamatjan, Hao-Wen Sim, Eric Chen, Sameer Agnihotri, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2018)

Glioma patients continue to carry a very poor prognosis despite maximal therapy, urging for the development of novel therapies. Previous studies have identified mutations of metabolic enzymes directly regulating cellular metabolism, specifically, isocitrate dehydrogenase (IDH1/2) mutation. IDH1/2 mutations occur early in glioma pathogenesis and result in the accumulation of oncometabolite 2-hydroxylgutarate (2-HG), with the preferential accumulation of the R relative to the S enantiomer of 2-HG. This metabolic reprogramming may help explain treatment resistance and highlight potential metabolic pathways involved in tumorigenesis. To investigate the metabolic profile of a cohort of gliomas, we used ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) to detect a set of 689 metabolites in 90 IDH1 mutant and IDH1 wildtype gliomas. Unsupervised consensus clustering identified two distinct metabolic subgroups of gliomas: metabolic group 1, which consists of only IDH1 mutated tumors (n=30) and metabolic group 2, which consists of all IDH1 wildtype tumors and a subset of IDH1 mutated tumors (n=60). We therefore, termed these IDH1 mutated tumors in metabolic group 2 as “GBM mimickers”. Importantly, comparison of IDH mutant tumors from metabolic group 1 versus the GBM mimickers showed distinct R:S 2-HG ratio differences, specifically with the GBM mimickers expressing significantly higher R:S 2-HG ratios (mean R:S 2-HG 2421.44 vs. 625.46, p=0.014). Moreover, the GBM mimickers showed significantly decreased progression free survival (20 months vs. 49 months, p<0.05, respectively) and increased tumor enhancement on imaging versus their IDH1 mutated counterparts in metabolic group 1 (100% vs. 37.5%, p<0.0001), suggesting that R:S 2-HG ratio may be a marker of poor outcome. CONCLUSION: Our data supports distinct metabolic subtypes of IDH mutant gliomas, and highlights the use of R:S 2-HG ratio as a potential marker of poor outcome in IDH mutant gliomas.
RDNA-05. SYNTHETIC SENSITIZATION OF MGMT-DEFICIENT TUMOR CELLS TO TEMOZOLOMIDE USING ATR INHIBITORS
Authors: Christopher Jackson, Seth Noorbakhsh, Ranjini Sundaram, Aravind Kalathil, Ranjit Bindra
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common primary brain tumor in adults. The current standard of care consists of surgery followed by temozolomide (TMZ) and radiation therapy (RT). TMZ is an alkylating agent that methylates guanine bases at the O6 position (O6meG). O6-meG-methyltransferase (MGMT) is a suicide enzyme that repairs TMZ-induced damage by removing these adducts. Patients with methylation of the MGMT promoter respond more readily to TMZ and survive approximately 9 months longer than patients with an unmethylated MGMT promoter. Despite this prognostic benefit, these patients still have a median survival of only 21.7 months. The purpose of this study is two-fold: 1) to better understand the DNA damage response pathways that are activated in MGMT-methylated glioma cells upon treatment with TMZ, and 2) to determine if inhibiting these activated pathways sensitizes the glioma cells to TMZ. We found that TMZ, unlike other alkylators tested, specifically induces growth delay, DNA damage, and G2-phase cell cycle arrest in MGMT-methylated cells, but not in isogenic MGMT-positive cells. TMZ also induces markers of replication stress in MGMT-methylated cells, specifically pChk1 S345 and pRPA32 S33. As these proteins are markers of ATR activation, we hypothesized that inhibition of ATR would further sensitize MGMT-methylated cells to TMZ. In vitro, ATR inhibitors increased sensitivity to TMZ by over 1000-fold in MGMT-methylated cells, but not in MGMT-expressing cells. Here, we report exquisite synergistic interactions between TMZ and inhibitors of a key DNA damage response protein, ATR, in MGMT-deficient cells. These data lay the foundation for future clinical trials testing this combination specifically in MGMT-methylated glioma. Since ATR inhibitors are radiosensitizers, it is possible that this combination of chemotherapeutics will further synergize with RT in the treatment of GBM. Future experiments will examine this potential three-way synergy.
TMIC-01. LOX DEPENDENT MACROPHAGE RECRUITMENT IN GBM
Authors: Y Alan Wang, Peiwen Chen
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most lethal form of brain cancer in adults with no effective therapeutics. Genomic profiling has stratified GBM into various subgroups, which are driven by specific genetic alternations of core signaling pathways, including RTK/RAS/PI-3K, P53 and RB pathways. The main reason for this failure is tumor-cell genetic heterogeneity, which induces aberrant activation of multiple signaling pathways. Stromal/immune cells in the tumor microenvironment (TME) are genetically stable, which not only play a pivotal role in GBM progression by affecting multiple cancer hallmarks, but can also be educated by cancer cells. However, whether and how the behavior and function of specific stromal/immune cells in the TME are regulated by genetic alternations in GBM remain relatively undefined. Here, we show that PTEN deficiency in GBM specifically triggers immune response by promoting macrophage recruitment, while without affecting macroglia and other immune cells. Using unbiased transcriptome profiling, we identified that lysyl oxidase (LOX) is preferentially secreted by PTEN-deficient cancer cells, and is a potent macrophage chemoattractant. Transcriptome profiling following Gene Set Enrichment Analysis and functional validation demonstrated that activation of SRC and AKT signaling pathways drives LOX upregulation in PTEN-deficient cancer cells, thus promoting macrophage recruitment. Following internalization into macrophages mediated by integrin b1, LOX promotes macrophage migration via a newly identified signaling pathway through phosphoprotein profiling. Genetic and pharmacological inhibition of LOX in PTEN-deficient cancer cells does not affect tumor cell proliferation in vitro, but markedly inhibits macrophage density and tumor growth in vivo. Clinically, LOX expression positively correlates with integrin b1, as well as macrophage signature and poor prognosis in GBM patients. LOX-integrin b1 axis is enriched in GBM patients with higher macrophage density, and that these patients show lower survival. Together, our study highlights the possibility of improving GBM treatment by targeting PTEN-LOX axis-mediated macrophage recruitment.
PATH-53. CEREBROSPINAL FLUID TARGET DEEP SEQUENCING IMPLICATES AN ALTERNATIVE ASSAY OF GLIOBLASTOMAS DRIVER GENES IN THE CLINICAL SETTINGS
Authors: Zhenqiang He, Hao Duan, Juehui Li, Yonggao Mou
Journal: Neuro-Oncology (2018)

AIM: The goal of the current study was to explore whether routine lumbar puncture and high-throughput sequencing of CSF could better identify tumor-driving mutations both contribute in glioblastomas development in patients and provide clinically meaningful insights into the driver genes of glioblastomas and their treatment response. We characterized genomic architecture and implicated mutation levels differ between cerebrospinal fluid (CSF) and plasma samples collected 7 days of clinical follow-up using targeted deep sequencing. We sequenced coding region, exon-intron boundaries and UTRs of 50 central nervous system cancer-associated genes in cell-free DNA from CSF obtained through routine lumbar puncture in 5 patients with Glioblastomas. Our results demonstrated that serial changes in circulating levels of important driver mutations correlate with different prognosis of the cohort. The comparison of CSF and plasma samples in each single patient with Glioblastomas shows that circulating tumour DNA in CSF better reflect the sequential change of the driver genes than that in plasma. CONCLUSIONS: Cerebrospinal fluid target deep sequencing implicates an alternative assay of glioblastomas driver genes in the clinical settings.
ACTR-07. COMPLETE, DURABLE RESPONSE OF A RECURRENT UNRESECTABLE GRADE III GLIOMA TO A REPURPOSED DRUG REGIMEN
Authors: Richard Kast, Michael Salacz
Journal: Neuro-Oncology (2018)

Some non-oncology drugs can be repurposed as adjuvants to traditional cytotoxic chemotherapies. Cancer after all uses dysregulated and pathologically activated, but otherwise normal, physiological growth factors, anti-apoptosis pathways and migration mechanisms. We manipulate these pathways every day in non-cancer medicine so it is straightforward to use these non-cancer related medicines to address dysregulated growth systems in cancer. We report here a 28 y/o man diagnosed in May 2011 with Grade II/III Astrocytoma, 1p/19q intact, IDH1 R132H wild type. Subtotal resection left mass-like FLAIR involving right internal capsule along with patchy enhancement. After 1 year of 5-day temozolomide, 20 mg bid, ending in Sept 2012, he was followed with serial MRI scans. After progression of enhancing tumor in May 2015, repeat biopsy demonstrated anaplastic (gemistocytic) astrocytoma. Radiation/temozolomide/naltrexone was followed by adjuvant therapy temozolomide 20 mg BID, celecoxib 200 mg daily, naltrexone 25 mg daily, and levetiracetam 1500 mg BID for seizure control. In June 2017 new enhancement appeared deep to the surgical cavity. On patient’s initiative, addition of valproic acid 500 mg BID to current therapy. He has tolerated this ongoing treatment with no toxicities and remained clinically asymptomatic, continuing to work full time. Over the interval (mid-2017 to summer 2018), the enhancing components of the tumor, which had persisted for years, have completely resolved. CONCLUSION: Repurposed drug cocktails, which can simultaneously and specifically target multiple tumor pathways remain a largely untested treatment for patients who face limited proven options. We report a patient who continues to do well in the face of an inoperable, poor molecular profile recurrent tumor with a inexpensive drug regimen that has yielded no toxicity. Repurposing non-oncology drugs to augment traditional cytotoxic chemotherapy hold great promise.
Abstract 18891: Racial Differences in End-of-life Care Associated With Heart Failure Hospitalizations in the United States: A Population-based Analysis From 2011-2012
Authors: Nilay Kumar, Rohan Khera, Neetika Garg
Journal: Circulation (2015)

Background and objectives: Racial disparities in healthcare delivery constitute a major public health problem in the US. There are few studies evaluating the effect of race on utilization of end-of-life (EOL) procedures in HF hospitalizations in the US. Hypothesis: Utilization of EOL procedures differs significantly between racial-ethnic groups independent of socioeconomic status (SES) or probability of in-hospital death. Methods: We used the 2011-2012 Nationwide/National Inpatient Sample to identify primary HF hospitalizations. EOL procedures of interest were intubation, tracheostomy and prolonged mechanical ventilation, hemodialysis, cardiopulmonary resuscitation, gastrostomy, enteral or parenteral nutrition. Relevant ICD-9 codes were used. We used residential ZIP code as a proxy for SES. Multivariate logistic models were used to evaluate racial differences in EOL care while adjusting for SES and probability of in-hospital mortality. Results: 375,740 hospitalizations representing 1.8 million hospitalizations nationwide were included in the study. Mean age was 72.6 (SD 14.6) years and 50.1% were women. Overall 7.81% were intubated, 0.69% underwent tracheostomy, and 6.55% underwent hemodialysis, 0.55% underwent CPR, 0.22% had a gastrostomy and 0.45% received enteral or parenteral nutrition. Blacks, Hispanics, Asians or Pacific Islanders and Other races were more likely to receive EOL procedures compared to Whites after adjusting for SES and probability of in-hospital death. (Fig) Use of any EOL procedure was associated with higher age and sex adjusted odds of in-hospital mortality (OR 6.54, 6.09 - 7.04; p&lt;0.001) and average charges ($76,917 vs. 35,841, p&lt;0.001). Conclusions: Racial-ethnic minorities hospitalized for HF are significantly more likely to receive aggressive EOL care compared to Whites. The reasons for racial differences in utilization of EOL care in HF should be investigated in future studies.
Targeted therapy against VEGFR-1, -2, and -3 by AZD2171 blocks tumor growth and angiogenesis, and enhances paclitaxel efficacy in an orthotopic lung cancer model
Authors: Kazuhisa Furutani, Ritsuko Komaki, Toshiyuki Imagumbai, Amir Onn, Joerg Jacoby, Erminia Massarelli, Maria Korshunova, Anderson Ryan, Juliane Jurgensmeier, Roy Herbst, Michael O'Reilly
Journal: Cancer Research (2007)

2121  Introduction: Targeted therapies against vascular endothelial growth factor (VEGF) signaling are currently being evaluated as a therapeutic approach for lung cancer. AZD2171 is a potent orally available small molecule tyrosine kinase inhibitor of VEGF receptors (VEGFR) -1, -2, and -3 that blocks angiogenesis and tumor growth. However, preclinical and clinical data suggest that antiangiogenic agents should be combined with conventional therapy for optimal treatment of advanced malignancies. We therefore evaluated the antitumor and antiangiogenic effects of AZD2171 alone or combined with paclitaxel in an orthotopic mouse model of human lung cancer.  Methods: Studies were performed in an orthotopic lung cancer model that closely mimics clinical patterns of lung cancer growth. Human lung adenocarcinoma cells (PC14) were injected into the left lungs of nude mice with lung tumors evident within 14 days. Mice (10/group) were randomized on day 14 after injection to treatment with AZD2171 (6 mg/kg/day po), paclitaxel (200 μg weekly ip), AZD2171 and paclitaxel, or vehicle. The experiment was terminated when control mice showed signs of morbidity. All animals were then sacrificed and assessed for tumor burden, pleural effusion and lymphatic metastasis. Tumor tissues were then subjected to immunohistochemical (IHC) analyses.  Results: AZD2171 treatment significantly reduced lung tumor burden (P  Conclusions: These data demonstrate that VEGF-receptor signaling blockade by AZD2171 inhibits tumor growth and angiogenesis in an orthotopic human lung adenocarcinoma model. The antitumor and antivascular effects of AZD2171 were substantially enhanced when AZD2171 was combined with paclitaxel. These findings provide support for continued study of AZD2171 with cytotoxic therapies and provide a basis for clinical trials of VEGFR blockade with chemotherapy.
ACTR-08. A PHASE II STUDY OF APATINIB PLUS TEMOZOLOMIDE IN ADULTS WITH REFRACTORY RECURRENT HIGH-GRADE GLIOMAS
Authors: Jun-ping Zhang, Jing-jing Ge, Cheng Li
Journal: Neuro-Oncology (2018)

There is no standard therapy for refractory recurrent high-grade gliomas. We assessed the efficacy and safety of apatinib, a new oral small-molecule tyrosine kinase inhibitor targeted vascular endothelial growth factor receptor 2, combined with temozolomide (TMZ) in patients with refractory recurrent high grade gliomas. METHOD: This was a single-arm phase prospective clinical trial. Thirty three patients with recurrent high-grade gliomas were enrolled from April 2016 to March 2018. They received oral apatinib (500mg qd) in combination with TMZ. TMZ was administrated at 200 mg/m2/d according to standard 5/28 days regimen for the patients who had not received TMZ before, and that patients who had experienced relapse from the standard 5/28 TMZ regimen, received continuous daily TMZ (50 mg/m2/d). After 12 cycles, the patients continued to take apatinib as maintenance until progression. The primary endpoint was a 6-month progression-free survival (PFS) rate. The 6-month PFS for glioblastoma (GBM) was 47.8% and 58.3% for anaplastic gliomas (AGs). The median PFS was 4.9 months for GBM and 6.3 months for AGs. The overall survival (OS) at 1 year was 36.2% for GBM and 17.9% for AGs. The median OS for GBM was 8.3 months and 10.6 months for AGs. The differences in PFS (P=0.77) or OS (P=0.70) between GBM and AGs did not reach significance. Five (25%) out of 20 patients with GBM demonstrated partial (3/20) or complete (2/20) radiographic response to treatment and 10/20 (50%) remained stable. Four (50%) out of 8 patients with AGs showed partial (3/8) or minor (1/8) response to treatment and 3/8 (37.5%) remained stable. The most common grade 3 to 4 nonhematologic toxicities were hypertension, hand-foot syndrome, proteinuria and elevated transaminase, which were acceptable. These data show that apatinib plus TMZ is effective and tolerable in patients with refractory recurrent high-grade gliomas.