tbuckley/cabot-search huggingface dataset:
IMMU-10. RADIOTHERAPY AND PD-1 BLOCKADE INCREASES TRYPTOPHAN METABOLISM IN BRAIN TUMOR-DRAINING SECONDARY LYMPHOID ORGANS
Authors: Rohan Savoor, Erik Ladomersky, Sebastian Otto-Meyer, Lijie Zhai, Kristen Lauing, Alicia Lenzen, Rimas Lukas, Derek Wainwright
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is an aggressive, incurable, primary brain tumor with a median survival of 15–20 months. High intratumoral expression of indoleamine 2,3-dioxygenase 1 (IDO1), an immunosuppressive enzyme that metabolizes tryptophan (Trp) into kynurenine (Kyn), is one factor that contributes to immunosuppression in GBM. Unexpectedly, we discovered that IDO1 enzyme activity becomes targetable in non-tumor cells after treatment with brain tumor radiation (RT) and PD-1 mAb (Ladomersky et al., 2018; CCR). The premise for this investigation is to evaluate IDO1 enzyme activity before and after radiation and PD-1 blockade, for the identification of non-brain tumor tissues that are active for immunosuppressive tryptophan metabolism. Wild-type (WT) and IDO1 knockout mice (IDO1KO) were intracranially-injected (ic.) with 2 × 105syngeneic GL261. At two weeks post-ic., mice were treated with RT (n=10/group) or PD-1 mAb. Mice were euthanized at day one (n=5/group) or day seven, following treatment (n=5/group). IDO1 metabolism was evaluated by HPLC for Trp and Kyn levels in the brain tumor, contralateral non-tumor brain, cervical lymph nodes and spleen. Radiation had an early effect at increasing the Kyn/Trp ratio, a proxy for IDO1 enzyme activity, in normal brain and draining lymph nodes (P<0.01). Interestingly, PD-1 blockade also led to an early increase in the Kyn/Trp ratio of lymph nodes (P<0.01), but not in normal brain. In contrast, spleen showed a late increase in the Kyn/Trp ratio (P<0.01). Strikingly, the majority of Kyn/Trp ratio changes were observed both in WT and IDO1KO mice. Our data suggest a systemic and tissue-selective change in Trp metabolism after radiation and PD-1 blockade. Unexpectedly, many of these changes were not specific to IDO1, suggesting a therapeutic inducibility of other immunosuppressive mediators, such as tryptophan dioxygenase (TDO). These data suggest that, effectively inhibiting tryptophan metabolism in subjects with brain tumors will likely require dual IDO1/TDO inhibition.
CADD-04. NANOPARTICLE DELIVERY OF miRNAs TO INHIBIT GBM STEM CELLS
Authors: Hernando Lopez, Kristen L Kozielski, Yuan Rui, Bachchu Lal, Hannah Vaughan, David R Wilson, Nicole Mihelson, Charles G Eberhart, Jordan J Green, John Laterra
Journal: Neuro-Oncology (2018)

Cancer cells arise from complementary genomic and epigenomic abnormalities that deregulate pathways that control cell proliferation and tissue homeostasis. Epigenetic modifications, involving deregulation of non-coding RNAs, are emerging as critical determinants of gene expression and essential drivers of neoplastic phenotypes. Our knowledge of how these complex epigenetic mechanisms operate in the context of cancer cell phenotype regulation remains limited. Non-coding RNAs, in particular miRNAs, are emerging as critical epigenetic regulators of cell fate and oncogenesis. MiRNAs act by selectively inhibiting gene expression primarily by targeting mRNA for degradation. Numerous miRNAs have been found to regulate tumorigenesis and cancer cell stemness by virtue of their capacity to target tumor-suppressing or tumor promoting transcripts. We recently showed that the coordinated actions of Oct4 and Sox2 induce a tumor-propagating stem-like state in GBM cells through a mechanism that involves the induction of DNMTs and down-regulation of a network of miRNAs through promoter DNA methylation. Two of the miRNAs repressed by Oct4/Sox2, miR-148a and miR-296-5p, efficiently inhibit the tumor propagating capacity of GBM stem-like, making them excellent candidates for therapeutic intervention. Options for treating high-grade brain tumors remain limited. Recent developments in nanomedicine provide new and exciting opportunities to treat and manage brain tumors. Cationic polymers are a class of biomaterials with great promise for targeted molecular therapeutics. We combined this cutting-edge technology with our newly discovered stem cell inhibiting miRNAs to develop nanoparticles to treat gliomas. We show these nano/miRs distribute throughout an established tumor in vivo, and more importantly, delivering these tumor-suppressing miRNAs using PBAE polymers inhibits the growth of established GBM tumor and prolongs survival in mouse models. Our findings demonstrate that identifying stem cell-inhibitory miRNAs in combination with current advances in nanomedicine will impact the development of novel therapies for treating GBM.
NIMG-47. A HISTOGRAM-BASED, BACK-PROJECTION METHOD FOR TREATMENT RESPONSE ASSESSMENT IN GLIOBLASTOMA USING MULTI B-VALUE ADVANCED DIFFUSION MRI
Authors: Melanie Morrison, Shah Islam, Adam Waldman, Matthew Grech-Sollars
Journal: Neuro-Oncology (2018)

Early and accurate assessment of therapeutic response in glioblastoma is important for clinical patient management, and as platform for clinical trials of novel therapies. Current response criteria such as RANO (Response Assessment in Neuro-Oncology) rely on semi-quantitative measurements with limited sensitivity and specificity, especially early during treatment. Functional diffusion maps based on voxel-to-voxel comparison of quantitative diffusion measures are confounded by change in tumour size. Towards improving response assessment, we propose a histogram-based, voxel back projection method using advanced quantitative diffusion MRI. We used least-square fitting to model four diffusion parameters from mono-, bi-, and stretch-exponential models, and performed a histogram analysis of all voxels located within ROIs dictated by the radiotherapy-planned clinical target volume. Histograms were generated for 10 patients with GBM at 2 time-points, before, and at 6 weeks of treatment with standard-of-care regimen (RT with concomitant and adjuvant temozolomide). For each parameter, percentile ranges corresponding to diffusion values with the greatest cumulative difference between the time points were identified, and associated voxels were back-projected onto their respective maps for spatial correspondence and comparison with standard radiological imaging. RESULTS & DISCUSSION: The greatest cumulative difference in diffusion parameters measured at baseline and at 6 weeks of treatment, spatially corresponded to voxels lying within regions of high FLAIR signal intensity and regions radiologically-defined as healthy brain. The magnitudes of diffusion imaging parameters within these regions were heterogeneously distributed and did not show a direct spatial correspondence to radiological signal intensities. This heterogeneous spatial distribution may be influenced by microcellular changes, for example, in areas of infiltrative tumor which are not visible on standard imaging. Further assessment of this dataset, augmented by on-going patient recruitment across multiple centres, will provide insight to the prognostic value of advanced diffusion MRI as a method for response assessment in glioblastoma.
RDNA-11. OVERCOMING RADIATION RESISTANCE IN MENINGIOMA: THE EMERGING ROLE OF CDK4/6 INHIBITOR
Authors: Arabinda Das, Daniel G McDonald, Abhay K Varma, Libby Infinger, William A Vandergrift, Scott M Lindhorst, Kenneth N Vanek, Joseph M Jenrette III, Pierre Giglio, Sunil J Patel, David Cachia
Journal: Neuro-Oncology (2018)

Meningiomas are common intracranial brain tumors. Despite surgery and/or radiation therapy, recurrence rates occur in approximately 8–10 % of tumors. This may be due to the dysregulation of the cyclin D and cyclin-dependent kinase (CDK) pathway in malignant meningioma cells and radiation-resistant meningioma cells. The cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway controls the cell cycle restriction point, and is commonly dysregulated in meningioma; making it a rational target for antimeningioma therapy. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function against Rb+ meningiomas cells in vitro, ex vivo and in vivo xenograft model. Meningioma tumors in SCID mice treated daily with intraperitoneal injections of palbociclib for 14 days dose dependly with X ray irradiation. Treatment effects were examined by immunoblot, cell viability, apoptosis, and cell cycle progression. Radiation resistance BENMEN1 cells were developed after exposure to repeated 320 kV X ray irradiation. Since CDK4 and CDK6 are proteins that are major part of a cell cycle regulatory pathway in meningioma that also includes p16, cyclin D, and the retinoblastoma (Rb) protein, we analyzed those parameters. Our both in vitro and in vivo data clearly demonstrate that pallbociclib (CDK 4/6 inhibitor) treatment reduced proliferation and has additional effects on cell cycling, including induction of an RB-associated G(1) arrest against Rb+ malignant meningioma cells and radiation-resistant meningioma cells. We did not see any significant effect of palbociclib on Rb – meningima cells. Our results also demonstrated that palbociclib treatment inhibits CDK4 and CDK6 expression and also decreases E2F target gene expression (CCNA2 and CCNE2). All together, our results provide strong evidence that palbociclib can be applied to Rb+ meningiomas as a therapeutic agent.
Disturbing Lack of Early Intervention Studies in Bipolar Disorder—Reply
Authors: Christoph U. Correll, Britta Galling, John M. Kane
Journal: JAMA Psychiatry (2018)

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IMMU-58. REDUCED NEOANTIGEN EXPRESSION AS A POSSIBLE IMMUNE EVASION MECHANISM DURING GLIOMA PROGRESSION
Authors: Takahide Nejo, Hirokazu Matushita, Takahiro Karasaki, Masashi Nomura, Genta Nagae, Shunsaku Takayanagi, Shota Tanaka, Satoshi Takahashi, Yosuke Kitagawa, Taijun Hana, Tsukasa Koike, Yoshitaka Narita, Motoo Nagane, Ryo Nishikawa, Keisuke Ueki, Hiroyuki Aburatani, Akitake Mukasa, Kazuhiro Kakimi, Nobuhito Saito
Journal: Neuro-Oncology (2018)

Limited success of immune-based therapies in glioma might be in part due to the lack of enough neoantigens (neoAgs) that can be targeted by immune effector cells. In addition, gliomas also show dynamic clonal evolution over time, possibly leading to immunoediting during progression. In this study, we evaluated neoAg expression change and its relation to immune microenvironment using matched primary and recurrent tumor samples from 25 glioma patients [8 IDH-wildtype glioblastoma (GBM), 9 IDH-mutant astrocytoma (LGG-A), and 8 oligodendroglioma (LGG-O)]. Predicted neoAgs (p-neoAgs) deriving from missense mutations were identified by whole-exome sequencing (WES) analysis and the MHC class I binding prediction algorism NetMHCpan2.8. Expressed neoAgs (e-neoAgs) among the p-neoAgs were determined by incorporating RNA sequencing (RNA-seq) data. The ratio of e-neoAgs to p-neoAgs (“neoAg expression ratio”) on each sample significantly decreased at recurrence (p = 0.003) and was particularly strong in neoAg with a higher affinity for MHC class I. Similar results were obtained for GBM, LGG-A, and LGG-O, when separately analyzed. RNA-seq-based differential gene expression analyses including gene ontology analysis and pair-designed gene set enrichment analysis illustrated that the cases with strongly reduced neoAg expression ratio compared to primary counterpart (top 8), but not those without (bottom 8), retained gene expression related to antigen presentation machinery and gained immune effector cells at recurrence. These in silicofindings were consistent with immunohistochemistry for CD8 and MHC class I on tumor samples. These data may suggest that the tumor cells with reduced neoAg expression survived at recurrence as a result of persistent anti-tumor immune responses in some gliomas under the standard treatment. Reduced neoAg expression and impaired APM during progression may play complementary roles in the immune evasion of gliomas.
IMMU-40. SINGLE-CELL LEVEL COMPARISON OF HISTOPATHOLOGY AND SINGLE-CELL RNA-SEQ DATABASES BETWEEN IDH-MUT AND –WT GLIOBLASTOMAS REVEALS DISTINCT INNATE IMMUNE MICROENVIRONMENTS THAT CAN BE EXPLOITED FOR THERAPEUTIC GAIN
Authors: Candice Poon, Katherine Liu, Paul Gordon, Runze Yang, Susobhan Sarkar, Reza Mirzaei, Tanveer Sheikh, Martha Hughes, Wee Yong, John Kelly
Journal: Neuro-Oncology (2018)

Most immune cells in the glioblastoma (GBM) microenvironment are microglia and macrophages (MMs), but they are poorly understood. We sought to characterize these innate immune cells in human untreated IDH-WT and rare IDH-MUT GBM tissue to elucidate differences underlying their disparate prognoses relevant to immunotherapy design. An in-house automated segmentation protocol that quantifies at the single-cell level was used to analyze newly diagnosed human GBM (9 IDH-WT, 4 IDH-MUT). Three large sections (3-8mm in diameter) were quantitated to capture potential spatial heterogeneity. Expression of CD68, HLA-A/B/C, TNFa, CD163, IL10, TGFB2, Iba1 intensity, and surface area were enumerated and combined into an activation profile in Iba1+ cells (MMs). Results were validated with flow cytometry. Human IDH-MUT (GSE89567) and –WT (GSE84465) single-cell RNA-seq databases were then compared using novel bioinformatics techniques to affirm results. MM content is drastically reduced in IDH-MUT compared to –WT GBMs (4.9 ± 1.4% vs. 37.2 ± 7.3% of all GBM cells, respectively; p=0.0154). Surprisingly, a large range of MM content was found in IDH-WT GBMs, from 1.6 ± 0.6% to 71.9 ± 13.4%. Positive correlation with flow cytometry corroborated these results (Pearson r=0.7296; p=0.026). Inflammatory phenotypic variability was again seen in MMs in both IDH-MUT and –WT GBMs, but IDH-MUT GBM-associated MMs were more activated/pro-inflammatory (124.5 ± 21.6 pro-inflammatory units vs. 54.0 ± 15.6 pro-inflammatory units; p=0.0265). Comparison of single-cell RNA-seq databases after normalization and dynamic pruning of hierarchical clustering dendrograms verified MMs in IDH-MUT GBMs were more pro-inflammatory, but that this was driven by anti-inflammatory macrophages in IDH-WT GBMs as opposed to microglia which were pro-inflammatory in all tumors (p < 0.01). This is one of the first studies to characterize MMs in untreated human IDH-MUT GBMs and identify dissimilarities to the IDH-WT innate immune microenvironment that can be targeted by immunotherapies. Also, considerable MM phenotypic heterogeneity suggests precision immunotherapy approaches are crucial.
Dosimetry of DNA etheno adducts, apoptosis and cell proliferation in liver from mice exposed to urethane or vinyl carbamate
Authors: Rong Wang, Alain Barbin
Journal: Cancer Research (2005)

1191  Urethane (ethyl carbamate, EC) and its metabolite vinyl carbamate (Vcar) induce tumors at various sites, including the liver, in rodents. Their mechanism of carcinogenicity is thought to involve the formation of promutagenic etheno adducts in DNA. To further our insight into this mechanism, we carried out dosimetry analysis of etheno DNA adduct formation and effects on cell cycle in the liver of suckling or juvenile mice treated with different doses (single i.p. injection) of EC (0 - 10,000 nmol/g bw) or Vcar (0 - 500 nmol/g bw). Six hours after treatment with Vcar, the formation of 1,N6-ethenoadenine (eA) was linear, with respect to dose, in both suckling and juvenile mice. The formation of N3,4-ethenocytosine (eC) was supralinear, but at much lower levels than eA. Following treatment with EC, the formation of eA followed a supralinear dose-response in suckling mice, as can be expected when metabolic activation becomes saturated; in juvenile mice, the dose-response for eA formation suggested a pharmacokinetics governed by both limited perfusion and saturation of metabolic activation. EC did not induce a significant increase in eC in mice. In contrast, the reaction of vinyl carbamate epoxide, the ultimate electrophilic metabolite of EC and Vcar, with DNA in vitro yielded more eC residues than eA residues. This strongly suggests that eC is repaired very efficiently in mice. In addition, the eA/eC ratio in liver DNA from mice treated with EC or Vcar increased linearly with the dose, indicating that the repair of eC was even faster at high doses. Apoptosis and proliferation of hepatocytes were measured at 6 h and 24 h after different doses of Vcar or EC. Vcar and EC induced apoptosis of hepatocytes in suckling and juvenile mice. These responses were non-linear and involved a practical dose threshold, which was higher for the stimulation of apoptosis than for stimulation of proliferation. The stimulation of hepatocyte proliferation was marginal in juvenile mice. At high doses of Vcar or EC, the proliferation of hepatocytes was inhibited or delayed. These dosimetry data should promote a better understanding of the mechanism of hepatocarcinogenesis induced by EC in rodents, and should assist in assessing the risk associated with exposure to EC (Supported by EU grant QLK4-CT-2000-00286).
ACTR-40. A PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF MARIZOMIB (MRZ) WITH TEMOZOLOMIDE (TMZ) AND RADIOTHERAPY (RT) IN NEWLY DIAGNOSED WHO GRADE IV MALIGNANT GLIOMA (GLIOBLASTOMA, ndGBM): FULL ENROLLMENT RESULTS
Authors: Daniela A Bota, Santosh Kesari, David Piccioni, Dawit Aregawi, Patrick Roth, Roger Stupp, Annick Desjardins, Steven D Reich, Ileana Elias, Mingyu Li, Nancy Levin, Benjamin Winograd, Warren Mason
Journal: Neuro-Oncology (2018)

Proteasome inhibition sensitizes glioma cells to TMZ and RT, providing a novel therapeutic strategy for ndGBM. MRZ, an irreversible, brain-penetrant, pan-proteasome inhibitor with anti-glioma activity was combined with standard-of-care (SOC) concomitant TMZ/RT followed by adjuvant TMZ in ndGBM (NCT02903069), to determine the recommended dose (RD). Patients were enrolled in separate concomitant (TMZ/RT+MRZ, N=15) and adjuvant (TMZ+MRZ, N=18) cohorts in dose-escalation (3 + 3 design), followed by dose-expansion (N=20) at RD (0.8 mg/m2) in concomitant followed by adjuvant treatment. MRZ infused IV (10 min) at increasing dose levels (0.55, 0.7, 0.8, and 1.0 mg/m2): Concomitant days 1, 8, 15, 29, 36; Adjuvant days 1, 8, 15 (28-day cycle). RESULTS (as of 02May2018): Mean age 55 years, 68% male. Most common treatment-emergent adverse events (TEAEs, 20% patients, all grades): fatigue, nausea, vomiting, hallucination, ataxia, headache. Dose-limiting toxicities (DLTs): 1 (fatigue) at 0.7 mg/m2 adjuvant cohort, 3 (ataxia/diarrhea; ataxia/confusion; myocardial infarction) in concomitant and 2 (delirium/ataxia; ataxia/fatigue) in adjuvant cohorts at 1.0 mg/m2. Grade 3 TEAEs in 11 of 12 patients at 1.0 mg/m2 including one Grade 4 and one Grade 5 TEAE; at 0.8 mg/m2 MRZ, Grade 3 TEAEs in 9 of 21 patients. MRZ demonstrated a steep dose-response with TEAEs/DLTs predominately CNS AEs (ataxia, hallucinations) which were dose-related, short-lasting, reversible and ameliorated by early dose reductions, allowing patients to remain on treatment. Currently 8 dose-escalation patients remain active in Cycle 10–23. Median OS for dose-expansion not yet estimated; 7 patients remain active, 1 death, median follow-up 4.1 months. MRZ at the RD with adjuvant TMZ+Tumor Treating Fields (Optune) is currently enrolling. An international Phase 3 trial (EORTC #1709-BTG, NCT03345095) has been launched in 2018 to assess the overall survival benefit of MRZ added to SOC in ndGBM.
ACTR-02. NRG ONCOLOGY/RTOG 0424: LONG-TERM RESULTS OF A PHASE II STUDY OF TEMOZOLOMIDE-BASED CHEMORADIOTHERAPY REGIMEN FOR HIGH-RISK LOW-GRADE GLIOMAS
Authors: Barbara Fisher, Peixin Zhang, David Macdonald, Arnab Chakravarti, Glenn Lesser, Sherry Fox, Stephen Coons, Leland Rogers, Maria Werner-Wasik, Thomas Doyle, Jean-Paul Bahary, John Fiveash, Joseph Bovi, Steven Howard, Michael Yu, David Dsouza, Nadia Laack, Mack Roach, Young Kwok, Daniel Wahl, John Stasser, Minhee Won, Minesh P Mehta
Journal: Neuro-Oncology (2018)

PURPOSE: To report the long-term outcomes and MGMT analysis of temozolomide (TMZ) and radiotherapy (RT) in a high-risk low-grade gliomas (LGG) population. PATIENTS/ For this single-arm phase II study, LGG patients with ≥3 risk factors (age ≥40, astrocytoma, bi-hemispheric tumor, size ≥6 cm or preoperative neurologic function status >1) received RT (54 Gy/30 fractions) with TMZ and up to 12 cycles of post-RT TMZ. The primary endpoint was overall survival (OS) at 3 years after registration. A one-sided Z-test was used to test the hazard rate based on the observed 3-year OS rate versus a prespecified historical control from the EORTC high-risk LGG population. Secondary endpoints included progression-free survival (PFS), and the association of survival outcomes with MGMT methylation status, for which the MGMT-STP27 prediction model was used based on 450k data. The initial report of this study was published in 2015, when the results of the MGMT analysis were unavailable. The study accrued 129 analyzable patients. The median follow-up for surviving patients was 9 years (range: 0.4–11.8), 4 years longer than previously reported. The 3-year OS rate was 73.5% (95% CI: 65.8–81.1%), superior to the historical control of 54% (p