bluuebunny/crossref_metadata_2025_split huggingface dataset:
SCIDOT-35. A NOVEL MODEL FOR THE OPTIMIZATION OF DRUG-DEVICE COMBINATIONS FOR THE TREATMENT OF BRAIN TUMORS
Authors: Killick-Cole Clare , Woolley Max , Johnson David , Lewis Owen , Moore Patrick , Fletcher Julia , Skinner Paul , Bienemann Alison , Gill Steven 
Published: November 2019

Abstract

BACKGROUND
Failure of many brain tumor treatments has been attributed to the inability of a compound to cross the blood-brain barrier. Convection-enhanced delivery (CED) offers a method to administer drugs directly to the tumor site, thereby mitigating this limitation. CED has been used in several preclinical and clinical studies, though an approved treatment is yet to come to fruition. A medical device suitable for repeated intraparenchymal delivery is valuable for brain tumor treatment strategies, but a lack of appropriate preclinical models capable of infusing clinically relevant volumes has hindered progress in clinical translation. Currently utilized preclinical models include porcine, which have limited use due to their growth rates and canine and non-human primates, which are restricted by ethical considerations. This study investigates the functional characteristics and stability of the Renishaw clinical Neuroinfuse™ drug delivery system in an ovine model.

METHODS
A head fixation frame was refined for ovine stereotactic surgery. Eight Romney ewes were implanted with the drug delivery system, comprising of four catheters and a transcutaneous port allowing chronic re-access infusions without repeated surgery. A maximum of four infusions were performed per subject, at four to eight-week intervals.

RESULTS
The implantation of the Neuroinfuse™ drug delivery system was well-tolerated in all subjects, without serious device related adverse events. Artificial CSF/gadolinium infusions were performed on five subjects. Three subjects were maintained for a follow-up study. Putaminal and thalamic distribution volumes remained stable over the re-access period of up to six months post-implantation.

CONCLUSION
Romney ewes are suitable for the stereotactic implantation of the Neuroinfuse™ chronic drug delivery system. Transcutaneous ports remained integrated for the study duration, allowing repeated intraparenchymal delivery. This novel preclinical model provides a stable platform for infusion regime optimization of drug-device combinations for chronic CED, which will undoubtably de-risk clinical translation in the neuro-oncology CED field.
SCIDOT-39. K16ApoE ENHANCES Aβ-ASSOCIATED 11C-PiB DEPOSITION AND PET SIGNAL IN APP/PS1 TRANSGENIC MICE
Authors: Brown Desmond , Sarkar Gobinda , Decklever Teresa , Curran Geoffry , Sarkar Ameet , Schmeichel Ann , Swaminathan Suresh , Kandimala Karunya , Jenkins Robert , Burns Terry , Lowe Val 
Published: November 2019

Abstract

OBJECTIVE
The K16ApoE peptide enhances delivery of multiple agents across the blood-brain barrier (BBB). Transgenic mouse models are central to elucidating the underlying pathophysiology of Alzheimer’s Disease (AD) and provide a system for evaluating novel therapeutic strategies. PET imaging plays a central clinical role in diagnosing human cases of AD but has had variable performance in mouse models. We investigated the role of K16ApoE to enhance delivery of a radiolabeled PET imaging tracer, 11C-PiB and assess whether this corresponds to improved PET sensitivity in APP/PS1 transgenic mice.

METHODS
Brain-delivery of 11C-PiB was accomplished by successive injections of K16ApoE and 11C-PiB. Distribution of 11C-PiB to the brain and heart was quantified via dynamic PET/CT imaging and digital autoradiography.

RESULTS
K16ApoE increased the brain uptake of 11C-PiB in both wild-type (WT) and APP/PS1 mice. Administration of K16ApoE increased the PET standard uptake value of 11C-PiB at 5 minutes in WT mice from 1.132 to 2.963 (p=0.006) and in APP/PS1 mice from 0.842 to 3.268 (p=0.016). Enhancement peaked at 5 minutes. Binding was reversible with similarly increased kinetics in both WT and APP/PS1 mice. The absolute values were higher in APP/PS1 mice suggesting increased retention. The increased retention in APP/PS1 mice was consistent with specific binding to A-beta plaques as unlabeled PiB reduced 11C-PiB signal retention.

CONCLUSION
K16ApoE mediates enhancement of 11C-PiB signal in APP/PS1 mice brains with increased PET sensitivity. There is increased uptake kinetics in both WT and APP/PS1 mice with specific A-beta plaque binding in the latter. This enhanced delivery of the PET tracer has implications for development and testing of new hypotheses and the efficacy of novel therapeutic paradigms. K16ApoE has potential for improving delivery of several agents across the BBB. This has implication for delivery of diagnostic and therapeutic agents for neurodegenerative and neuro-oncologic diseases.
CSIG-13. PROTEIN KINASE CI DRIVES BOTH TUMOR INVASION AND PROLIFERATION AND IS A COMPELLING TARGET FOR THE TREATMENT OF GLIOBLASTOMA
Authors: Kenchappa Rajappa , Luu Amanda , West Rita , Mladek Ann , Sarkaria Jann , Liu Yi , Murray Nicole , Fields Alan , Rosenfeld Steven 
Published: November 2019

Abstract
In glioblastoma (GBM), invasion and proliferation are reciprocally related—e.g., targeting one stimulates the other. Thus, effective therapy for GBM requires finding targets that drive both invasion and proliferation and which are druggable, ideally with FDA approved therapeutics. We find that the atypical protein kinase C isoform, PKCi meets these criteria. Using a human GBM tissue microarray, we find that PKCi protein expression fits a bimodal distribution, with >35% of GBMs showing high levels of PKCi expression. Genetic deletion of Prkci, the gene encoding mouse PKCi, impairs tumor invasion and proliferation both in vitro and in vivo, and significantly prolongs survival in an immunocompetent PDGF-driven orthotopic mouse model of GBM. PKCi can be selectively targeted with Auranofin, a small molecule PKCi inhibitor that has been FDA approved for treatment of inflammatory diseases. Like genetic deletion of Prkci Auranofin treatment significantly prolongs survival in our murine GBM model, and does so to a similar degree. Interestingly, analysis of a panel of human and murine GBM cells reveals that sensitivity to Auranofin inhibition of transformed growth directly correlates with expression of PKCi, indicating that PKCi expression profiling could serve as a predictive biomarker for responsiveness to Auranofin. However, genetically deleting or pharmacologically inactivating PKCi does not permanently arrest tumor growth, implying that GBM cells acquire mechanisms that allow them to compensate for the loss of this important signaling molecule. We are currently examining potential “escape” mechanisms through ‘omics-based approaches, which may enable us to enhance the therapeutic potential of Auranofin. Taken together, our results demonstrate that PKCi is a compelling therapeutic target for treatment of GBM that deserves further investigation.
RARE-51. RITUXIMAB, METHOTREXATE, BCNU, ETOPOSIDE, AND PREDNISONE (RMBVP) FOR THE TREATMENT OF RELAPSED/RECURRENT PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA: A RETROSPECTIVE SINGLE CENTER STUDY
Authors: Reiss Samantha , Yerram Prakirthi , Modelevsky Lisa , Grommes Christian 
Published: November 2019

Abstract

BACKGROUND
Primary Central Nervous System Lymphoma (PCNSL) is an aggressive rare non-Hodgkin lymphoma. Prognosis is particularly poor for relapsed/recurrent (R/R) patients with no established treatment modality. Methotrexate/BCNU/Teniposide/Prednisone with or without rituximab has efficacy in newly diagnosed PCNSL. Here, we report efficacy and toxicity of RMBVP for the treatment of R/R PCNSL.

METHODS
This retrospective study at MSKCC included PCNSLs treated with MBVP for R/R disease between 5/2009 and 5/2019. Methotrexate (3.5 g/m2; day 1 and 15), etoposide (100 mg/m2; day 2), BCNU (100 mg/m2; day 3), prednisone (60 mg/m2/day; day 1–5) and rituximab (500 mg/m2; day 0 and 14) were given in 28-day cycles. Granulocyte colony-stimulating factor support was given for 5 days in between doses of chemotherapy.

RESULTS
Thirty patients received MBVP; 27 (90%) received RMBVP with a median of 2 cycles given (0.5–5). Median age was 66 years (23–81); median KPS was 70 (30–90); 14 (46.7%) were women. Median prior lines of therapy were 2 (1–5); all received prior methotrexate. Median time from last treatment was 1 month (0–88.3; 21 (70%) < 12 months). Of twenty-nine evaluable patients for response, 23 (76.7%) had a response (9 complete response (CR) (30%), 5 CR-unconfirmed (16.7%), 8 partial response (26.7%), 1 stable disease (3%)). At a median follow up of 14.2 months, median progression free survival (PFS) was 15.6 months and median overall survival was not reached. Median PFS was poorer for patients with < 12 months since last chemotherapy, 10.1 vs 60.6 months. Rates of serious (grade 3 or 4) neutropenia, anemia, thrombocytopenia and transaminitis were 20%, 20%, 16.7%, and 16.7%, respectively. One patient experienced grade 3 nephrotoxicity. No treatment related mortalities occurred.

CONCLUSIONS
RMBVP is a tolerable treatment option for R/R PCNSL, particularly in those with recurrent disease.
CBMT-13. 3DEP SYSTEM TO TEST THE ELECTRICAL PROPERTIES OF DIFFERENT CELL LINES AS PREDICTIVE MARKERS OF OPTIMAL TUMOR TREATING FIELDS (TTFIELDS) FREQUENCY AND SENSITIVITY
Authors: Giladi Moshe , Zeevi Einav , Gotlib Karnit , Wenger Cornelia , Naveh Ariel , Bomzon Ze’ev , Kirson Eilon , Weinberg Uri , Kinzel Adrian , Palti Yoram 
Published: November 2019

Abstract

BACKGROUND
Tumor Treating Fields (TTFields; approved anti-neoplastic treatment modality) are delivered via application of low intensity, intermediate frequency, alternating electrical fields. The electrical properties of cells (eg, permittivity and conductivity) determine the optimal TTFields frequency that would elicit the greatest cell count reduction. Currently, no predictive markers exist to determine TTFields response and optimal frequency for individual patient application. The study goal was to evaluate the correlation between electrical properties of cells and TTFields’s optimal frequency and sensitivity. The 3DEPTM reader (LabTech) determines cellular electrical properties, including permittivity and conductivity, by using dielectrophoresis (DEP) force. DEP is a physical effect that generates a force on polarizable particles, such as cells, subjected to non-uniform electric fields.

METHODS
Utilizing the 3DEP reader, baseline electrical properties (permittivity and conductivity) of 17 cell lines from different tumor-types were determined. Curves were analyzed using 2-way ANOVA. The optimal TTFields frequency of each cell line was determined by evaluating TTFields cytotoxicity at various frequencies using the inovitroTM system. Electrical properties of each cell line were compared with the optimal TTFields frequency and sensitivity.

RESULTS
Significant differences (P< 0.001) were demonstrated between the lower frequency range of the 3DEP curves that correspond to cellular membrane capacitance at TTFields optimal frequencies of 150 kHz (9 cell lines) and 200 kHz (8 cell lines). Also, membrane capacitance was a good predictor of TTFields sensitivity based on curve differences within the low-frequency range.

CONCLUSIONS
These results demonstrate that cell membrane capacitance correlates with TTFields optimal frequency and sensitivity. Based on these data, there is a strong rational to further explore the potential of measuring the electrical properties of cells as predictive markers to help determine the optimal TTFields frequency for individual patient application and to identify ideal treatment-responders to TTFields.
CBMT-16. EGFRvIII EXPRESSION CONFERS CHEMOSENSITIVITY BY INCREASING DNA MISMATCH REPAIR PROTEIN EXPRESSION AND REPLICATION STRESS
Authors: Struve Nina , Binder Zev A , Stead Lucy F , Brend Tim , Bagley Stephen J , Faulkner Claire , Ott Leonie , Müller-Goebel Justus , Weik Anna-Sophie , Hoffer Konstantin , Rieckmann Thorsten , Christin Parplys Ann , Burmester Jasmin , Henze Marvin , Morrissette Jennifer J D , Schüller Ulrich , Petersen Cordula , Rothkamm Kai , Kurian Kathreena M , Short Susan C , Kriegs Malte 
Published: November 2019

Abstract
MGMT promoter methylation is the only accepted biomarker with prognostic role in GBM but its routine implementation is limited partly response to TMZ is heterogeneous, but also due to lack of effective alternative treatment options. Therefore, additional biomarkers are needed to enable better prediction of survival and to improve individualized treatment of GBM patients. A potential new biomarker is the epidermal growth factor receptor variant III (EGFRvIII). This constitutively activated deletion variant is present in approximately one third of all IDH wildtype GBM, but its relevance to treatment response is poorly understood. The aim of the present study was to analyze the impact of endogenous EGFRvIII expression on chemosensitivity and the mechanisms underlying any differential treatment response. EGFRvIII expression was associated with prolonged median overall survival but only for GBM patients with MGMT promoter methylated tumors. In line with this, we observed increased TMZ sensitivity of EGFRvIII+ and MGMT promoter methylated cells, which translated into improved survival in xenograft experiments. The increased TMZ sensitivity was associated with an elevated DNA damage induction accompanied by an increased expression of DNA mismatch repair (MMR) proteins in EGFRvIII+ cell lines and EGFRvIII+ GBM patient samples. Subsequently, only a moderate reduction in MMR protein expression resulted in a dramatic TMZ resistance, suggesting that EGFRvIII expression specifically sensitized MGMT deficient cells to TMZ treatment by upregulating MMR. Furthermore, EGFRvIII expression in GBM cell lines was accompanied by increased DNA damage, replication fork slowing, stalling and enhanced origin firing, implying replication stress. Targeting of EGFRvIII-dependent replication stress by irinotecan led to hypersensitivity of EGFRvIII+ cells. Taken together this study illustrates that EGFRvIII-induced upregulation of MMR and replication stress increases chemosensitivity thereby highlighting the vulnerability of EGFRvIII+ GBM to available treatments. These important data may also guide the development of new and more effective personalized strategies.
CBMT-22. REVERSING THE WARBURG EFFECT BY TARGETING NICOTINAMIDE PHOSPHORIBOSYLTRANSFERASE (NAMPT), THE RATE-LIMITING ENZYME OF NAD+ SALVAGE PATHWAY INCREASES, CHEMOSENSITIVITY TO TEMOZOLOMIDE IN GLIOMA CELLS
Authors: Sharma Pratibha , Senapedis William , Sampath Deepa , Puduvalli Vinay 
Published: November 2019

Abstract

BACKGROUND
Glioma cells metabolize glucose primarily through incomplete, non-oxidative glycolysis even in the presence of oxygen (the Warburg effect) which provides a constant supply of substrate for proliferation and generates an acidic environment that favors invasion and immunosuppression. NAMPT, the rate-limiting enzyme of the NAD+ salvage pathway, regulates key metabolic processes preferentially used in glioma energy metabolism. Inhibition of NAMPT could have global impact on glioma cell metabolism and could be a promising strategy for glioma therapy. This study examined the effect of NAMPT inhibition using KPT-9274 and FK866 (NAMPTi) on glycolysis and glioma cell metabolism.

METHODS
Metabolic changes related to NAMPT inhibition were examined in glioma cell lines and patient derived glioma stem-like cells (GSC). Mass spectrometry was used for metabolic profiles and the generated data was annotated by comparison against an extensive metabolite library to identify relevant metabolites. The Agilent Seahorse assay was utilized to determine treatment-related changes in glycolysis.

RESULTS
NAMPT inhibition caused NAD, NADH, NADP, NADPH, and ATP depletion in glioma cells. Global metabolomics results showed an accumulation of GMP, IMP, AMP and myo-inositol indicating reprogramming of glioma cell metabolism for de novo purine biosynthesis. Additionally, an accumulation of glucose- and fructose-1,6 bisphosphate in NAMPTi treated cells indicated dysfunctional glycolysis. This was confirmed by the Agilent glycolysis stress test by which NAMPTi-treated glioma cells showed a reduction in glycolysis, glycolytic capacity and reserves. NAMPTi treated cells showed downregulation of LDHA due to NAD depletion. Further, downregulation of LDHA enhanced the chemosensitivity of glioma cells to temozolomide.

CONCLUSIONS
NAMPTi cause profound disruption of glycolysis, reduced glycolytic capacity and glycolytic reserve in gliomas and GSCs irrespective of O[6]-methylguanine-DNA methyltransferase promoter methylation or IDH1 status. Targeting NAMPT to disrupt the Warburg effect is a novel strategy for developing effective therapies against glioma to overcome heterogeneity.
CBMT-23. NON-CANONICAL FUNCTIONS OF TERT IN GLIOBLASTOMA
Authors: Ferdosi Shayesteh , Taylor Brett , Bollam Saumya , Gokhale Vijay , Hurley Laurence , Dhruv Harshil , Berens Michael 
Published: November 2019

Abstract
Telomerase is an enzyme with a catalytic subunit, telomerase reverse transcriptase (TERT), that is in charge of telomere elongation in the nucleus. Promotor region of TERT is commonly mutated across cancers, especially in glioblastoma (GBM) with over 80% frequency. In the absence of any effective molecular targeting therapy for GBM, elucidating oncogenic signaling of TERT could open new avenues in GBM treatment. Canonically, mutations of TERT, which result in TERT upregulation, maintain telomere length in the nucleus and promote indefinite proliferation of cancer cells. However, a non-canonical function of TERT in the mitochondria has recently been suggested. We screened GBM cell models against a novel small molecule inhibitor (RG1534, Reglagene Inc.) that interferes with the functionality of a mutated hTERT promoter. RG1534 selectively suppresses glioma cell viability without affecting non-transformed normal human astrocytes. More interestingly, RG1534 treatment leads to rapid apoptosis induction in glioma cell lines that does not correlate with the time course of the telomere shortening effect. We further validated this rapid apoptosis behavior in glioma cell lines using siRNA and CRISPR/Cas-9 mediated hTERT knockdown. We also measured the protein expression of TERT in subcellular fractions of glioma cell lines and demonstrated the presence of higher TERT expression in mitochondrial extract compared to the nucleus. Finally, using MitoSOX dye we assessed ROS generation in glioma cells in response to an oxidant with or without TERT expresssion. In summary, our results demonstrate that non-canonical functions of TERT may play critical role in glioma pathobiology and require more detail investigation.
CBMT-30. TARGETING NICOTINAMIDE ADENINE DINUCLEOTIDE BIOSYNTHESIS IN CNS TUMORS
Authors: Lindsay Ken , Brenner Charles , Hockenbery David , Paddison Patrick 
Published: November 2019

Abstract
Nicotinamide adenine dinucleotide (NAD) metabolic pathways have been shown to be critical targets in many cancers, including brain tumors. However, inhibiting nicotinamide metabolism has had limited efficacy in the clinic to date due to on-target side effects. To identify new metabolic vulnerabilities in human Glioblastoma, we performed a chemical library screen using 250 inhibitors of metabolic enzymes in Glioblastoma stem-like cells (GSCs) (0131 and 0827) and control hNPC-CB660 cells. Among the screen hits, we identified FK866, an inhibitor of the NAD salvage enzyme NAMPT, as having GSC-selective cytotoxicity. Taking an advantage of an alternative NAD precursor salvage pathway, we show that cytotoxicity with inhibitors of the NAMPT salvage enzyme for neural stem cells was abrogated by media addition of nicotinamide riboside (NR), while certain glioblastoma stem-like cells (GSCs) remained exquisitely sensitive. Examining our GSC isolates, we observed that hypersensitivity correlated with low/absent expression of NMRK1, a kinase required for utilization of NR. We find that 5–20% of most tumor types (CNS, non-CNS) exhibit comparably low NMRK1 mRNA expression. In looking for associations with oncogenic drivers, we noted significant negative correlation with MYCN and MYC expression for multiple tumors. We have additional data suggesting that MYC/MYCN induces the NMRK1low state via transcriptional repression. These results suggest that NAMPT inhibitors, already in clinical trials, can be administered with NR to widen the therapeutic index for NMRK1low tumors. This combined theranostic approach could protect NMRK1-proficient normal cells without compromising treatment efficacy in NMRK1low tumor cells.
CBMT-33. VISUALIZING THE METABOLISM OF GLIOBLASTOMA PATIENT-DERIVED ORTHOTOPIC XENOGRAFTS BY MASS SPECTROMETRY IMAGING
Authors: Upendra Rao Jyotsna , Gibson Katherine , Hamm Gregory , Wright Alan , Fala Maria , Mair Richard , Tsyben Anastasia , Goodwin Richard , Brindle Kevin 
Published: November 2019

Abstract
INTRODUCTION. Glioblastoma multiforme (GBM) has a dismal prognosis, which has been attributed to extensive inter- and intra-tumoural heterogeneity. To investigate the metabolic heterogeneity of GBM, we employed desorption electrospray ionization (DESI) imaging on snap frozen samples of GBM patient-derived orthotopic xenografts (PDOX) in rat brains, following infusion of [U-13C]glucose. METHODS. Athymic nude rats (n=3) were infused with [U-13C]glucose (0.4 mg/g body weight bolus, 0.012 mg/g/min at 300 µL/h infusion [1]) for 40, 80 and 120 min, followed by cardiac puncture to measure blood [U-13C]glucose levels using 13C NMR spectroscopy. A second set of rats (n=2) were implanted intracranially with patient-derived GBM cells. The presence of tumour was confirmed by T2-weighted MRI. One animal was infused with [U-13C]glucose for 2 h, while another with [12C]glucose. The brains were snap frozen in liquid nitrogen followed by analysis with DESI imaging in negative ion mode (35 µm resolution). RESULTS. After a 2 h infusion, 43% of the circulating glucose was 13C labelled. Unsupervised spatial clustering of the MSI data resulted in segmentation of normal brain from tumour. Levels of [12C and 13C]glucose were high in the peri-tumoural region and low within the tumour. [12C and 13C]lactate showed the opposite distribution, indicating that the rate of glucose utilization within the tumour exceeded the rate of delivery. The peri-necrotic and peri-tumoural areas had higher levels of glutamate compared to the rest of the tumour. CONCLUSIONS. The results demonstrate that the PDOX is metabolically heterogeneous and differs from surrounding brain. While the tumour was predominately glycolytic, the presence of glutamate in peri-necrotic and peri-tumoral regions indicates the presence of increased TCA cycle activity. Comparison of MSI data with histological staining of brain sections should yield additional information about the relationship between the tumour and its microenvironment.