tbuckley/cabot-search huggingface dataset:
MBRS-56. SYSTEMATIC DRUG REPURPOSING IDENTIFIES DIGOXIN AS A DRUG THAT PROLONGS SURVIVAL IN PDOX MODELS OF GROUPS 3 AND 4 MEDULLOBLASTOMA AT CLINICALLY RELEVANT DOSES
Authors: Sarah Injac, Lei Huang, Hong Zhao, Qi Lin, Mari Kogiso, Chris Man, Xiao-nan Li, Stephen Wong, Ching Lau
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. While current 5-year EFS is >75 %, recurrent MB continues to have dismal outcomes and survivors face significant treatment-related sequelae. Drug repositioning is a promising strategy which allows for accelerated translation into the clinical setting. To apply this approach to Groups 3 and 4 medulloblastoma, we used a novel algorithm to identify driver signaling pathways by integrating mRNA expression, DNA-copy number, DNA-methylation and DNA-seq profiles from >1,800 patients. By combining these driver pathways with the targeted effects of 1,309 drugs from connectivity map database, we identified the cardiac glycoside family of compounds as potential inhibitors of tumor growth. These findings were first validated in MB-derived cell lines which showed high rates of growth inhibition. Patient-derived orthotopic-xenograft (PDOX) models of Group 3 (ICb-2555MB) and 4 MB (ICb-1078MB) were then treated with digoxin (2 mg/kg i.p.) for 2 cycles of 14 days. Digoxin treatment significantly prolonged survival in both models compared to untreated controls (p=0.001; p=0.031). Studies using the Group 3 model further demonstrated that the observed survival benefit is synergistic with radiation. Furthermore, the average digoxin trough levels in treated mice (2.4 ng/mL +/- 0.4) were similar to target levels in patients taking digoxin, suggesting the potential for rapid translation of these findings into a clinical setting. Finally, digoxin-mediated cell killing occurs in vivo via apoptosis and does not require loss of HIF-1 alpha protein.
Abstract 14717: Zika Myocarditis, Risk Factors, Prior Arbovirus Infection Brings Out the Worst
Authors: Karina A Gonzalez Carta, Ivan J Mendoza Britto, Enrique J Alvirez-Gonzalez, Igor Morr, Yolimar Meza, Vicente Finizola, Coromoto Gomez, Francesca Misticchio, Nahir Martinez, Thomas Allison, Carmen Terzic, Juan Marques, Ivan J Mendoza Mujica
Journal: Circulation (2017)

Introduction:  Zika infection (ZIKV) is considered the worst epidemic of this century. Research on the relationship between ZIKV and myocarditis is lacking. Experimental animals infused with Dengue virus became more susceptible to disease and death from ZIKV.   Objectives:  This study sought to describe the risk factor that predisposes to ZIKAV Myocarditis.   Methods:  We enrolled 12 cases of Zika with new Myocarditis in a prospective observational multicenter study. Clinical and laboratory evaluation including Zika confirmation and other virus or parasitic infection, ECG, Echocardiogram, Holter, coronary arteriography (2) and cardiac MRI were performed.   Results:  Of the 12 patients 8 (75%) were females with a mean age of 51±17 years. New arrhythmias were detected in 11 patients including new onset atrial fibrillation in 4 cases, atrial tachycardia in 2 patients and new left bundle branch block in 1 case. New Heart Failure (HF) was present in 6 cases, 5 presented with low ejection fraction (EF) and 1 with preserved EF, preeclampsia and moderate to severe pericardial effusion. Five are hypertensive, 8 (75%) with history of Dengue infection (Dengue Ig G (+) and Ig M (-)) and one with past history of Chikungunya.   Conclusions:  The importance of awareness, Zika Myocarditis is more than a possibility. Prior Dengue infection and comorbidities enhance ZIKV infection and may increase the risk of developing myocarditis. Further studies are needed to define the incidence of cardiac involvement in Zika.
LGG-59. REMARKABLE OBJECTIVE RESPONSE AND FAVORABLE SURVIVAL FOR BRAF-V600E CHILDHOOD LOW-GRADE GLIOMAS TO BRAF INHIBITORS COMPARED CONVENTIONAL CHEMOTHERAPY
Authors: Michal Zapotocky, Scott Ryall, Kohei Fukuoka, Ana Guerreiro Stucklin, Julie Bennett, David Sumerauer, Zdenek Pavelka, Ofelia Cruz, Palma Solano, Maria Luisa Garre, Peter Hauser, Didier Frappaz, Jordan Hansford, Nisreen Amayiri, Helena Morse, Magnus Sabel, Anne Grete Bechensteen, Jack Su, Matthias Karajannis, Jonathan Finlay, David Eisenstat, Adela Canete, Helen Toledano, Sonika Dahiya, Sarah Leary, Theodore Nicolaides, Elisabeth Finch, Sabine Mueller, Jean Mulcahy Levy, David Ellison, Alvaro Lassaletta, Valerie Larouche, Vijay Ramaswamy, Peter Dirks, Tara McKeown, Ute Bartels, Eric Bouffet, Cynthia Hawkins, Uri Tabori
Journal: Neuro-Oncology (2018)

Activation of the MAPK pathway represents a hallmark of pediatric low-grade glioma (pLGG) and is frequently caused by BRAF alterations. BRAF-V600E represent an aggressive type of pLGG with less than optimal response to conventional chemo-radiation approaches. While clinical trials using BRAF-V600E inhibitors are ongoing, these data are not yet available. We have assembled an international cohort of BRAF-V600E glioma patients treated off-label with BRAF inhibitors as a monotherapy. Complete molecular, clinical and imaging data is being collected and compared to previous chemo-radiation therapies. Ongoing data form the taskforce on 40 BRAF-V600E gliomas from 25 international institutions is summarized below. The most prevalent histologies were ganglioglioma, pilocytic astrocytoma and pleomorphic xanthoastrocytoma, located mainly in the chiasm, brainstem and temporal lobes. Strikingly, 66% of BRAF V600E pLGG patients achieved partial response (PR) to targeted inhibitors versus only 6.6% response to conventional chemotherapy (p<0.001). Five patients progressed during treatment 0.5 to 2.1 years after the start of BRAF inhibitor therapy. Additionally, 3 pLGG progressed after discontinuation of therapy. Two-year progression-free survival was 84.2% (95%CI,69.3-100) versus 50% (95%CI,32.2-77.5) with targeted agents and chemotherapy, respectively (p=0.021). Interestingly, 6 patients with BRAF V600E positive high-grade glioma did not exhibit objective responses to BRAF inhibitor therapy and the majority suffered from early progression. Our data suggest BRAF inhibitors to be potent therapeutic agents in BRAF-V600E pLGG but not HGG. Future studies aimed at mechanism of resistance and differential response to targeted agents are required.
Distinguishing Mild, Moderate, and Severe Hidradenitis Suppurativa—Reply
Authors: Schapoor Hessam, Lisa Scholl, Michael Sand, Lutz Schmitz, Sarah Reitenbach, Falk G. Bechara
Journal: JAMA Dermatology (2018)

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DIPG-56. PRECLINICAL STUDIES OF DIANHYDROGALACTITOL (VAL-083) IN DIPG, AS SINGLE AGENT OR AS A COMBINATION WITH RADIATION OR AZD1775
Authors: Anne Steino, Jeffrey Bacha, Dennis Brown, Sabine Mueller
Journal: Neuro-Oncology (2018)

Despite decades of trials, the prognosis for diffuse intrinsic pontine gliomas (DIPG) remains dismal. DIPG is inoperable and standard treatment is radiation alone, as the addition of chemotherapeutic agents, such as temozolomide, have not improved survival. In addition to inherent chemoresistance, treatment of DIPG is impeded by an intact blood-brain barrier (BBB). VAL-083 is a structurally unique bi-functional DNA-targeting agent that readily crosses the BBB. VAL-083 forms interstrand DNA crosslinks at N7-guanine, resulting in DNA double-strand breaks (DSB), S/G2-phase cell-cycle arrest, and ultimately cancer cell death. We have previously demonstrated that VAL-083 is able to overcome temozolomide-resistance in vitro and in vivo, and that its cytotoxicity is independent of the DNA-repair enzyme O6-methylguanine DNA-methyltransferase (MGMT). MGMT is almost universally expressed in DIPG and its expression is strongly correlated with temozolomide-resistance. VAL-083’s distinct mechanism-of-action suggests the potential for combination with inhibitors of DNA DSB repair or S/G2 cell-cycle progression (e.g. Wee1 inhibitor AZD1775). Here, we investigated the effects of VAL-083 in combination with radiation, AZD1775 or irinotecan (topoisomerase inhibitor) in three DIPG cell-lines: SF10693 (H3.1), SF8628 (H3.3) and NEM157 (H3.3). VAL-083 showed activity at low uM-concentration in all three cell-lines. In addition, VAL-083 showed synergy with AZD1775 in all three cell-lines. Combined with its ability to cross the BBB, accumulate in brain tumor tissue and overcome MGMT-related chemoresistance, these results suggest VAL-083 as a potentially attractive treatment option for DIPG as single agent or in combination with AZD1775. Combination studies with radiation are ongoing and will be presented at the meeting.
RADI-10. RADIOGENOMIC CORRELATION OF THE NEWLY PROPOSED MOLECULAR CHARACTERISATION OF GLIONEURONAL TUMOURS OF THE BRAIN
Authors: Kshitij Mankad, Ai Peng Tan, Wajanat Jan, Thomas J Stone, Thomas S Jacques
Journal: Neuro-Oncology (2018)

AIM: Stone et al. recently published the molecular characterisation of glioneuronal tumours, classifying them into 2 groups based upon methylation and expression profiles: Group 1 predominantly with BRAF and Group 2 predominantly with FGFR1 mutations. Our aim was to study differentiating neuroimaging features between these two groups on the same patient cohort to develop a neuroradiological assessment tool-kit. As the first step, an unblinded review of the presentation MRI scans was conducted by two Paediatric Neuroradiologists (KM and AP) to evaluate for discerning radiological features between the two groups. A tool-kit emerged following this consensus read. A third Paediatric Neuroradiologist (WJ) then blinded to the molecular subgrouping classified the cohort radiologically using this tool-kit to validate its accuracy. MR imaging on 31 patients was reviewed (15-group 1 and 16-group 2). The tool-kit showed the following distinguishing assessment categories: (1) Tumour margins: ill-defined in 100% group 1, well-circumscribed in 100% group 2 tumours; (2) FLAIR-rim: present in 0% group 1, 88% group 2; 3) Location: temporal lobe in 80% group 1, extra-temporal in 75% group 2; 4) Enhancement patterns- Hazy, ‘out-of-focus’ enhancement in 73% group 1 tumours, half of group 2 tumours showed enhancement and it was well-defined; 5) Extension to the ependymal margin: present in 69% group 2 tumours. When this tool-kit was employed by the third neuroradiologist blinded to the molecular diagnoses, 90% accuracy was achieved. We were able to develop a validated neuroradiological tool-kit to differentiate between the two major genetically-defined subgroups of glioneuronal tumours.
MBRS-59. MiR-1253, A CANDIDATE TUMOR SUPPRESSOR microRNA IN NON-SHH/WNT MEDULLOBLASTOMA
Authors: Ranjana Kanchan, Naveen Kumar Perumal, Wasim Naseer, Deborah Perry, Surinder Batra, Sidharth Mahapatra
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is the most common malignant pediatric tumor of the central nervous system (CNS) and a leading cause of childhood morbidity and mortality. Haploinsufficiency of 17p13.3 is reported in up to 50% of human MB cases. Included within this locus is miR-1253, which is exclusively expressed in the brain and an important regulator of bone morphogenic proteins that play a critical role in cerebellar development. Recently, two oncogenic targets of miR-1253, i.e. TGIF2 and ALX4, were identified in SHH medulloblastoma. Based upon these observations, we hypothesized that miR-1253 may be a putative tumor suppressor gene that undergoes epigenetic silencing in pediatric medulloblastoma. We first discovered reduced expression of miR-1253 in 24 clinical specimens and in 7 medulloblastoma cell lines. We then learned that miR-1253 silencing is accomplished via hypermethylation; expectedly, de-methylation of miR-1253 using 5-AzaC, resulted in recovery of expression with a subsequent decline in MB cell proliferation. MiR-1253 restoration was further concomitant with activation of apoptotic pathways and cell cycle arrest at G0/G1 phase. Moreover, miR-1253 overexpression led to a reduction in cell proliferation, colony formation, migration and invasive potential of MB tumor cell lines. Taken together, these data suggest that miR-1253 may possess tumor suppressor qualities, i.e. 1) loss of expression via epigenetic silencing and 2) negative trophic effects on tumor cell growth and migration. This would be the first time such an effect has been attributed to miR-1253 in the context of medulloblastoma.
QOL-53. METFORMIN RESULTS IN HIPPOCAMPAL REMODELING AND IMPROVED MEMORY ENCODING IN PAEDIATRIC BRAIN TUMOR SURVIVORS TREATED WITH CRANIAL RADIATION: A PILOT RANDOMIZED CONTROLLED CROSSOVER STUDY
Authors: Ramy Ayoub, Freda Miller, Kiran Beera, Cynthia de Medeiros, Suzanne Laughlin, Eric Bouffet, Donald Mabbott
Journal: Neuro-Oncology (2018)

Although curative, cranial radiation results in hippocampal insult and memory impairment in children with brain tumours. Metformin stimulates hippocampal neurogenesis and improves memory performance in mice. We conducted a pilot double-blind randomized controlled cross-over trial to examine feasibility and test the effects of metformin versus placebo on hippocampal volume and declarative memory in pediatric brain tumor survivors treated with either focal or whole brain radiotherapy. Twenty-four participants (Age = 13.96 ± 3.51) (M=14, F=7) were randomly assigned to complete consecutive 12-week cycles of Metformin (A) and Placebo (B) in either an AB or BA sequence: 10-week washout occurred at crossover. Assessment at baseline and immediately following treatment for each condition included: (a) structural MRI to obtain overall/subfield hippocampal volume and (b) testing of memory encoding/retrieval. Linear mixed modelling was used to test the effects of treatment condition and time on difference from baseline scores: an interaction term was used to test for carryover. Adherence was high and participants tolerated metformin. No change in overall hippocampal volume was observed bilaterally - but increased volume in the right subiculum and fimbria was evident for metformin vs. placebo (p’s < .05). Notably, decreased right CA3 volume was evident for metformin carryover – suggesting a remodeling of hippocampal structure. Treatment with metformin resulted in improved memory encoding immediately and at carryover (p’s < .05). Metformin may be effective for normalizing hippocampal structure and memory encoding in paediatric brain tumor survivors and warrants consideration in larger trials.
Andexanet Alfa: First Global Approval
Authors: Young-A Heo
Journal: Drugs (2018)

Intravenous andexanet alfa [coagulation factor Xa (recombinant), inactivated-zhzo; Andexxa®] is a first-in-class recombinant modified factor Xa protein that has been developed by Portola Pharmaceuticals as a universal antidote to reverse anticoagulant effects of direct or indirect factor Xa inhibitors. In May 2018, andexanet alfa received its first global approval in the USA for use in patients treated with rivaroxaban and apixaban, when reversal of anticoagulant effects is required in life-threatening or uncontrolled bleeding. Intravenous andexanet alfa is under regulatory review in the EU and is undergoing clinical development in Japan. This article summarizes the milestones in the development of andexanet alfa leading to this first global approval for reversing anticoagulation of rivaroxaban and apixaban in adults.
LGG-20. MOLECULARLY-DEFINED DIFFUSE LEPTOMENINGEAL GLIONEURONAL TUMOR (DLGNT) COMPRISES TWO SUBGROUPS WITH DISTINCT CLINICAL AND GENETIC FEATURES
Authors: Maximilian Y Deng, Felix Sahm, Martin Sill, Jason Chiang, David Capper, Till Milde, Martin Ebinger, Martin Schuhmann, Jens Schittenhelm, Camelia-Maria Monoranu, Andrey Korshunov, David Ellison, Andreas von Deimling, Stefan M Pfister, David Jones
Journal: Neuro-Oncology (2018)

Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent a rare CNS neoplasm included in the latest WHO classification update from 2016. The wide spectrum of histological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have provided insight into key genetic alterations in pediatric brain tumors. Through genome-wide DNA methylation screening of >25,000 tumors, we discovered a distinct class comprising 31 tumors, mostly diagnosed as DLGNTs. Copy number profiles derived from the methylation arrays revealed unifying characteristics, including loss of chromosomal arm 1p in 100% of cases. Furthermore, this molecular DLGNT class could be subdivided into two subgroups (DLGNT-pediatric and DLGNT-adult), with all DLGNT-adult additionally displaying gain of chromosomal arm 1q. Co-deletion of 1p/19q was frequently observed in both subgroups, especially in DLGNT-pediatric cases. Both subgroups also displayed recurrent genetic alterations leading to an aberrant MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most frequent event. Other alterations included fusions of NTRK1/2/3 and TRIM33:RAF1. Age at diagnosis was significantly lower (median 5 vs 14 years, p<0.005) and clinical course less aggressive, in the DLGNT-pediatric group (5-yr OS 100%, vs 50% in DLGNT-adult). Our study proposes an additional molecular layer to the current histopathological classification of DLGNT, of particular use for cases not displaying typical morphological or radiological characteristics. Recurrent 1p deletion and MAPK/ERK pathway activation represent diagnostic and therapeutic biomarkers, laying the foundation for future clinical trials with e.g. MEK inhibitors that may improve the clinical outcome of patients with DLGNT.
MBRS-53. ENHANCED EFFICACY OF NANO-FORMULATED VISMODEGIB SHOWS THE POTENTIAL FOR POLYOXAZOLINE MICELLES TO IMPROVE DRUG DELIVERY TO BRAIN TUMORS
Authors: Duhyeong Hwang, Yuling Zhao, Hedi Liu, Alexander Kabanov, Timothy Gershon, Marina Sokolsky
Journal: Neuro-Oncology (2018)

For the roughly 30% of medulloblastoma patients with SHH-subgroup tumors, drugs that disrupt SHH signaling offer the potential of improved efficacy with reduced toxicity compared to current, non-targeted treatment. The FDA-approved SMO inhibitor vismodegib, which targets SHH signaling at the cell membrane, has been shown to be safe and effective for the treatment of basal cell carcinoma. In SHH-subgroup medulloblastomas, however, initial responses to vismodegib, have been followed by resistance that develops during treatment. We hypothesized that improving the delivery of the drug across the blood-brain barrier would forestall the development of resistance. To test this hypothesis, we developed a novel, nanoparticle formulation of vismodegib, encapsulated in polyoxazoline micelles (POx-vismo). These nanoparticles showed high drug loading, and small, consistent particle size. We then compared the efficacy of POx-vismo to conventional vismodegib in mice genetically-engineered to develop medulloblastoma. We treated GFAP-cre/SmoM2 (G-Smo) mice with either POx-vismo or conventional vismodegib, administered by IP injection at postnatal days 12 and 13 and then every other day. Both formulations induced an initial response. However, POx-vismo-treated mice survived significantly longer than mice treated with conventional vismodegib. While no mice were cured by either formulation, our results show the superiority of POx-vismo and highlight the potential for polyoxazoline micelle drug delivery to increase the efficacy of approved and experimental agents for brain tumor therapy. The anti-tumor effect of vismodegib, optimized in POx-vismo is significant and may, in combination with additional treatments such as radiation, lead to new treatment approaches.
CRAN-13. FAMILIAL PEDIATRIC CLEAR CELL MENINGIOMA WITH GERMLINE SMARCE1 MUTATION
Authors: Pournima Navalkele, Miguel Guzman, Hailey Pintz, Amelia Kirby, Thomas Geller, Saleem Abdulrauf
Journal: Neuro-Oncology (2018)

Clear cell meningioma (CCM) is a rare low grade pediatric brain tumor with potential to metastasize and recur. We report a case of familial CCM with literature review. A 6-year-old girl presented with cognitive decline, sub-acute headaches and emotional lability. MRI brain showed an enhancing tumor infiltrating the pre-pontine area, extending into cerebellopontine angle along brainstem and middle cranial fossa. Neurosurgical resection confirmed meningioma grade II, clear cell variant. Tumor cytogenetics (SNP) revealed 2 chromosome aberrations, a 95 Mb gain on 13q12.11-q34 and a 62 Mb gain on 20p13-q13.33 and 3 areas of absence of heterozygosity on chromosomes 5 and 17, encompassing the TERT and NF1 genes (including region for SMARCE1 gene). 25-year-old mother had multiple intracranial clear cell meningioma. Neurofibromatosis (NF) type 1 was ruled out clinically. Germline testing excluded NF type 2 and SMARCB1. Germline SMARCE1 testing revealed a pathogenic variant (c.525delT) in both individuals. This is the first American case report of familial pediatric CCM. Familial CCM is more commonly associated with germline SMARCE1 tumor suppressor gene mutations than NF2 mutations. A UK case series has described familial CCM with germline SMARCE1 mutation with 14% incidence in solitary meningioma. Others have described familial meningioma concordance through SMARCE1 testing with screening guidelines for familial CCM and recommendation for SMARCE1 antibody testing for CCM diagnosis.