tbuckley/cabot-search huggingface dataset:
The development of mesenchymal stem cell therapy in the present, and the perspective of cell-free therapy in the future
Authors: Yusuke Watanabe, Atsunori Tsuchiya, Shuji Terai
Journal: Clinical and Molecular Hepatology (2020)

Cirrhosis is a chronic condition that can lead to liver failure. Currently, the viable option for decreasing mortality is liver transplantation. However, transplant surgery is highly invasive. Therefore, cell-based therapy has been developed as an alternative. Based on promising findings from preclinical research, some new trials have been registered. One of them was autologous bone marrow cell infusion therapy and found that ameliorating liver fibrosis activated liver regeneration. Now, majority of trials focus on low-immunogenicity mesenchymal stem cells (MSCs) appropriate for allogeneic administration. However, despite about 20 years of research, only a limited number of cell-based therapies have entered routine practice. Furthermore, potential shortcomings of cell-based therapy include a limit on the number of cells, which may be administered, as well as their failure to infiltrate target organs. On the other hand, these research show that MSCs act as "conducting cells" and regulate host cells including macrophages via extracellular vesicles (EVs) or exosome signals, leading to ameliorate liver fibrosis and promote regeneration. Therefore, the concept of cell-free therapy, which makes use of cell-derived EVs or exosomes, is attracting attention. Cell-free therapies may be safely administered in large doses and are able to infiltrate target organs. However, development of cell-free therapy exhibits its own set of challenges and such therapy may not be completely curative in the context of liver disease. This review describes the history of cell-based therapy research and recent advances in cell-free therapy, as well as discussing the need for more effective therapies.
EPEN-18. CROSS-SPECIES GENOMICS IDENTIFIES <i>GLI2</i> AS AN ONCOGENE OF <i>C11orf95</i> FUSION-POSITIVE SUPRATENTORIAL EPENDYMOMA
Authors: Tuyu Zheng, David R Ghasemi, Konstantin Okonechnikov, Andrey Korshunov, Martin Sill, Jens-Martin Hübner, Kendra K Maaß, Matija Snuderl, Johannes Gojo, Ulrich Schüller, Nicolas U Gerber, Pablo Hernáiz-Driever, Till Milde, Dominik Sturm, Rebecca Chapman, Richard G Grundy, Andreas von Deimling, David T W Jones, Marcel Kool, Stefan M Pfister, Felix Sahm, Daisuke Kawauchi, Kristian W Pajtler
Journal: Neuro-Oncology (2020)

Abstract The majority of supratentorial ependymomas (ST-EPN) are driven by fusions between RELA and a zinc finger containing gene, C11orf95. Apart from fusions to the Hippo effector YAP1, which affects a small group of infant patients, the oncogenic mechanism of remaining ST-EPNs is unclear. Aiming at refining the molecular classification of ST-EPNs, we analyzed methylation profiles, RNA and DNA sequencing results as well as clinical data in a cohort of 617 ST-EPNs. Unsupervised clustering analysis of DNA methylation data revealed four distinct clusters that formed in addition to the known molecular groups ST-EPN-RELA and –YAP1. Tumors within these additional clusters were characterized by fusions of C11orf95 to numerous fusion partners different from RELA, e.g. MAML2, MAML3, NCOA2 and SS18, suggesting a general role of C11orf95 in tumorigenesis of ST-EPN. Transforming capacity of newly identified fusion genes was validated using an electroporation-based in vivo gene transfer technology. All fusion genes were sufficient to drive malignant transformation in the cerebral cortex of mice and resulting tumors faithfully recapitulated molecular characteristics of their human counterparts. We found that both, the partner gene and the zinc finger DNA binding domain of C11orf95, were essential to exert tumorigenesis. When exploring genes commonly upregulated in C11orf95 fusion-expressing tumors of human and murine origin, the Sonic Hedgehog effector gene Gli2 was identified as a promising downstream target. Subsequent co-expression of C11orf95:RELA and a dominant negative form of Gli2 indeed hampered tumorigenesis. We thus propose GLI2 as a potential therapeutic downstream target of C11orf95 fusion-dependent oncogenic signaling in ST-EPN.
LGG-11. INSTITUTIONAL EXPERIENCE OF BRAF TARGETING THERAPY
Authors: Gino Bardi Lola, Mariko Sato
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The use of BRAF inhibitors is widely accepted in adult oncology as treatment for BRAF mutated cancers. BRAF alterations are frequently found in both pediatric low grade and high-grade gliomas, which has opened a new door to targeted therapies for pediatric gliomas. Targeted therapy drugs are associated with predictable patterns of adverse events. However treating in children may potentiate unique challenges. We present our institutional experience of targeted therapy with a focus on adverse events. METHODS We conducted a retrospective chart review of patients treated with BRAF and/or MEK inhibitors between 2015–2019. RESULTS There are nine patients treated with either MEK inhibitor(n=) or the combination therapy(n=). The most common diagnosis was Pilocytic astrocytoma. Targeted therapy was chosen as salvage therapy in all patients. The most common side effect was a pruritic erythematous rash, observed in 8 out of 9 patients. Cardiac toxicity (Grade 2, n=1) and GI toxicity (Grade 3, n=1) were found in patients treated with MEK inhibitor. Both cases resulted in cessation of therapy or significant decreased dose respectively. While two patients died due to progression of disease and two other continued to progress, 5 patients have demonstrated stable disease while on therapy. CONCLUSIONS Our study revealed the incidence of severe adverse events in two patients with BRAF targeted therapy. Due to the potential life-long use of targeted therapy, it is important to follow guidelines of adverse event monitoring and to develop a prevention and management strategy for severe adverse events.
GCT-21. CENTRAL NERVOUS SYSTEM GERMINOMA - PONDERING THE NEXT STEPS
Authors: Mohamed S AbdelBaki, Ute Bartels
Journal: Neuro-Oncology (2020)

Abstract Central nervous system germinoma (CNS) represents one successful example where the introduction of chemotherapy into the treatment allowed significant and meaningful reductions in the volume and dose of radiation therapy while maintaining excellent outcomes. However, the long-term toxicities and morbidities of the current therapies, in addition to their substantial negative impact on the social wellbeing of germinoma patients, should clearly indicate that the current achievements are not enough. While stepwise cutback of the radiation therapy needs to be commended, real progress must be achieved in the exploration and investigation of biological and molecular markers. Furthermore, the differences that still exist between the several working groups around the globe in determining the tumor marker cut-offs that help diagnose these tumors illustrate their shortcomings, and therefore the need for newer and more reliable methods. Additionally, efforts should focus on the inclusion of metastatic and basal ganglia/thalamic germinomas in future prospective clinical trials given the lack of evidence on the best treatment strategy for these patients. A comprehensive review of all major CNS germinoma clinical trials will be presented aiming to lay a foundation for researchers and clinicians alike who are currently working on designing innovative approaches for this group of patients. This review also details the current issues of debate, and provides suggestions which may assist in the design of future prospective clinical trials for children with CNS germinomas.
Gene dosage manipulation alleviates manifestations of hereditary <i>PAX6</i> haploinsufficiency in mice
Authors: Behnam Rabiee, Khandaker N. Anwar, Xiang Shen, Ilham Putra, Mingna Liu, Rebecca Jung, Neda Afsharkhamseh, Mark I. Rosenblatt, Gerald A. Fishman, Xiaorong Liu, Mahmood Ghassemi, Ali R. Djalilian
Journal: Science Translational Medicine (2020)

Pharmacological induction of wild-type PAX6 allele improved ocular abnormalities induced by PAX6 haploinsufficiency in mice.
EPID-27. THE VANISHING TUMOR PHENOMENON IN THE DIAGNOSIS OF PRIMARY CNS LYMPHOMA
Authors: Eunji Yim, Yoshie Umemura, Yilun Sun, Larry Junck
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Steroid is commonly initiated for newly recognized brain tumors. For primary CNS lymphoma (PCNSL), however, its lympholytic effect can partially treat the tumor and obfuscate the surgical-pathological diagnosis needed to initiate chemotherapy. Evidence for this remains controversial. In this study we investigated the incidence of the vanishing tumor phenomenon and its association with steroid use. METHODS Patients &amp;gt; age 18 with PCNSL were identified from January 1, 2000 to April 30, 2020 within the University of Michigan Health System. Clinic and operative notes, pathology, imaging, and lumbar puncture results were reviewed. Inclusion required histopathologic diagnosis from brain tissue, cerebrospinal fluid, or autopsy, including diagnosis on repeat biopsy. Patients with prior/concurrent systemic lymphoma, HIV, organ transplant, or diagnosis established from primary ocular disease were excluded. Date(s) of biopsy, steroid initiation, and recurrence (by imaging) were abstracted. We defined vanishing tumor as a lesion whose radiographic improvement or disappearance resulted in deferred or nondiagnostic biopsy, with later confirmation of PCNSL. Steroid use and vanishing tumor were modeled using univariable logistic regression. RESULTS We identified 162 cases of PCNSL, of which 103 patients (63.6%) received steroids prior to biopsy. Twenty-three had vanishing tumor: 11 with deferred biopsies, 12 with non-diagnostic biopsies. Twenty-two of the 23 received steroid. Mean cumulative dose, in dexamethasone equivalents, was 555 + 704 mg prior to nondiagnostic/deferred biopsy (N=17) compared to 186 + 376 mg prior to successful biopsy (N=76) (Wilcoxon p&amp;lt; .001). Median time to recurrence after deferred or non-diagnostic biopsy (N=21) was 53 days (range: 8–648); two cases never recurred. Steroid use increased the risk of vanishing tumor by 14% per 100 mg dexamethasone equivalent (95% CI of odds ratio [1.03–1.29], p=0.02). CONCLUSION Vanishing tumor phenomenon is common in PCNSL, delays diagnosis, and is driven by steroid use.
INNV-20. ELEVATED INTRACRANIAL PRESSURE WITHOUT HYDROCEPHALUS IN PATIENTS WITH NEUROFIBROMATOSIS 2
Authors: Lindsay Robell, Rebecca Harrison, Kaylyn Sinicrope, John Slopis, Ian McCutcheon
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Neurofibromatosis 2 is a tumor predisposition syndrome associated with multiple tumors of the central and peripheral nervous systems. Schwannomas and meningiomas are commonly observed. The occurrence of communicating hydrocephalus in this population has been observed clinically but not characterized in the literature. METHODS We present a retrospective case series of patients with NF2 and communicating hydrocephalus followed in the Neurofibromatosis clinic at MD Anderson Cancer Center. RESULTS We identified 11 patients in our Neurofibromatosis clinic with symptomatic elevation in intracranial pressure (ICP). All patients presented with worsening headaches, while six patients also presented with visual complaints leading to the diagnosis of elevated ICP. Dedicated venous imaging with either MRV or CTV was available for review in five patients. Occlusion or stenosis of the venous system (dural venous sinuses or internal jugular vein) was seen in nine patients. All patients had evidence of plaque-like meningiomas, and two patients had cervical schwannomas. Only one patient had radiographic evidence of obstructive hydrocephalus. All patients were treated for symptomatic elevated ICP with placement of a ventriculoperitoneal (VP) shunt. Three patients received acetazolamide prior to shunting, while one patient received acetazolamide after shunt placement. Seven (7/11) patients had documented improvement or resolution of headache after VP shunt placement. Two (2/6) patients had documented improvement or resolution of visual complaints. CONCLUSIONS We present 11 patients with NF2 who developed symptomatic elevation in ICP, ten patients without evidence of obstructive hydrocephalus and one with obstructive hydrocephalus. We hope to raise awareness of this clinical phenomena, previously uncharacterized in the literature. We propose a multifactorial mechanism involving plaque-like meningiomas, venous sinus stenosis, obstruction of cerebral venous outflow and cervical/jugular schwannomas in the development of symptomatic elevated ICP without evidence of obstructive hydrocephalus in patients with NF2.
TMOD-15. EFFICACY OF THE MDM2 INHIBITOR KRT-232 IN GLIOBLASTOMA PATIENT-DERIVED XENOGRAFT MODELS
Authors: Rachael Vaubel, Ann Mladek, Yu Zhao, Shiv K Gupta, Minjee Kim, Afroz S Mohammad, Katrina Bakken, Lihong He, Zeng Hu, Danielle M Burgenske, Brett L Carlson, William F Elmquist, Jann Sarkaria
Journal: Neuro-Oncology (2020)

Abstract Non-genotoxic reactivation of p53 by MDM2 inhibitors represents a promising therapeutic strategy for tumors with wild-type TP53, particularly tumors harboring MDM2 amplification. MDM2 controls p53 levels by targeting it for degradation, while disruption of the MDM2-p53 interaction causes rapid accumulation of p53 and activation of the p53 pathway. We examined the efficacy of the small molecule MDM2 inhibitor KRT-232, alone and in combination with radiation therapy (RT), in MDM2-amplified and/or p53 wildtype patient-derived xenograft (PDX) models of glioblastoma in vitro and in vivo. In vitro, glioblastoma PDX explant cultures showed sensitivity to KRT-232, both tumors with MDM2 amplification (GBM108 and G148) and non-amplified but TP53-wildtype lines (GBM10, GBM14, and GBM39), with IC50s ranging from 300-800 nM in FBS culture conditions. A TP53 p.F270C mutant PDX (GBM43) was inherently resistant, with IC50 &amp;gt;3000 nM. In the MDM2-amplified GBM108 line, KRT-232 led to a robust (5-6 fold) induction of p53-target genes p21, PUMA, and NOXA, with initiation of both apoptosis and senescence. Expression of p21 and PUMA was greater with KRT-232 in combination with RT (25-35 fold induction), while stable knock-down of p53 in GBM108 led to complete resistance to KRT-232. In contrast, GBM10 showed lower induction of p21 and PUMA (2-3 fold) and was more resistant to KRT-232. In an orthotopic GBM108 xenograft model, treatment with KRT-232 +/- RT for one week extended survival from 22 days (placebo) to 46 days (KRT-232 alone); combination KRT-232 + RT further extended survival (77 days) over RT alone (31 days). KRT-232 is an effective treatment in a subset of glioblastoma pre-clinical models alone and in combination with RT. Further studies are underway to understand the mechanisms conferring innate sensitivity or resistance to KRT-232.
BIOM-53. DIFFUSION MR IMAGING DERIVED APPARENT DIFFUSION COEFFICIENT AS A POTENTIAL BIOMARKER OF CLINICAL OUTCOME IN RECURRENT CENTRAL NERVOUS SYSTEM LYMPHOMA
Authors: Ka-wai Ho, Anton Nosov, Robert Young, Christian Grommes
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Studies have shown that diffusion-weighted imaging (DWI) derived apparent diffusion coefficient (ADC) measurements inversely correlate with tumor cell density and may have prognostic value in newly-diagnosed CNS lymphoma patients. This study characterizes ADC measurements in a relapsed/refractory CNS lymphoma population and describes the potential prognostic value of ADC measurements in these patients. METHODS ADC measurements were assessed in immunocompetent patients enrolled on a prospective clinical trial studying ibrutinib-based treatment in recurrent/refractory CNS lymphoma (NCT02315326; 42 treated with single agent ibrutinib and 15 with an ibrutinib containing combination). Measurements were normalized to values contralateral to the lesion to generate an ADC measurement ratio. Imaging and clinical variables were correlated with treatment response. High-quality lesions were defined as areas with clear delineation from preserved brain parenchyma ≥ 10mm in maximal transverse dimension. Cerebral spinal fluid (CSF) was collected at time of MR imaging in all patients. RESULTS Thirty-nine out of 57 patients had lesions with measurable ADC of which 17 (44%) were high-quality ADC lesions. The median ADCmean ratio was 0.909 (range 0.497–1.444). There was no association between ADC ratios and tumor volume, CSF cell count, or CSF protein. The high-quality lesions had a median ADCmean ratio of 0.774 (range 0.497–1.051). These patients with a high ADCmean ratio (≥ 0.774) had increased rates of partial and complete responses (p=0.057) as well as a longer progression free survival (PFS; median not reached) compared to those with low ADCmean ratios (&amp;lt; 0.774; median PFS=1.5 months, p=0.016). CONCLUSION ADC ratios in the recurrent CNS population do not correlate with tumor size, cell count, or protein in the CSF. In high-quality DWI measurements, ADC might be a prognostic marker in relapsed/refractory CNS lymphoma patients treated with ibrutinib.
Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study
Authors: Jacob P Laubach, Fredrik Schjesvold, Mário Mariz, Meletios A Dimopoulos, Ewa Lech-Maranda, Ivan Spicka, Vania T M Hungria, Tatiana Shelekhova, Andre Abdo, Lutz Jacobasch, Chantana Polprasert, Roman Hájek, Árpád Illés, Tomasz Wróbel, Anna Sureda, Meral Beksac, Iara Z Gonçalves, Joan Bladé, S Vincent Rajkumar, Ajai Chari, Sagar Lonial, Andrew Spencer, Pierre Maison-Blanche, Philippe Moreau, Jesus F San-Miguel, Paul G Richardson
Journal: The Lancet Oncology (2020)
Targeting phosphatidylinositol 3‐kinase gamma (PI3Kγ): Discovery and development of its selective inhibitors
Authors: Jingyu Zhu, Kan Li, Li Yu, Yun Chen, Yanfei Cai, Jian Jin, Tingjun Hou
Journal: Medicinal Research Reviews (2020)

Abstract Phosphatidylinositol 3‐kinase gamma (PI3Kγ) has been regarded as a promising drug target for the treatment of advanced solid tumors, leukemia, lymphoma, and inflammatory and autoimmune diseases. However, the high level of structural conservation among the members of the PI3K family and the diverse physiological roles of Class I PI3K isoforms (α, β, δ, and γ) highlight the importance of isoform selectivity in the development of PI3Kγ inhibitors. In this review, we provide an overview of the structural features of PI3Kγ that influence γ‐isoform selectivity and discuss the structure‐selectivity‐activity relationship of existing clinical PI3Kγ inhibitors. Additionally, we summarize the experimental and computational techniques utilized to identify PI3Kγ inhibitors. The insights gained so far could be used to overcome the main challenges in development and accelerate the discovery of PI3Kγ‐selective inhibitors.
DIPG-79. H3K27M INDUCES EPIGENETIC AND ONCOGENIC CHANGES THAT ARE PARTIALLY REVERSED BY SMALL MOLECULE AURORA KINASE B/C INHIBITION
Authors: Hannah Chatwin, Rakeb Lemma, John DeSisto, Aaron Knox, Shelby Mestnik, Aidan Reid, Rajeev Vibhakar, Sujatha Venkataraman, Adam Green
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor with no curative treatments. Approximately 80% of DIPGs contain an H3K27M mutation. The implications of the mutation and how they may be targeted are not fully understood. We established an H3K27M effect-isolating model by transducing H3K27-wildtype lines (HSJD-GBM-001, normal human astrocytes) with lentiviral-packaged H3K27M. We characterized H3K27M-related changes through western blot, phenotypic assays, and RNA-seq. Drug screening of H3K27-wildtype and matched H3K27M-transduced lines was used to identify targets more effective with H3K27M present. Patient-derived pediatric glioblastoma and DIPG lines (BT-245, SU-DIPG-IV, HSJD-DIPG-007, SU-DIPG-XIII*, SF7761) were used for validation. We observed increased H3K27ac and decreased H3K27me3, as well as increased proliferative and migratory abilities, with the addition of H3K27M to H3K27-wildtype lines. RNA-seq showed downregulation of cell cycle regulation and upregulation of epithelial-mesenchymal transition. GSK1070916, an Aurora kinase B/C inhibitor, was isolated from a synthetic lethality screen with H3K27M. GSK1070916 showed strong efficacy in native H3K27M lines (IC50s=60nM-1250nM), superior to the Aurora kinase A inhibitor alisertib, to which all cell lines showed substantial resistance. Combination of both drugs was not synergistic. GSK1070916 treatment caused increased H3K27me3 and decreased H3S10ph and H3S28ph. GSK1070916 induced apoptosis and S-phase stall. The H3K27M mutation induces epigenetic, phenotypic, and cell cycle regulation changes resulting in relaxation of transcriptional controls and more aggressive growth. Aurora kinase B/C inhibition is a novel therapeutic modality for DIPG that appears capable of reversing some H3K27M-related epigenetic changes, inducing apoptosis, and repressing uncontrolled cellular division.
DIPG-12. TARGETING EPIGENETIC MODIFIERS TO INDUCE IMMUNE SIGNALING IN DIPG
Authors: Ashley Tetens, Allison Martin, Antje Arnold, Orlandi Novak, Charles Eberhart, Andrew Feinberg, Eric Raabe, Michael Koldobskiy
Journal: Neuro-Oncology (2020)

Abstract DIPG is a universally fatal pediatric brainstem tumor with no effective therapy. Recent work has shown that over 80% of DIPG cases harbor the H3K27M mutation leading to global loss of the repressive H3K27 trimethylation mark, global DNA hypomethylation, and a distinct gene expression signature. We sought to exploit epigenetic vulnerabilities in DIPG through the use of DNA methyltransferase inhibitors and histone deacetylase (HDAC) inhibitors. We find that treatment with low-dose 5-aza-2’-deoxycytidine (decitabine), alone and in combination with HDAC inhibitors, elicits profound genome-wide demethylation in DIPG patient-derived neurosphere cell lines, impairs proliferation, and induces apoptosis. We show that this treatment induces immune activation, with induction of type I interferon signaling, increased expression of major histocompatibility complexes, and expression of tumor antigens. These results suggest that the immunogenicity of DIPG may be modulated by epigenetic therapies, suggesting the possibility of novel combination approaches to immunotherapy of DIPG in the future.
RETRACTED: ORIENT-3: A randomized, open-label, phase III study of sintilimab versus docetaxel in previously treated advanced/metastatic squamous non-small cell lung cancer (sqNSCLC)
Authors: Y. Shi, L. Wu, X. Yu, P. Xing, J. Zhou, A. Wang, J. Shi, Y. Hu, Z. Wang, G. An, Y. Fang, S. Sun, C. Zhou, C. Wang, F. Ye, X. Li, J. Wang, M. Wang, Y. Liu, Y. Zhao
Journal: Annals of Oncology (2020)