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Diffuse intrinsic pontine

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https://www.readbyqxmd.com/read/29662203/potent-antitumor-efficacy-of-anti-gd2-car-t-cells-in-h3-k27m-diffuse-midline-gliomas
#1
Christopher W Mount, Robbie G Majzner, Shree Sundaresh, Evan P Arnold, Meena Kadapakkam, Samuel Haile, Louai Labanieh, Esther Hulleman, Pamelyn J Woo, Skyler P Rietberg, Hannes Vogel, Michelle Monje, Crystal L Mackall
Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs) with mutated histone H3 K27M (H3-K27M)1-5 are aggressive and universally fatal pediatric brain cancers 6 . Chimeric antigen receptor (CAR)-expressing T cells have mediated impressive clinical activity in B cell malignancies7-10 , and recent results suggest benefit in central nervous system malignancies11-13 . Here, we report that patient-derived H3-K27M-mutant glioma cell cultures exhibit uniform, high expression of the disialoganglioside GD2...
April 16, 2018: Nature Medicine
https://www.readbyqxmd.com/read/29621254/il-13-receptors-as-possible-therapeutic-targets-in-diffuse-intrinsic-pontine-glioma
#2
Noah E Berlow, Matthew N Svalina, Michael J Quist, Teagan P Settelmeyer, Viktor Zherebitskiy, Mari Kogiso, Lin Qi, Yuchen Du, Cynthia E Hawkins, Esther Hulleman, Xiao-Nan Li, Sakir H Gultekin, Charles Keller
Diffuse intrinsic pontine glioma (DIPG) is a universally fatal childhood cancer of the brain. Despite the introduction of conventional chemotherapy and radiotherapy, improvements in survival have been marginal and long-term survivorship is uncommon. Thus, new targets for therapeutics are critically needed. Early phase clinical trials exploring molecularly-targeted therapies against the epidermal growth factor receptor (EGFR) and novel immunotherapies targeting interleukin receptor-13α2 (IL-13Rα2) have demonstrated activity in this disease...
2018: PloS One
https://www.readbyqxmd.com/read/29594041/dnx-2401-an-oncolytic-virus-for-the-treatment-of-newly-diagnosed-diffuse-intrinsic-pontine-gliomas-a-case-report
#3
Sonia Tejada, Ricardo Díez-Valle, Pablo D Domínguez, Ana Patiño-García, Marisol González-Huarriz, Juan Fueyo, Cande Gomez-Manzano, Miguel Angel Idoate, Joanna Peterkin, Marta M Alonso
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive glial brain tumors that primarily affect children, for which there is no curative treatment. Median overall survival is only one year. Currently, the scientific focus is on expanding the knowledge base of the molecular biology of DIPG, and identifying effective therapies. Oncolytic adenovirus DNX-2401 is a replication-competent, genetically modified virus capable of infecting and killing glioma cells, and stimulating an anti-tumor immune response. Clinical trials evaluating intratumoral DNX-2401 in adults with recurrent glioblastoma have demonstrated that the virus has a favorable safety profile and can prolong survival...
2018: Frontiers in Oncology
https://www.readbyqxmd.com/read/29551750/effects-of-fkbp12-and-type-ii-bmp-receptors-on-signal-transduction-by-alk2-activating-mutations-associated-with-genetic-disorders
#4
Aiko Machiya, Sho Tsukamoto, Satoshi Ohte, Mai Kuratani, Mai Fujimoto, Keigo Kumagai, Kenji Osawa, Naoto Suda, Alex N Bullock, Takenobu Katagiri
Various substitution mutations in ALK2, a transmembrane serine/threonine kinase receptor for bone morphogenetic proteins (BMPs), have been identified in patients with genetic disorders such as fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine glioma (DIPG) and heart defects. In this study, we characterized the ALK2 mutants R258G, G328V and F246Y, which were identified in patients with severe FOP, DIPG and unusual hereditary skeletal dysplasia, respectively. Both R258G and G328V were gain-of-function mutations, but F246Y was equivalent to wild-type ALK2...
March 15, 2018: Bone
https://www.readbyqxmd.com/read/29512900/phase-1-trial-pharmacokinetics-and-pharmacodynamics-of-dasatinib-combined-with-crizotinib-in-children-with-recurrent-or-progressive-high-grade-and-diffuse-intrinsic-pontine-glioma
#5
Alberto Broniscer, Sujuan Jia, Belinda Mandrell, Dima Hamideh, Jie Huang, Arzu Onar-Thomas, Amar Gajjar, Susana C Raimondi, Ruth G Tatevossian, Clinton F Stewart
BACKGROUND: Progressive/recurrent high-grade and diffuse intrinsic pontine gliomas (DIPGs) are fatal. Treatments targeting molecular pathways critical for these cancers are needed. METHODS: We conducted a phase 1 study (rolling-six design) to establish the safety and maximum tolerated dose (MTD) of dasatinib, an oral platelet-derived growth factor receptor A (PDGFRA) inhibitor, and crizotinib, an oral c-Met inhibitor, in such patients. Pharmacokinetics of both agents were performed...
March 7, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29484440/importance-of-immune-monitoring-approaches-and-the-use-of-immune-checkpoints-for-the-treatment-of-diffuse-intrinsic-pontine-glioma-from-bench-to-clinic-and-vice-versa-review
#6
Jorge Augusto Borin Scutti
On the basis of immunological results, it is not in doubt that the immune system is able to recognize and eliminate transformed cells. A plethora of studies have investigated the immune system of patients with cancer and how it is prone to immunosuppression, due in part to the decrease in lymphocyte proliferation and cytotoxic activity. The series of experiments published following the demonstration by Dr Allison's group of the potential effect of anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) paved the way for a new perception in cancer immunotherapy: Immune checkpoints...
February 23, 2018: International Journal of Oncology
https://www.readbyqxmd.com/read/29484131/dual-targeting-of-mitochondrial-function-and-mtor-pathway-as-a-therapeutic-strategy-for-diffuse-intrinsic-pontine-glioma
#7
Maria Tsoli, Jie Liu, Laura Franshaw, Han Shen, Cecilia Cheng, MoonSun Jung, Swapna Joshi, Anahid Ehteda, Aaminah Khan, Angel Montero-Carcabosso, Pierre J Dilda, Philip Hogg, David S Ziegler
Diffuse Intrinsic Pontine Gliomas (DIPG) are the most devastating of all pediatric brain tumors. They mostly affect young children and, as there are no effective treatments, almost all patients with DIPG will die of their tumor within 12 months of diagnosis. A key feature of this devastating tumor is its intrinsic resistance to all clinically available therapies. It has been shown that glioma development is associated with metabolic reprogramming, redox state disruption and resistance to apoptotic pathways...
January 26, 2018: Oncotarget
https://www.readbyqxmd.com/read/29456798/-18-f-radiolabeled-panobinostat-allows-for-positron-emission-tomography-guided-delivery-of-a-histone-deacetylase-inhibitor
#8
Harikrishna Kommidi, Umberto Tosi, Uday B Maachani, Hua Guo, Christopher S Marnell, Benedict Law, Mark M Souweidane, Richard Ting
Histone deacetylase (HDAC) inhibition is becoming an increasingly popular approach to treat cancer, as HDAC overexpression is common in many malignancies. The blood-brain barrier (BBB) prevents systemically delivered drugs from reaching brain at effective concentration, making small-molecule-HDAC inhibition in brain tumors particularly challenging. To circumvent the BBB, novel routes for administering therapeutics are being considered in the clinic, and a need exists for drugs whose deliveries can be directly imaged, so that effective delivery across the BBB can be monitored...
February 8, 2018: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29435175/rest-upregulates-gremlin-to-modulate-diffuse-intrinsic-pontine-glioma-vasculature
#9
Shavali Shaik, Bridget Kennis, Shinji Maegawa, Keri Schadler, Yang Yanwen, Keri Callegari, Rishi R Lulla, Stewart Goldman, Javad Nazarian, Veena Rajaram, Jason Fangusaro, Vidya Gopalakrishnan
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive glial tumor that occurs in children. The extremely poor median and 5-year survival in children afflicted with DIPG highlights the need for novel biology-driven therapeutics. Here, we have implicated the chromatin remodeler and regulator of brain development called RE1 Silencing Transcription Factor (REST), in DIPG pathology. We show that REST protein is aberrantly elevated in at least 21% of DIPG tumors compared to normal controls. Its knockdown in DIPG cell lines diminished cell growth and decreased their tumorigenicity in mouse intracranial models...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29397521/end-of-life-care-of-children-with-diffuse-intrinsic-pontine-glioma
#10
Fyeza Hasan, Kevin Weingarten, Adam Rapoport, Eric Bouffet, Ute Bartels
The end-of-life management of children with diffuse intrinsic pontine glioma (DIPG) is challenging. Families cope with debilitating symptoms and make complex decisions regarding their child's care. However, there is little evidence guiding palliative care provision for these children. Our objective was to describe the dying trajectory of children with DIPG, their symptoms, the care they require and the end-of-life decisions made for them. This retrospective cohort study analyzed the end-of-life care of 41 consecutive patients with DIPG who died between January 2001 and June 2010...
February 3, 2018: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29393845/h3-k27m-mutant-gliomas-in-adults-vs-children-share-similar-histological-features-and-adverse-prognosis
#11
Bette K Kleinschmidt-DeMasters, Jean M Mulcahy Levy
BACKGROUND: H3 K27M mutation was originally described in pediatric diffuse intrinsic pontine gliomas (DIPGs), but has been recently recognized to occur also in adult midline diffuse gliomas, as well as midline tumors with other morphologies, including gangliogliomas (GGs), anaplastic GGs, pilocytic astrocytomas (PAs), and posterior fossa ependymomas. In a few patients with H3 K27M-mutant tumors with these alternate morphologies, longer survival has been reported, making grading difficult for the neuropathologist...
February 2, 2018: Clinical Neuropathology
https://www.readbyqxmd.com/read/29393184/chemotherapy-of-intracranial-gliomas-in-children
#12
Keita Terashima
Under specific indications, chemotherapy may play an important role in the treatment of pediatric patients with intracranial gliomas. It can be effectively administered in inoperable low-grade tumors, particularly with the use of combination regimens based on carboplatin and vincristine. In very young children with high-grade gliomas (HGG), chemotherapy may result in control of tumor growth, which allows to postpone fractionated radiation therapy (FRT). At the same time, in difference with adults, there is no current evidence that addition of chemotherapy to aggressive surgical resection followed by FRT has any positive impact on survival of pediatric patients with non-pontine HGG...
2018: Progress in Neurological Surgery
https://www.readbyqxmd.com/read/29369515/reirradiation-in-patients-with-diffuse-intrinsic-pontine-gliomas-the-canadian-experience
#13
Alvaro Lassaletta, Douglas Strother, Normand Laperriere, Juliette Hukin, Magimairajan Issai Vanan, Karen Goddard, Lucie Lafay-Cousin, Donna L Johnston, Shayna Zelcer, Michal Zapotocky, Revathi Rajagopal, Vijay Ramaswamy, Cynthia Hawkins, Uri Tabori, Annie Huang, Ute Bartels, Eric Bouffet
OBJECTIVE: Clinical trials have failed to demonstrate a survival benefit of adjuvant chemotherapy in diffuse intrinsic pontine gliomas (DIPG). Radiation therapy (RT) is the only effective treatment thus far and reirradiation (rRT) has become an option at the time of progression. The aim of this study was to review the Canadian experience of DIPG rRT with a focus on the safety and possible efficacy of this approach. METHOD: We retrospectively reviewed the demographic, clinical, and RT data of patients with DIPG treated in Canada with rRT...
January 25, 2018: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/29367943/using-cystine-knot-proteins-as-a-novel-approach-to-retarget-oncolytic-measles-virus
#14
Sangeet Lal, Corey Raffel
Modified measles virus (MV) has effective oncolytic activity preclinically and is currently being investigated in clinical trials for various types of cancer. We investigated the use of cystine knot proteins (CKPs) to direct MV activity. CKPs are short polypeptides that bind their targets with high affinity. We used a CKP that binds αvβ3, αvβ5, and α5β1 integrins with single-digit nanomolar affinity to retarget MV to the integrins (MV-CKPint). MV-CKPint infected, replicated in, and killed human glioblastoma, medulloblastoma, diffuse intrinsic pontine glioma (DIPG), and melanoma cancer cells in vitro, all of which express the target integrins...
December 15, 2017: Molecular Therapy Oncolytics
https://www.readbyqxmd.com/read/29364085/characterization-of-diffuse-intrinsic-pontine-glioma-radiosensitivity-using-synchrotron-microbeam-radiotherapy-and-conventional-radiation-therapy-in-vitro
#15
L M Smyth, P A W Rogers, J C Crosbie, J F Donoghue
Synchrotron microbeam radiation therapy is a promising preclinical radiotherapy modality that has been proposed as an alternative to conventional radiation therapy for diseases such as diffuse intrinsic pontine glioma (DIPG), a devastating pediatric tumor of the brainstem. The primary goal of this study was to characterize and compare the radiosensitivity of two DIPG cell lines (SF7761 and JHH-DIPG-1) to microbeam and conventional radiation. We hypothesized that these DIPG cell lines would exhibit differential responses to each radiation modality...
February 2018: Radiation Research
https://www.readbyqxmd.com/read/29244086/cerebral-blood-flow-changes-after-radiation-therapy-identifies-pseudo-progression-in-diffuse-intrinsic-pontine-gliomas
#16
Raphael Calmon, Stephanie Puget, Pascale Varlet, Volodia Dangouloff-Ros, Thomas Blauwblomme, Kevin Beccaria, David Grevent, Christian Sainte-Rose, David Castel, Marie-Anne Debily, Christelle Dufour, Stéphanie Bolle, Frederic Dhermain, Ana Saitovitch, Monica Zilbovicius, Francis Brunelle, Jacques Grill, Nathalie Boddaert
Background: The interval between progression and death in diffuse intrinsic pontine glioma (DIPG) is usually < 6 months. However, reports of longer patient survival following radiotherapy, in the presence of radiological signs of progression, suggest that these cases may be comparable to pseudo-progression observed in adult glioblastoma. Our aim was to identify such cases and compare their multimodal MRI features with those of patients that did not present the same evolution. Methods: Multimodal MRI of 43 children treated for DIPG were retrospectively selected at four time points: baseline, after-radiotherapy, during true-progression, and at the last-visit...
December 13, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/29241176/surgery-of-intracranial-gliomas-in-children
#17
James A Balogun, James T Rutka
Gliomas are the most common type of brain cancer in the pediatric patients, constituting about 50% of all childhood intracranial tumors. This is a highly heterogeneous group, varying from the benign WHO histopathological grades I and II to malignant WHO grades III and IV. The histology and location are significant prognostic factors, which influence the decision for surgical intervention, as well as the extent of possible tumor removal. In low-grade gliomas, surgery remains the initial option and should be directed at gross total resection in favorable locations, such as the cerebral hemispheres and the cerebellum...
2018: Progress in Neurological Surgery
https://www.readbyqxmd.com/read/29207163/preclinical-analysis-of-mtor-complex-1-2-inhibition-in-diffuse-intrinsic-pontine-glioma
#18
Patrick C Flannery, John A DeSisto, Vladimir Amani, Sujatha Venkataraman, Rakeb T Lemma, Eric W Prince, Andrew Donson, Erin E Moroze, Lindsey Hoffman, Jean M Mulcahy Levy, Nicholas Foreman, Rajeev Vibhakar, Adam L Green
Diffuse intrinsic pontine glioma (DIPG) is an incurable childhood brain tumor. The mechanistic target of rapamycin (MTOR), a key oncogene, functions as two distinct signaling complexes, MTORC1 and MTORC2. We set out to determine the preclinical efficacy and mechanism of action of MTOR inhibitors in DIPG. We evaluated the MTORC1 inhibitor everolimus and the MTORC1/2 inhibitor AZD2014 in three patient-derived DIPG cell lines using cell culture models. We created dose-response curves for both compounds. We measured phenotypic effects on cell self-renewal, apoptosis, cell cycle, differentiation, senescence, and autophagy...
February 2018: Oncology Reports
https://www.readbyqxmd.com/read/29203539/novel-and-shared-neoantigen-derived-from-histone-3-variant-h3-3k27m-mutation-for-glioma-t-cell-therapy
#19
Zinal S Chheda, Gary Kohanbash, Kaori Okada, Naznin Jahan, John Sidney, Matteo Pecoraro, Xinbo Yang, Diego A Carrera, Kira M Downey, Shruti Shrivastav, Shuming Liu, Yi Lin, Chetana Lagisetti, Pavlina Chuntova, Payal B Watchmaker, Sabine Mueller, Ian F Pollack, Raja Rajalingam, Angel M Carcaboso, Matthias Mann, Alessandro Sette, K Christopher Garcia, Yafei Hou, Hideho Okada
The median overall survival for children with diffuse intrinsic pontine glioma (DIPG) is less than one year. The majority of diffuse midline gliomas, including more than 70% of DIPGs, harbor an amino acid substitution from lysine (K) to methionine (M) at position 27 of histone 3 variant 3 (H3.3). From a CD8+ T cell clone established by stimulation of HLA-A2+ CD8+ T cells with synthetic peptide encompassing the H3.3K27M mutation, complementary DNA for T cell receptor (TCR) α- and β-chains were cloned into a retroviral vector...
January 2, 2018: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29198324/developing-chemotherapy-for-diffuse-pontine-intrinsic-gliomas-dipg
#20
REVIEW
Ho-Shin Gwak, Hyeon Jin Park
Prognosis of diffuse intrinsic pontine glioma (DIPG) is poor, with a median survival of 10 months after radiation. At present, chemotherapy has failed to show benefits over radiation. Advances in biotechnology have enabled the use of autopsy specimens for genomic analyses and molecular profiling of DIPG, which are quite different from those of supratentorial high grade glioma. Recently, combined treatments of cytotoxic agents with target inhibitors, based on biopsied tissue, are being examined in on-going trials...
December 2017: Critical Reviews in Oncology/hematology
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