Publications by authors named "Hiroaki Katagi"

16 Publications

  • Page 1 of 1

Therapeutic targeting of transcriptional elongation in diffuse intrinsic pontine glioma.

Neuro Oncol 2021 Jan 20. Epub 2021 Jan 20.

Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Background: DIPG is associated with transcriptional dysregulation driven by H3K27 mutation. The super elongation complex (SEC) is required for transcriptional elongation through release of RNA polymerase II (Pol II). Inhibition of transcription elongation by SEC disruption can be an effective therapeutic strategy of H3K27M-mutant diffuse intrinsic pontine glioma (DIPG). Here, we tested the effect of pharmacological disruption of the SEC in H3K27M-mutant DIPG to advance understanding of the molecular mechanism and as a new therapeutic strategy for DIPG.

Methods: Short hairpin RNAs (shRNAs) were used to suppress the expression of AF4/FMR2 4 (AFF4), a central SEC component, in H3K27M-mutant DIPG cells. A peptidomimetic lead compound KL-1 was used to disrupt a functional component of SEC. Cell viability assay, colony formation assay, and apoptosis assay were utilized to analyze the effects of KL-1 treatment. RNA- and ChIP-sequencing were used to determine the effects of KL-1 on gene expression and chromatin occupancy. We treated mice bearing human H3K27M-mutant DIPG xenografts with KL-1. Intracranial tumor growth was monitored by bioluminescence image and therapeutic response was evaluated by animal survival.

Results: Depletion of AFF4 significantly reduced the cell growth of H3K27M-mutant DIPG. KL-1 increased genome-wide Pol II occupancy and suppressed transcription involving multiple cellular processes that promote cell proliferation and differentiation of DIPG. KL-1 treatment suppressed DIPG cell growth, increased apoptosis, and prolonged animal survival with human H3K27M-mutant DIPG xenografts.

Conclusions: SEC disruption by KL-1 increased therapeutic benefit in vitro and in vivo, supporting a potential therapeutic activity of KL-1 in H3K27M-mutant DIPG.
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http://dx.doi.org/10.1093/neuonc/noab009DOI Listing
January 2021

Mesenchymal Stem Cells Successfully Deliver Oncolytic Virotherapy to Diffuse Intrinsic Pontine Glioma.

Clin Cancer Res 2021 Mar 3;27(6):1766-1777. Epub 2020 Dec 3.

Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Purpose: Diffuse intrinsic pontine glioma (DIPG) is among the deadliest of pediatric brain tumors. Radiotherapy is the standard-of-care treatment for DIPG, but offers only transient relief of symptoms for patients with DIPG without providing significant survival benefit. Oncolytic virotherapy is an anticancer treatment that has been investigated for treating various types of brain tumors.

Experimental Design: Here, we have explored the use of mesenchymal stem cells (MSC) for oncolytic virus (OV) delivery and evaluated treatment efficacy using preclinical models of DIPG. The survivin promoter drives the conditional replication of OV used in our studies. The efficiency of OV entry into the cells is mediated by fiber modification with seven lysine residues (CRAd.S.pK7). Patients' samples and cell lines were analyzed for the expression of viral entry proteins and survivin. The ability of MSCs to deliver OV to DIPG was studied in the context of a low dose of irradiation.

Results: Our results show that DIPG cells and tumors exhibit robust expression of cell surface proteins and survivin that enable efficient OV entry and replication in DIPG cells. MSCs loaded with OV disseminate within a tumor and release OV throughout the DIPG brainstem xenografts in mice. Administration of OV-loaded MSCs with radiotherapy to mice bearing brainstem DIPG xenografts results in more prolonged survival relative to that conferred by either therapy alone ( < 0.01).

Conclusions: Our study supports OV, CRAd.S.pK7, encapsulated within MSCs as a therapeutic strategy that merits further investigation and potential translation for DIPG treatment.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956061PMC
March 2021

Senescence Induced by BMI1 Inhibition Is a Therapeutic Vulnerability in H3K27M-Mutant DIPG.

Cell Rep 2020 10;33(3):108286

Department of Pediatrics and Section of Pediatric Hematology/Oncology/BMT, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; The Morgan Adams Foundation Pediatric Brain Tumor Research Program, Children's Hospital Colorado, Aurora, CO, USA.

Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.
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http://dx.doi.org/10.1016/j.celrep.2020.108286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574900PMC
October 2020

Convection-Enhanced Delivery of Enhancer of Zeste Homolog-2 (EZH2) Inhibitor for the Treatment of Diffuse Intrinsic Pontine Glioma.

Neurosurgery 2020 Jul 16. Epub 2020 Jul 16.

Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background: Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brain tumor and the majority of patients die within 2 yr after initial diagnosis. Factors that contribute to the dismal prognosis of these patients include the infiltrative nature and anatomic location in an eloquent area of the brain, which precludes total surgical resection, and the presence of the blood-brain barrier (BBB), which reduces the distribution of systemically administered agents. Convection-enhanced delivery (CED) is a direct infusion technique to deliver therapeutic agents into a target site in the brain and able to deliver a high concentration drug to the infusion site without systemic toxicities.

Objective: To assess the efficacy of enhancer of zeste homolog-2 (EZH2) inhibitor by CED against human DIPG xenograft models.

Methods: The concentration of EZH2 inhibitor (EPZ-6438) in the brainstem tumor was evaluated by liquid chromatography-mass spectrometry (LC/MS). We treated mice-bearing human DIPG xenografts with EPZ-6438 using systemic (intraperitoneal) or CED administration. Intracranial tumor growth was monitored by bioluminescence image, and the therapeutic response was evaluated by animal survival.

Results: LC/MS analysis showed that the concentration of EPZ-6438 in the brainstem tumor was 3.74% of serum concentration after systemic administration. CED of EPZ-6438 suppressed tumor growth and significantly extended animal survival when compared to systemic administration of EPZ-6438 (P = .0475).

Conclusion: Our results indicate that CED of an EZH2 inhibitor is a promising strategy to bypass the BBB and to increase the efficacy of an EZH2 inhibitor for the treatment of DIPG.
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http://dx.doi.org/10.1093/neuros/nyaa301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666886PMC
July 2020

Radiosensitization by Histone H3 Demethylase Inhibition in Diffuse Intrinsic Pontine Glioma.

Clin Cancer Res 2019 09 21;25(18):5572-5583. Epub 2019 Jun 21.

Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG. We evaluated the effects of GSK-J4 on genes associated with DNA double-strand break (DSB) repair in DIPG cells by RNA sequence, ATAC sequence, and quantitative real-time PCR. Radiation-induced DNA DSB repair was analyzed by immunocytochemistry of DSB markers γH2AX and 53BP1, DNA-repair assay, and cell-cycle distribution. Clonogenic survival assay was used to determine the effect of GSK-J4 on radiation response of DIPG cells. response to radiation monotherapy and combination therapy of RT and GSK-J4 was evaluated in patient-derived DIPG xenografts.

Results: GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility in DIPG cells. GSK-J4 sustained high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNA DSB repair through homologous recombination pathway. GSK-J4 reduced clonogenic survival and enhanced radiation effect in DIPG cells. studies revealed increased survival of animals treated with combination therapy of RT and GSK-J4 compared with either monotherapy.

Conclusions: Together, these results highlight GSK-J4 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744979PMC
September 2019

ABC Transporter Inhibition Plus Dexamethasone Enhances the Efficacy of Convection Enhanced Delivery in H3.3K27M Mutant Diffuse Intrinsic Pontine Glioma.

Neurosurgery 2020 05;86(5):742-751

Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.

Background: An impermeable blood-brain barrier and drug efflux via ATP-binding cassette (ABC) transporters such as p-glycoprotein may contribute to underwhelming efficacy of peripherally delivered agents to treat diffuse intrinsic pontine glioma (DIPG).

Objective: To explore the pharmacological augmentation of convection-enhanced delivery (CED) infusate for DIPG.

Methods: The efficacy of CED dasatinib, a tyrosine kinase inhibitor, in a transgenic H3.3K27M mutant murine model was assessed. mRNA expression of ABCB1 (p-glycoprotein) was analyzed in 14 tumor types in 274 children. In Vitro viability studies of dasatinib, the p-glycoprotein inhibitor, tariquidar, and dexamethasone were performed in 2 H3.3K27M mutant cell lines. Magnetic resonance imaging (MRI) was used to evaluate CED infusate (gadolinium/dasatinib) distribution in animals pretreated with tariquidar and dexamethasone. Histological assessment of apoptosis was performed.

Results: Continuous delivery CED dasatinib improved median overall survival (OS) of animals harboring DIPG in comparison to vehicle (39.5 and 28.5 d, respectively; P = .0139). Mean ABCB1 expression was highest in K27M gliomas. In Vitro, the addition of tariquidar and dexamethasone further enhanced the efficacy of dasatinib (P < .001). In Vivo, MRI demonstrated no difference in infusion dispersion between animals pretreated with dexamethasone plus tariquidar prior to CED dasatinib compared to the CED dasatinib. However, tumor apoptosis was the highest in the pretreatment group (P < .001). Correspondingly, median OS was longer in the pretreatment group (49 d) than the dasatinib alone group (39 d) and no treatment controls (31.5 d, P = .0305).

Conclusion: ABC transporter inhibition plus dexamethasone enhances the efficacy of CED dasatinib, resulting in enhanced tumor cellular apoptosis and improved survival in H3.3K27M mutant DIPG.
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http://dx.doi.org/10.1093/neuros/nyz212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443593PMC
May 2020

Targeting Processive Transcription Elongation via SEC Disruption for MYC-Induced Cancer Therapy.

Cell 2018 10;175(3):766-779.e17

Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg, School of Medicine, 303 E. Superior Street, Chicago, IL 60611, USA. Electronic address:

The super elongation complex (SEC) is required for robust and productive transcription through release of RNA polymerase II (Pol II) with its P-TEFb module and promoting transcriptional processivity with its ELL2 subunit. Malfunction of SEC contributes to multiple human diseases including cancer. Here, we identify peptidomimetic lead compounds, KL-1 and its structural homolog KL-2, which disrupt the interaction between the SEC scaffolding protein AFF4 and P-TEFb, resulting in impaired release of Pol II from promoter-proximal pause sites and a reduced average rate of processive transcription elongation. SEC is required for induction of heat-shock genes and treating cells with KL-1 and KL-2 attenuates the heat-shock response from Drosophila to human. SEC inhibition downregulates MYC and MYC-dependent transcriptional programs in mammalian cells and delays tumor progression in a mouse xenograft model of MYC-driven cancer, indicating that small-molecule disruptors of SEC could be used for targeted therapy of MYC-induced cancer.
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http://dx.doi.org/10.1016/j.cell.2018.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422358PMC
October 2018

Pulmonary tumor thrombotic microangiopathy associated with urothelial carcinoma of the urinary bladder: antemortem diagnosis by pulmonary microvascular cytology.

Clin Case Rep 2015 Sep 29;3(9):735-9. Epub 2015 Jul 29.

Division of Respiratory Medicine, Department of Internal Medicine, Jikei University School of Medicine Tokyo, Japan.

PTTM (Pulmonary tumor thrombotic microangiopathy) is very difficult to diagnose before death. We report a case of urothelial carcinoma of the urinary bladder associated with PTTM in which an antemortem diagnosis by PMC (pulmonary microvascular cytology). PMC may represent the only chance for diagnosis and achievement of remission in PTTM.
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http://dx.doi.org/10.1002/ccr3.330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574788PMC
September 2015

Paraneoplastic Syndrome of Angiomatoid Fibrous Histiocytoma May Be Caused by EWSR1-CREB1 Fusion-induced Excessive Interleukin-6 Production.

J Pediatr Hematol Oncol 2015 Oct;37(7):554-9

Departments of *Pediatrics §Pathology ‡Division of Pediatric Surgery †Division of Molecular Genetics, Institute of DNA Medicine, The Jikei University School of Medicine ∥Department of Pathology, National Center for Child Health and Development Departments of ¶Pediatric Hematology and Oncology Research #Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.

We describe a 7-year-old girl with angiomatoid fibrous histiocytoma (AFH) presenting severe inflammatory symptoms. The cytokine/chemokine profile of serum samples before and after surgery demonstrated that interleukin (IL)-6 had decreased by the greatest percentage. The AFH cells were immunopathologically positive for IL-6 and Tyr705-phosphorylation of signal transducer and activator of transcription 3. The EWSR1-CREB1 fusion gene detected in the tumor leads to continuous activation of CREB1 and IL-6 production, because the promoter region of IL-6 has a CREB binding site. Thus, IL-6 plays pivotal roles in both paraneoplastic syndrome and the oncogenesis of AFH.
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http://dx.doi.org/10.1097/MPH.0000000000000390DOI Listing
October 2015

Useful Strategy of Pulmonary Microvascular Cytology in the Early Diagnosis of Intravascular Large B-cell Lymphoma in a Patient with Hypoxemia: A Case Report and Literature Review.

Intern Med 2015 1;54(11):1403-6. Epub 2015 Jun 1.

Division of Respiratory Medicine, Department of Internal Medicine, Jikei University School of Medicine, Kashiwa Hospital, Japan.

Intravascular large B-cell lymphoma (IVLBCL) is a rare extranodal lymphoma characterized by the presence of tumor cells within blood vessels, and it is considered to be a subtype of diffuse large B-cell lymphoma. We report a case of IVLBCL presenting as progressive hypoxemia. In this case, a definitive diagnosis could not be achieved by repeated transbronchial lung biopsy, a bone marrow biopsy, and a random skin biopsy, and the ultimate diagnosis was made on the basis of a pulmonary microvascular cytology (PMC) examination. Therefore, PMC is considered to be a useful strategy for the diagnosis of IVLBCL, particularly in this critically ill patient suffering from hypoxemia.
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http://dx.doi.org/10.2169/internalmedicine.54.4379DOI Listing
January 2016

Correlation between clinical characteristics and chest computed tomography findings of pulmonary cryptococcosis.

Pulm Med 2015 12;2015:703407. Epub 2015 Feb 12.

Department of Internal Medicine, Division of Respiratory Medicine, Jikei University School of Medicine, Tokyo, Japan.

Objective: The aim of this study was to review HIV-negative patients with pulmonary cryptococcosis to analyze the correlations between clinical characteristics and chest computed tomography (CT) findings.

Methods: We retrospectively analyzed medical records of 16 HIV-negative patients with pulmonary cryptococcosis diagnosed at our institution, and clinical characteristics of the patients with nodules or masses without ground-glass attenuation (GGA)/consolidation type were compared with those of patients with inclusive GGA or consolidation type.

Results: Host status was immunocompromised (81.2%) in most of the patients, and 6 (37.5%) were asymptomatic. The most frequent radiologic abnormalities on chest CT scans were one or more nodules (87.5%), GGA (37.5%), and consolidations (18.8%). Most lesions were located in the lower lung. Levels of hemoglobin and platelets were significantly lower in patients with inclusive GGA or consolidation type. Although the differences were not significant, patients with inclusive GGA or consolidation type tended to have a C-reactive protein level of ≥1.0 mg/dL.

Conclusion: If a patient with anemia and thrombocytopenia shows GGA or consolidation in the lung, pulmonary cryptococcosis should be given careful consideration.
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http://dx.doi.org/10.1155/2015/703407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342071PMC
January 2016

Pulmonary pleomorphic carcinoma detected as a result of pneumothorax and the subsequent occurrence of multiple cystic metastases.

Case Rep Med 2014 20;2014:219273. Epub 2014 Aug 20.

Department of Internal Medicine, Division of Respiratory Medicine, Jikei University School of Medicine, Tokyo, Japan.

A 39-year-old man was admitted for spontaneous pneumothorax. He underwent pulmonary resection to correct the lesion causing the air leakage, and a pathological diagnosis of pulmonary pleomorphic carcinoma was made because we thought that the pneumothorax developed due to the direct rupture of necrotic neoplastic tissue into the pleural cavity. After the operation, the patient received chemotherapy, during which multiple cystic metastases gradually developed in the lung that caused repeated occurrences of pneumothorax. Clinicians must be careful to recognize that pneumothorax can also be a complication of primary and various metastatic pulmonary malignancies.
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http://dx.doi.org/10.1155/2014/219273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4158116PMC
September 2014

Characterization of non-alcoholic steatohepatitis-derived hepatocellular carcinoma as a human stratification model in mice.

Anticancer Res 2014 Sep;34(9):4849-55

Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan Department of Endoscopy, The Jikei University School of Medicine, Tokyo, Japan.

The therapeutic strategy against hepatocellular carcinoma (HCC) is determined by tumor stage and liver function. Improvements of stratification contribute to extending the survival of patients. However, stratification has been attributed little attention in animal models largely due to the lack of suitable models. Herein we showed that the recently-reported, non-alcoholic steatohepatitis-derived HCC model (STAM model) is the first murine model in which the concept of human stratification is applicable by demonstrating the following features: (i) at least 4 detectable tumor nodules; (ii) average tumor growth rate of 150 % from 16 to 20 weeks of age; (iii) no visible metastasis; and (iv) relatively preserved liver function. These observations suggested that HCC in STAM mice is equivalent to stages B to C of the Barcelona Clinic Liver Cancer (BCLC) staging system for humans. Application of the stratification concept to experimental animals will create new avenues to establish pharmacological intervention against HCC.
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September 2014

Pulmonary Hodgkin's lymphoma presenting with a bulging fissure sign.

Intern Med 2014 1;53(17):2021-2. Epub 2014 Sep 1.

Department of Internal Medicine, Division of Respiratory Medicine, Jikei University School of Medicine, Kashiwa Hospital, Japan.

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http://dx.doi.org/10.2169/internalmedicine.53.2722DOI Listing
July 2015

Pulmonary and retroperitoneal lesions induced by methotrexate-associated lymphoproliferative disorder in a patient with rheumatoid arthritis.

Mod Rheumatol 2016 1;26(3):441-4. Epub 2014 Apr 1.

c Division of Respiratory Diseases, Department of Internal Medicine , Jikei University School of Medicine , Tokyo , Japan.

A 78-year-old man had fatigue and appetite loss for 5 months. He had been receiving low-dose methotrexate for rheumatoid arthritis. Computed tomography revealed multiple pulmonary infiltrations and muddiness of the fatty tissue surrounding the right kidney, ureter wall thickening, and hydroureter/nephrosis, which were suspected retroperitoneal fibrosis. Lung biopsy revealed polymorphic/lymphoplasmacytic lymphoproliferative disorder. Methotrexate withdrawal resulted in spontaneous regression. Therefore, retroperitoneal lesion may account for the diagnosis as having retroperitoneal lymphoproliferative disorder, not retroperitoneal fibrosis.
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http://dx.doi.org/10.3109/14397595.2014.898559DOI Listing
December 2016

Global analysis of the expression patterns of transcriptional regulatory factors in formation of embryoid bodies using sensitive oligonucleotide microarray systems.

Biochem Biophys Res Commun 2004 Dec;325(1):265-75

Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.

We manufactured a highly sensitive oligonucleotide microarray system comprised entirely of transcription regulatory factors (a TF oligo microarray) in order to comprehensively analyze the expression profiles of transcription factors in mice. We compared the expression profiles of transcription regulatory factors in mouse embryonic stem (ES) cells and ES-differentiated cells by using this TF oligo microarray, a cDNA microarray, a GeneChip system, and quantitative RT-PCR. The TF oligo microarray was able to comprehensively analyze the expression profile of transcription regulatory factors. In addition, we used the manufactured TF oligo microarray to analyze the expression patterns of transcriptional regulatory factors during the formation of embryoid bodies. The TF array was able to reveal the chronologic expression profile of transcription regulatory factors involved in embryogenesis or the maintenance of pluripotency in ES cells.
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http://dx.doi.org/10.1016/j.bbrc.2004.10.025DOI Listing
December 2004
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