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PubMed | Dana-Farber Cancer Institute, The Broad Institute of MIT and Harvard, Harvard University, University of California at San Diego and 5 more.
Type: Journal Article | Journal: Cancer cell | Year: 2016

Mutations in SF3B1, which encodes a spliceosome component, are associated with poor outcome in chronic lymphocytic leukemia (CLL), but how these contribute to CLL progression remains poorly understood. We undertook a transcriptomic characterization of primary human CLL cells to identify transcripts and pathways affected by SF3B1 mutation. Splicing alterations, identified in the analysis of bulk cells, were confirmed in single SF3B1-mutated CLL cells and also found in cell lines ectopically expressing mutant SF3B1. SF3B1 mutation was found to dysregulate multiple cellular functions including DNA damage response, telomere maintenance, and Notch signaling (mediated through KLF8 upregulation, increased TERC and TERT expression, or altered splicing of DVL2 transcript, respectively). SF3B1 mutation leads to diverse changes in CLL-related pathways.


News Article | February 21, 2017
Site: www.businesswire.com

CAMBRIDGE, Mass.--(BUSINESS WIRE)--H3 Biomedicine Inc., a biopharmaceutical company specializing in the discovery and development of precision medicines for oncology and a member of Eisai’s global Oncology Business Group, announced today that Peter G. Smith, Ph.D., will become the company’s chief scientific officer, effective March 1, 2017. Dr. Smith transitions to his new position from vice president, Drug Discovery Biology. “Since joining H3 shortly after the company’s inception, Pete has been essential to the rapid success of the company and a driving force behind our pre-clinical and clinical advancements,” said Dr. Markus Warmuth, president and CEO of H3 Biomedicine. “Under Pete’s scientific leadership, H3 brought forward its first two oncology drug candidates and established a robust pre-clinical program that shows enormous promise.” In his role as chief scientific officer, Dr. Smith will be responsible for setting the scientific strategy and priorities for H3 Biomedicine, as well as overseeing day-to-day research operations. “I am grateful for this recognition of my contributions to H3, and am honored to be part of such a transformative company,” said Dr. Smith. “It has been a privilege to help H3 advance from a young, discovery-stage company to one with a strong clinical footprint and the potential to grow that even further over the next few years.” Dr. Smith joined H3 Biomedicine in 2011 as the director of Target Biology, and soon advanced to the position of vice president, Drug Discovery Biology. Within this capacity, he led a multidisciplinary team of scientists towards the identification and early development of novel small molecule oncology therapeutics. Under Dr. Smith’s leadership, H3’s scientific team has delivered two clinical stage compounds (H3B-8800 and H3B-6527), and a third pre-clinical compound which is scheduled for clinical introduction in Q2 2017. Dr. Smith came to H3 Biomedicine from Millennium Pharmaceuticals/Takeda Oncology in Cambridge, Mass., where he held positions of increasing scientific and management responsibility in the oncology discovery group. Prior to Millennium, Dr. Smith served as a post-doctoral researcher at the Dana-Farber Cancer Institute, Harvard Medical School; at the Molecular Medicine Unit, St James’s University Hospital, University of Leeds, U.K.; and at the Cancer Research Unit, University of Newcastle upon Tyne, U.K. Dr. Smith earned a Ph.D. from the Cancer Research Unit at the University of Newcastle upon Tyne, U.K. and a B.Sc. in pharmacology from the University of Sheffield, U.K. About H3 Biomedicine Inc. H3 Biomedicine is a Cambridge, Massachusetts-based biopharmaceutical company specializing in the discovery and development of precision oncology treatments, which was established as a subsidiary of Eisai’s U.S. pharmaceutical operation, Eisai Inc. Using modern synthetic chemistry, chemical biology, and human genetics, H3 Biomedicine seeks to bring the next generation of cancer treatments to market with the goal of improving the lives of patients. For more information, please visit www.h3biomedicine.com.


Kim E.,Sloan Kettering Cancer Center | Ilagan J.O.,Fred Hutchinson Cancer Research Center | Liang Y.,Yale University | Daubner G.M.,ETH Zurich | And 25 more authors.
Cancer Cell | Year: 2015

Mutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2's normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2, which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis. © 2015 Elsevier Inc.


Taylor S.J.,Boehringer Ingelheim Pharmaceuticals | Padyana A.K.,Boehringer Ingelheim Pharmaceuticals | Abeywardane A.,Boehringer Ingelheim Pharmaceuticals | Liang S.,Boehringer Ingelheim Pharmaceuticals | And 11 more authors.
Journal of Medicinal Chemistry | Year: 2013

Chymase plays an important and diverse role in the homeostasis of a number of cardiovascular processes. Herein, we describe the identification of potent, selective chymase inhibitors, developed using fragment-based, structure-guided linking and optimization techniques. High-concentration biophysical screening methods followed by high-throughput crystallography identified an oxindole fragment bound to the S1 pocket of the protein exhibiting a novel interaction pattern hitherto not observed in chymase inhibitors. X-ray crystallographic structures were used to guide the elaboration/linking of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over cathepsin G and that mitigated a number of liabilities associated with poor physicochemical properties of the series it was derived from. © 2013 American Chemical Society.


Decker S.,Albert Ludwigs University of Freiburg | Zirlik K.,Albert Ludwigs University of Freiburg | Djebatchie L.,Albert Ludwigs University of Freiburg | Hartmann D.,Albert Ludwigs University of Freiburg | And 8 more authors.
Blood | Year: 2012

Hedgehog (HH) signaling is activated in various lymphoid malignancies, but conflicting results exist about its role in chronic lymphocytic leukemia (CLL). Here, we demonstrate that the expression of essential HH pathway components like GLI1, PTCH1, and the HH ligands is highly diverse in CLL. A subset of 36.7% of 60 tested CLL samples responded to all 3 SMOOTHENED (SMO) inhibitors, whereas 40% were completely resistant. Responsiveness correlated with elevated GLI1 and PTCH1 transcript levels and the presence of trisomy 12, whereas no other karyotype correlated with responsiveness. All trisomy 12 CLLs displayed constitutive HH pathway activation driven by autocrine DESERT HH (DHH) ligand secretion, which could be blocked by the HH-blocking Ab 5E1. Cocultures with DHH-expressing BM stromal cells reduced sensitivity of CLLs to SMO-inhibitor treatment by activation of noncanonical ERK phosphorylation directly downstream of the PTCH1 receptor without involvement of SMO and could be overcome by the HH-blocking Ab 5E1 or a combination of SMO and ERK inhibitors. Our results demonstrate that the HH-signaling pathway is an interesting therapeutic target for a subset of patients with CLL, characterized by high GLI1 and PTCH1 transcript levels, and all patients with trisomy 12 and indicate HH-blocking Abs to be favorable over SMO inhibitors in overcoming stroma-mediated protective effects. © 2012 by The American Society of Hematology.


Micel L.N.,Aurora University | Micel L.N.,Childrens Hospital Colorado | Tentler J.J.,Aurora University | Smith P.G.,H3 Biomedicine | Eckhardt S.G.,Aurora University
Journal of Clinical Oncology | Year: 2013

The ubiquitin proteasome system (UPS) regulates the ubiquitination, and thus degradation and turnover, of many proteins vital to cellular regulation and function. The UPS comprises a sequential series of enzymatic processes using four key enzyme families: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-carrier proteins), E3 (ubiquitin-protein ligases), and E4 (ubiquitin chain assembly factors). Because the UPS is a crucial regulator of the cell cycle, and abnormal cell-cycle control can lead to oncogenesis, aberrancies within the UPS pathway can result in a malignant cellular phenotype and thus has become an attractive target for novel anticancer agents. This article will provide an overall review of the mechanics of the UPS, describe aberrancies leading to cancer, and give an overview of current drug therapies selectively targeting the UPS. © 2013 by American Society of Clinical Oncology.


PubMed | Howard Hughes Medical Institute, Fred Hutchinson Cancer Research Center, Sloan Kettering Cancer Center, ETH Zurich and 3 more.
Type: Journal Article | Journal: Cancer cell | Year: 2015

Mutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2s normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2, which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis.


PubMed | H3 Biomedicine., Massachusetts General Hospital and H3 Biomedicine;
Type: | Journal: Journal of visualized experiments : JoVE | Year: 2015

Although targeted therapies are initially effective, resistance inevitably emerges. Several methods, such as genetic analysis of resistant clinical specimens, have been applied to uncover these resistance mechanisms to facilitate follow-up care. Although these approaches have led to clinically relevant discoveries, difficulties in attaining the relevant patient material or in deconvoluting the genomic data collected from these specimens have severely hampered the path towards a cure. To this end, we here describe a tool for expeditious discovery that may guide improvement in first-line therapies and alternative clinical management strategies. By coupling preclinical in vitro or in vivo drug selection with next-generation sequencing, it is possible to identify genomic structural variations and/or gene expression alterations that may serve as functional drivers of resistance. This approach facilitates the spontaneous emergence of alterations, enhancing the probability that these mechanisms may be observed in the patients. In this protocol we provide guidelines to maximize the potential for uncovering single nucleotide variants that drive resistance using adherent lines.


CAMBRIDGE, Mass.--(BUSINESS WIRE)--H3 Biomedicine Inc., a biopharmaceutical company specializing in the discovery and development of precision medicines for oncology and a member of Eisai's global Oncology Business Group, announced today that data from the company’s lead cancer program were presented at the 2016 American Society of Hematology (ASH) Meeting in San Diego, Calif. The oral presentation detailed pre-clinical findings from the company’s lead cancer compound, H3B-8800, demonstrating its potential efficacy in models of spliceosome mutant myeloid malignancies including a novel patient-derived xenograft system for chronic myelomonocytic leukemia (CMML). Also collaborating in this program along with H3 Biomedicine, were additional cancer research groups from Memorial Sloan Kettering Cancer Center (New York, NY) and Moffitt Cancer Center, (Tampa, Fla.). “The data presented at ASH highlights the continued progress of our H3B-8800 program and establishes the clinical rationale for development of the compound in myeloid malignancies which has recently begun clinical trials,” said Markus Warmuth, M.D., Chief Executive Officer and President of H3 Biomedicine. “Approximately 50% of myelodysplastic syndrome, secondary AML and CMML patients harbor a spliceosome mutation and these populations are in need of new treatment options.” H3’s ASH presentation provides an overview of the pre-clinical discovery of H3B-8800, an orally available modulator of the SF3b complex that shows potent splicing modulation in vitro and preferential cell killing of spliceosome mutant cells. “Our deep expertise in RNA biology has uncovered a mechanistic rationale for the targeted treatment of spliceosome mutant cancers with H3B-8800,” said Pete Smith, PhD, Vice President, Biology for H3Biomedicine. “The data presented at ASH demonstrates the compelling activity of H3B-8800 in cell line and patient-derived xenograft models of spliceosome mutant hematological malignancies.” H3B-8800 is currently in Phase I clinical trials in advanced myeloid malignancies. The early clinical studies will evaluate safety, pharmacokinetics, pharmacodynamics and efficacy in patients with mutations in SF3B1, SRSF2, U2AF1 and ZRSR2 spliceosome genes. About H3B-8800 H3B-8800 is an oral, potent, and selective small molecule modulator of splicing factor 3b subunit 1 (SF3B1) that is being developed by H3 Biomedicine as a potential anticancer therapeutic agent. In pre-clinical studies, H3B-8800 showed dose dependent modulation of canonical and aberrant splicing when dosed orally at tolerated doses. More importantly, oral administration of H3B-8800 demonstrated preferential antitumor activity in several pre-clinical xenograft models carrying spliceosome mutations. H3 Biomedicine’s lead research and discovery programs in splicing are designed to develop drugs that target the vulnerabilities related to deregulated RNA homeostasis in cancer. About H3 Biomedicine Inc. H3 Biomedicine is a Cambridge, Massachusetts-based biopharmaceutical company specializing in the discovery and development of precision oncology treatments, which was established as a subsidiary of Eisai's U.S. pharmaceutical operation, Eisai Inc. Using modern synthetic chemistry, chemical biology, and human genetics, H3 Biomedicine seeks to bring the next generation of cancer treatments to market with the goal of improving the lives of patients. For more information, please visit http://www.h3biomedicine.com/.


— Bile Duct Cancer (Cholangiocarcinoma) - Companies Involved in Therapeutics Development are 4SC AG, Adgero Biopharmaceuticals Inc, Agios Pharmaceuticals Inc, Ariad Pharmaceuticals Inc, ArQule Inc, Array BioPharma Inc, Arrien Pharmaceuticals LLC, Aslan Pharmaceuticals Pte Ltd, Bavarian Nordic A/S, Bayer AG, BeiGene Ltd, Blueprint Medicines Corp, Boehringer Ingelheim GmbH, Boston Biomedical Inc, Bristol-Myers Squibb Company, Celgene Corp, CellAct Pharma GmbH, Cellceutix Corp, Cellular Biomedicine Group Inc, Concordia International Corp, Cornerstone Pharmaceuticals Inc, Daiichi Sankyo Company Ltd, Delcath Systems Inc, Eisai Co Ltd, Eli Lilly and Company, Exelixis Inc, F. Hoffmann-La Roche Ltd, H3 Biomedicine Inc, Halozyme Therapeutics Inc, Hutchison MediPharma Ltd, Incyte Corp, Innopharmax Inc, INSYS Therapeutics Inc, Johnson & Johnson, Komipharm International Co Ltd, Loxo Oncology, Inc., Mebiopharm Co Ltd, MedImmune LLC, Merck & Co Inc, NanoCarrier Co Ltd, NormOxys Inc, Novartis AG, NuCana BioMed Ltd, Oasmia Pharmaceutical AB, OncoTherapy Science Inc, Ono Pharmaceutical Co Ltd, Panacea Pharmaceuticals Inc, PCI Biotech Holding ASA, Pfizer Inc, Pharma Mar SA, Provecs Medical GmbH, Puma Biotechnology Inc, RedHill Biopharma Ltd, Sanofi, Senhwa Biosciences Inc, Shanghai Pharmaceutical Co Ltd, Sun Pharma Advanced Research Company Ltd, SynCore Biotechnology Co Ltd, SyntheX Inc, Taiwan Liposome Company Ltd, tella Inc, Threshold Pharmaceuticals Inc and VasGene Therapeutics Inc. Bile duct cancer or cholangiocarcinoma are tumors that occur in the bile duct. Symptoms include discomfort in the tummy area (abdomen), loss of appetite, high temperatures (fevers) and weight loss. Treatment includes chemotherapy and radiation therapy. The Bile Duct Cancer (Cholangiocarcinoma) (Oncology) pipeline guide also reviews of key players involved in therapeutic development for Bile Duct Cancer (Cholangiocarcinoma) and features dormant and discontinued projects. The guide covers therapeutics under Development by Companies /Universities /Institutes, the molecules developed by Companies in Phase III, Phase II, Phase I, Preclinical and Discovery stages are 1, 49, 18, 10 and 3 respectively. Similarly, the Universities portfolio in Phase II, Phase I and Preclinical stages comprises 1, 1 and 4 molecules, respectively. Bile Duct Cancer (Cholangiocarcinoma) (Oncology) pipeline guide helps in identifying and tracking emerging players in the market and their portfolios, enhances decision making capabilities and helps to create effective counter strategies to gain competitive advantage. The guide is built using data and information sourced from Global Markets Direct’s proprietary databases, company/university websites, clinical trial registries, conferences, SEC filings, investor presentations and featured press releases from company/university sites and industry-specific third party sources. Additionally, various dynamic tracking processes ensure that the most recent developments are captured on a real time basis. Inquire more about this report at http://www.reportsnreports.com/contacts/inquirybeforebuy.aspx?name=786901 Note:Certain content / sections in the pipeline guide may be removed or altered based on the availability and relevance of data. • The pipeline guide provides a snapshot of the global therapeutic landscape of Bile Duct Cancer (Cholangiocarcinoma) (Oncology). • The pipeline guide reviews pipeline therapeutics for Bile Duct Cancer (Cholangiocarcinoma) (Oncology) by companies and universities/research institutes based on information derived from company and industry-specific sources. • The pipeline guide covers pipeline products based on several stages of development ranging from pre-registration till discovery and undisclosed stages. • The pipeline guide features descriptive drug profiles for the pipeline products which comprise, product description, descriptive licensing and collaboration details, R&D brief, MoA & other developmental activities. • The pipeline guide reviews key companies involved in Bile Duct Cancer (Cholangiocarcinoma) (Oncology) therapeutics and enlists all their major and minor projects. • The pipeline guide evaluates Bile Duct Cancer (Cholangiocarcinoma) (Oncology) therapeutics based on mechanism of action (MoA), drug target, route of administration (RoA) and molecule type. • The pipeline guide encapsulates all the dormant and discontinued pipeline projects. • The pipeline guide reviews latest news related to pipeline therapeutics for Bile Duct Cancer (Cholangiocarcinoma) (Oncology) • Procure strategically important competitor information, analysis, and insights to formulate effective R&D strategies. • Recognize emerging players with potentially strong product portfolio and create effective counter-strategies to gain competitive advantage. • Find and recognize significant and varied types of therapeutics under development for Bile Duct Cancer (Cholangiocarcinoma) (Oncology). • Classify potential new clients or partners in the target demographic. • Develop tactical initiatives by understanding the focus areas of leading companies. • Plan mergers and acquisitions meritoriously by identifying key players and it’s most promising pipeline therapeutics. • Formulate corrective measures for pipeline projects by understanding Bile Duct Cancer (Cholangiocarcinoma) (Oncology) pipeline depth and focus of Indication therapeutics. • Develop and design in-licensing and out-licensing strategies by identifying prospective partners with the most attractive projects to enhance and expand business potential and scope. • Adjust the therapeutic portfolio by recognizing discontinued projects and understand from the know-how what drove them from pipeline. For more information, please visit http://www.reportsnreports.com/reports/786901-bile-duct-cancer-cholangiocarcinoma-pipeline-review-h2-2016.html

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