DOCSLIB.ORG

Antiangiogenic Therapy and Surgical Practice

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Antiangiogenic Therapy and Surgical Practice Review Antiangiogenic therapy and surgical practice A. R. John1,2,S.R.Bramhall1 andM.C.Eggo2 1Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, and 2Division of Medical Sciences, The Medical School, University of Birmingham, Birmingham, UK Correspondence to: Mr A. R. John, Division of Medical Sciences, The Medical School, University of Birmingham, Birmingham B15 2TT, UK (e-mail: [email protected]) Background: Antiangiogenic therapy has become a reality with the recent introduction of bevacizumab, a monoclonal antibody against vascular endothelial growth factor. Methods: Relevant medical literature from PubMed, National Institute for Health and Clinical Excellence and National Institutes of Health websites to August 2007 was reviewed. Results and conclusions: Although often described as the fourth modality of treatment after surgery, radiotherapy and chemotherapy, many antiangiogenic drugs have failed to live up to expectations. Nevertheless, research continues and there are reasons to believe that antiangiogenic therapy may yet have a future in the clinical setting. Paper accepted 31 October 2007 Published online in Wiley InterScience (www.bjs.co.uk). DOI: 10.1002/bjs.6108 Introduction of EGFR will inhibit the growth of the tumour cells directly and inhibition of VEGFR will inhibit angiogenesis. Other The term angiogenesis, defined as the sprouting of new receptors that are targeted include platelet-derived growth vessels from pre-existing vasculature, was first used by factor receptor, fibroblast growth factor receptor 1 and John Hunter in 1787 when describing the growth of blood rearranged during transfection (RET) tyrosine kinase. vessels in a reindeer antler. It is only recently, however, Also shown in Table 1 is bevacizumab, a humanized form that its importance in reproduction, development, wound of a monoclonal antibody to VEGF, that binds to VEGF healing and various disease states has been recognized. and inhibits its actions. Bevacizumab has been approved for Today, over 20 angiogenic growth factors and over use in human cancers; this is described in the next section. 300 angiogenesis inhibitors are known. These have the The other factors have shown promise in in vivo animal potential to be exploited clinically to regulate (reduce) the models of tumours, but have been less effective in humans, blood supply to cancers and so limit their growth. leading to termination of trials or their development. Table 2 shows compounds that are naturally occurring 28 Antiangiogenesis agents currently used in vivo inhibitors of angiogenesis. Folkman postulated the existence of endogenous inhibitors of angiogenesis when The principal regulators of angiogenesis are the vascular he observed that metastases often flourished after removal endothelial growth factors (VEGFs) and their receptors of the primary tumour. He and his group have pioneered (VEGFRs). Table 1 shows the antiangiogenic compounds this area of research, with the discovery of endostatin and that are targeted at VEGFs and VEGFRs, and which have angiostatin as a result. These compounds apparently inhibit been used in vivo. The VEGFRs are receptor tyrosine angiogenesis by several mechanisms, which are beginning kinases (RTKs) whose expression is largely confined to to be characterized21,29–35. They are usually smaller endothelial cells. Other RTKs with ubiquitous expression cleavage products of larger structural or extracellular matrix can, however, also stimulate angiogenesis, and inhibitors proteins. The importance of these naturally occurring that inhibit these RTKs, in addition to VEGFRs, are inhibitors has been exemplified in Down’s syndrome, which likely to be of greater benefit than specific inhibitors. For is associated with a low incidence of solid organ tumours example ZD6474, AEE788 and CP547 632 inhibit the owing to the increased serum levels of endostatin36. receptor for epidermal growth factor (EGFR). Inhibition Zorick and colleagues37 proposed that an increase of Copyright 2008 British Journal of Surgery Society Ltd British Journal of Surgery 2008; 95: 281–293 Published by John Wiley & Sons Ltd 282 A. R. John, S. R. Bramhall and M. C. Eggo Table 1 Antiangiogenic inhibitors that target vascular endothelial growth factor or its receptors Antiangiogenic factor Target Effect Reference Inhibition of VEGF pathway Semaxanib (SU5416) VEGFR1, VEGFR2 Inhibits EC growth, increases sensitivity to radiation 1,2 therapy in in vivo models SU6668 PDGFR, VEGFR2, FGFR1 Apoptosis of ECs 3 SU011248 VEGFR1, PDGFR, c-Kit, Apoptosis of ECs, inhibits tumour cell proliferation 4 FGFR1 ZD6474 VEGFR2, EGFR, RET tyrosine Inhibits ECs; direct antitumour effect at higher 5 kinase concentrations? Vatalanib (PTK787/ZK222584) VEGFR1, VEGFR2, PDGFR-β, Inhibits EC proliferation, survival, migration, permeability 6 C-kit tyrosine kinase and capillary sprouting Sorafenib (BAY 43-9006) Raf kinase, VEGFR2, Inhibits tumour cell proliferation and tumour angiogenesis 7 PDGFR-β, VEGFR3 CP 547 632 VEGFR2, EGFR, PDGFR-β Inhibits tumour growth and angiogenesis 8 AG013736 VEGFR, PDGFR, c-Kit Inhibits EC proliferation 9 AZD2171 VEGFR, PDGFR-β, c-Kit Inhibits proliferation, vessel area, length and branching 10 AEE788 EGFR, VEGFR Inhibits angiogenesis and tumour growth 11 Monoclonal antibodies Bevacizumab VEGF Inhibits cell proliferation, survival, permeability, migration 12 and nitric oxide production IMC-1C11 VEGFR2 Inhibits EC proliferation 13 Other mechanisms of VEGF pathway inhibition Cellular immunotherapy (CD8-positive VEGFR Cytotoxic activity, release of cytokines in the milieu of 14 cytotoxic lymphocytes) tumour Aplidine VEGFR1 Reduces VEGFR1 expression, cell cycle arrest in G1 15 Antisense oligonucleotides VEGF-AS VEGF mRNA degradation, reduces viability of cells 16,17 VEGF trap VEGF Binds to and inactivates circulating VEGF 18 VEGF(R), vascular endothelial growth factor (receptor); EC, endothelial cell; PDGFR, platelet-derived growth factor receptor; FGFR, fibroblast growth factor receptor; EGFR, epidermal growth factor receptor; RET, rearranged during transfection. Table 2 Endogenous inhibitors of angiogenesis Antiangiogenic factor Target Effect Reference Endostatin Broad spectrum; VEGFR2, integrin α5β1, others? Inhibits proliferation and migration of ECs, and direct 19,20 antitumour effect Angiostatin ATP synthase, integrin αvβ3, angiomotin, annexin II Inhibits EC migration and proliferation, and induces 21,22 apoptosis Thrombospondin 1 MMP-9, CD36 Inhibits EC proliferation and migration, and induces 23 apoptosis PEX MMP-2 Regulates invasive behaviour of new vessels 24 Interleukin 12 VEGF, MMP-9, TIMP-1 Inhibits EC proliferation and migration 25 Arresten α1β1 integrin Inhibits EC tube formation, EC proliferation and migration 26 Canstatin Cell surface integrin? Inhibits EC migration, tube formation, and induces 27 apoptosis VEGF(R), vascular endothelial growth factor (receptor); EC, endothelial cell; ATP, adenosine 5-triphosphate; MMP, matrix metalloproteinase; PEX, C-terminal haemopexin fragment of MMP-2; TIMP, tissue inhibitor of metalloproteinase. about a third of endostatin levels in serum was enough with; it aggregates easily and loses bioactivity; and problems to inhibit the development of solid tumours in affected exist with mode of delivery, biphasic dose response39 and individuals. bioavailability. Modified forms of endostatin are being Despite Folkman’s inspired hypothesis and the hopes of developed in Folkman’s laboratory to allow large-scale the stock market, endostatin has failed to live up to its early production of a stable, active form of the protein, but expectations in clinical trials38. Several explanations have clinical trials are at least a couple of years away. A modified been put forward for this: the protein is difficult to work form of endostatin, Endostar (Medgenn Bioengineering, Copyright 2008 British Journal of Surgery Society Ltd www.bjs.co.uk British Journal of Surgery 2008; 95: 281–293 Published by John Wiley & Sons Ltd Antiangiogenic therapy 283 Table 3 Putative antiangiogenic inhibitors Antiangiogenic factor Target Effect Reference MMP inhibitor TIMP-2 MMP-2, integrin α3β1 Inhibits bFGF-induced EC growth and angiogenesis, blocks 41,42 VEGF-induced EC proliferation via integrins and MMP-independent action TIMP-3 VEGFR Blocks binding of VEGF to VEGFR and stabilizes death receptor, 43 resulting in apoptosis of ECs Batimastat (BB94) MMP Broad-spectrum inhibitors of MMP activity, leading to 44 suppression of both EC and tumour cell migration and invasion Marimastat (BB2516) MMP As for batimastat 44 COX-2 inhibitors Celecoxib COX-2 receptor Inhibits migration and survival of ECs mediated by PGE and VEGF 45 Indomethacin COX-1, COX-2 Inhibits angiogenesis through reduction of VEGF expression, 46,47 apoptosis of tumour cells SC236 COX-2 Defective vascular assembly 48 Integrin blockers VitaxinTM αvβ3 integrin Inhibits bFGF-induced angiogenesis, induces apoptosis in new 49 ECs SCH 22153 αvβ3andαvβ5 integrins Inhibition of VEGF-induced EC proliferation and tumour growth in 50 animal models EGFR inhibitors Small molecules Erlotinib (OS1574/TarcevaTM) EGF Cell cycle arrest, apoptosis, inhibition of angiogenesis, cell 51 invasion and metastasis Gefitinib (ZD1839/IressaTM) EGFR Inhibits EGF-induced migration and tube formation, blocks 52,53 EGF-induced upregulation of VEGF and IL-8, inhibits cellular proliferation, and promotes apoptosis Monoclonal antibody Cetuximab (C225) EGFR Induction of apoptosis, G0/G1 cell cycle arrest, inhibition of 54 tumour cell
Load more

Recommended publications
  • Tanibirumab (CUI C3490677) Add to Cart
    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
    [Show full text]
  • Supplemental Table
    Supplementary Information DMD-AR-2020-000131 Evaluation of the disconnect between hepatocyte and microsome intrinsic clearance and in vitro in vivo extrapolation performance. Beth Williamson, Stephanie Harlfinger, Dermot F McGinnity Drug Metabolism and Pharmacokinetics, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK. Table S1. Compound physicochemical properties and in vitro ADME data. ACD ACD ACD Human Hep CLint Human Mic CLint Human Main Name MW Ion Class HBD HBA TPSA LogD 6 fuinc pKa A1 pKa B1 LogP (µL/min/x10 ) (µL/min/mg) fup isoform Chlorpromazine 318.9 Base 2 32 9.6 3.4 5.4 20 39 0.060 0.026 CYP2D6 Prochlorperazine 374.0 Base 3 35 7.7 3.6 4.8 12 2 0.023 0.141 CYP2D6 Dipyridamole 504.6 Neutral 4 12 145 6.5 3.8 0.3 28 96 0.407 0.048 UGT Erlotinib 393.4 Neutral 1 7 75 5.5 3.3 3.0 5 20 0.504 0.052 CYP3A Promethazine 284.4 Base 2 32 9.1 2.8 4.6 9 1 0.144 0.090 CYP2D6 Propranolol 259.4 Base 2 3 41 9.5 1.3 3.3 10 29 0.467 0.243 CYP2D6 Rosiglitazone 357.4 Neutral 1 5 97 6.3 6.5 2.5 2.8 13 37 0.514 0.003 Other Ondansetron 293.4 Base 4 40 6.8 1.6 2.8 3 8 0.842 0.435 CYP3A Amsacrine 393.5 Neutral 2 5 89 8.2 3.1 3.2 11 40 0.434 0.007 CYP1A Antazoline 265.4 Base 1 3 28 10.3 1.4 3.6 52 195 0.726 0.562 CYP3A Gefitinib 446.9 Base 1 7 69 7.0 3.7 3.7 4 44 0.214 0.035 CYP3A Edaravone 174.2 Neutral 1 3 33 2.7 0.5 1.1 2 65 0.828 0.001 UGT Semaxanib 238.3 Neutral 2 2 45 13.2 1.5 3.4 3.0 28 68 0.036 0.031 CYP3A Verapamil 454.6 Base 6 64 8.1 2.6 4.0 23 180 0.548 0.155 CYP3A Imatinib 493.6 Base 2 7 86 13.3 7.6 2.5 3.1 3 35 0.405
    [Show full text]
  • Characterization of the Small Molecule Kinase Inhibitor SU11248 (Sunitinib/ SUTENT in Vitro and in Vivo
    TECHNISCHE UNIVERSITÄT MÜNCHEN Lehrstuhl für Genetik Characterization of the Small Molecule Kinase Inhibitor SU11248 (Sunitinib/ SUTENT in vitro and in vivo - Towards Response Prediction in Cancer Therapy with Kinase Inhibitors Michaela Bairlein Vollständiger Abdruck der von der Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt der Technischen Universität München zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation. Vorsitzender: Univ. -Prof. Dr. K. Schneitz Prüfer der Dissertation: 1. Univ.-Prof. Dr. A. Gierl 2. Hon.-Prof. Dr. h.c. A. Ullrich (Eberhard-Karls-Universität Tübingen) 3. Univ.-Prof. A. Schnieke, Ph.D. Die Dissertation wurde am 07.01.2010 bei der Technischen Universität München eingereicht und durch die Fakultät Wissenschaftszentrum Weihenstephan für Ernährung, Landnutzung und Umwelt am 19.04.2010 angenommen. FOR MY PARENTS 1 Contents 2 Summary ................................................................................................................................................................... 5 3 Zusammenfassung .................................................................................................................................................... 6 4 Introduction .............................................................................................................................................................. 8 4.1 Cancer ..............................................................................................................................................................
    [Show full text]
  • Using Next-Generation Sequencing to Find Targetable Genomic Lesions in a Case of Relapsed Extramedullary Acute Myeloid Leukemia
    Open Access Annals of Hematology & Oncology Case Report Using Next-Generation Sequencing to Find Targetable Genomic Lesions in a Case of Relapsed Extramedullary Acute Myeloid Leukemia Miller KC, Dias AL, Patnaik MM and Litzow MR* Division of Hematology, Mayo Clinic, USA Abstract *Corresponding author: Litzow MR, Division of Next-generation sequencing (NGS) has catalyzed a revolution in our Hematology, Mayo Clinic, Rochester, MN, 200 First understanding and treatment of leukemia, in some cases revealing cryptic Street SW, Rochester, MN 55905, USA genomic alterations that can be specifically targeted with drugs, such as tyrosine kinase inhibitors (TKIs). Herein we describe a case of relapsed extramedullary Received: January 15, 2017; Accepted: February 17, acute myeloid leukemia (AML), for which NGS of a tumor biopsy revealed 2017; Published: February 20, 2017 several genomic lesions, including an uncommon ETV6-ABL1 fusion oncogene. Consequently, we began treatment with the TKI dasatinib, in combination with 5-azacitidine. This report demonstrates the clinical value of using NGS to find targeted therapies for patients with hematological malignancies such as AML. Keywords: Extramedullary acute myeloid leukemia; Myeloid sarcoma; ETV6-ABL1; Dasatinib; Next-generation sequencing (NGS) Introduction (dim, variable), and myeloperoxidase (partial). Ki67 proliferative staining was high at approximately 90%. Bone marrow (BM) biopsy Next-generation sequencing (NGS) technology is rapidly demonstrated 4% myeloid blasts. Cytogenetic studies from the BM evolving, and has begun to unravel the unique complexities of aspirate showed complex cytogenetic abnormalities with six out of 20 hematologic malignancies. Using this technology, there has been metaphases demonstrating +8, +20, deletion 9p, deletion 16p, and a a recent, robust effort to parse hematologic diseases such as acute balanced translocation between chromosomes 1 and 11.
    [Show full text]
  • Hypertension Secondary to Anti-Angiogenic Therapy: Experience with Bevacizumab
    ANTICANCER RESEARCH 27: 3465-3470 (2007) Hypertension Secondary to Anti-angiogenic Therapy: Experience with Bevacizumab AMITKUMAR PANDE1, JEFFREY LOMBARDO2, EDWARD SPANGENTHAL1 and MILIND JAVLE3 Departments of 1Medicine and 2Pharmacy, Roswell Park Cancer Institute, Elm and Carlton Sts, Buffalo, NY 14263; 3Department of GI Medical Oncology, UT-MD Anderson Cancer Institute, Unit 426, 1515 Holcombe Ave, Houston, TX 77030, U.S.A. Abstract. Background: Hypertension (HT) is a common single agents or in combination with cytotoxic chemotherapy complication of anti-angiogenic therapy. Its incidence, treatment and radiotherapy so as to achieve synergistic or additive and complications are undefined. Patients and Methods: effects. Hypertension is a consistent toxicity of patients Retrospective review of patients treated with bevacizumab (BV) treated with anti-angiogenic agents and the incidence of this from 2003-5. Common toxicity criteria (CTC) for adverse events complication is likely to increase with increasing use of anti- version 3.0 were used. Results: Fifty-five out of the 154 patients angiogenic therapy. No current guidelines exist regarding treated with BV (35%) experienced HT. Eleven (20%) developed the management of hypertension in this situation. The a new onset HT and 44 (80%) experienced an exacerbation of widest experience with anti-angiogenic therapy is with pre-existing HT. HT developed after a median of 11 weeks at a bevacizumab (BV), a recombinant humanized monoclonal median BV dose of 10 mg/kg. HT severity was grade 1 (n=1), antibody. BV binds to and inhibits the activity of VEGF grade 2 (n=29) or grade 3 (n=22); 3 experienced hypertensive which results in failure of interaction between VEGF and complications.
    [Show full text]
  • Role of Vegfs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models
    International Journal of Molecular Sciences Review Role of VEGFs/VEGFR-1 Signaling and Its Inhibition in Modulating Tumor Invasion: Experimental Evidence in Different Metastatic Cancer Models 1 1 2, 1, , Claudia Ceci , Maria Grazia Atzori , Pedro Miguel Lacal y and Grazia Graziani * y 1 Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; [email protected] (C.C.); [email protected] (M.G.A.) 2 Laboratory of Molecular Oncology, “Istituto Dermopatico dell’Immacolata-Istituto di Ricovero e Cura a Carattere Scientifico”, IDI-IRCCS, Via dei Monti di Creta 104, 00167 Rome, Italy; [email protected] * Correspondence: [email protected]; Tel.: +30-0672596338 Equally contributing co-last authors. y Received: 21 January 2020; Accepted: 14 February 2020; Published: 18 February 2020 Abstract: The vascular endothelial growth factor (VEGF) family members, VEGF-A, placenta growth factor (PlGF), and to a lesser extent VEGF-B, play an essential role in tumor-associated angiogenesis, tissue infiltration, and metastasis formation. Although VEGF-A can activate both VEGFR-1 and VEGFR-2 membrane receptors, PlGF and VEGF-B exclusively interact with VEGFR-1. Differently from VEGFR-2, which is involved both in physiological and pathological angiogenesis, in the adult VEGFR-1 is required only for pathological angiogenesis. Besides this role in tumor endothelium, ligand-mediated stimulation of VEGFR-1 expressed in tumor cells may directly induce cell chemotaxis and extracellular matrix invasion. Furthermore, VEGFR-1 activation in myeloid progenitors and tumor-associated macrophages favors cancer immune escape through the release of immunosuppressive cytokines. These properties have prompted a number of preclinical and clinical studies to analyze VEGFR-1 involvement in the metastatic process.
    [Show full text]
  • Systematic Analysis of Gene Expression Profiles Reveals
    Zhang et al. Cancer Cell Int (2019) 19:337 https://doi.org/10.1186/s12935-019-1056-y Cancer Cell International PRIMARY RESEARCH Open Access Systematic analysis of gene expression profles reveals prognostic stratifcation and underlying mechanisms for muscle-invasive bladder cancer Ping‑Bao Zhang1,2, Zi‑Li Huang3, Yong‑Hua Xu3, Jin Huang4, Xin‑Yu Huang1 and Xiu‑Yan Huang1* Abstract Background: Muscle‑invasive bladder cancer (MIBC) is originated in the muscle wall of the bladder, and is the ninth most common malignancy worldwide. However, there are no reliable, accurate and robust gene signatures for MIBC prognosis prediction, which is of the importance in assisting oncologists to make a more accurate evaluation in clinical practice. Methods: This study used univariable and multivariable Cox regression models to select gene signatures and build risk prediction model, respectively. The t‑test and fold change methods were used to perform the diferential expres‑ sion analysis. The hypergeometric test was used to test the enrichment of the diferentially expressed genes in GO terms or KEGG pathways. Results: In the present study, we identifed three prognostic genes, KLK6, TNS1, and TRIM56, as the best subset of genes for muscle‑invasive bladder cancer (MIBC) risk prediction. The validation of this stratifcation method on two datasets demonstrated that the stratifed patients exhibited signifcant diference in overall survival, and our stratifca‑ tion was superior to three other stratifcations. Consistently, the high‑risk group exhibited worse prognosis than low‑ risk group in samples with and without lymph node metastasis, distant metastasis, and radiation treatment. Moreover, the upregulated genes in high‑risk MIBC were signifcantly enriched in several cancer‑related pathways.
    [Show full text]
  • Snapshot: Breast Cancer Kornelia Polyak and Otto Metzger Filho Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215 USA
    SnapShot: Breast Cancer Kornelia Polyak and Otto Metzger Filho Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215 USA Frequency of breast cancer subtypes Subtype Stage 5 year OS (%) 10 year OS (%) *DCIS 0 99 98 TNBC Triple-negative breast cancers are ER-PR-HER2- and show significant, I 98 95 but not complete, overlap with the basal-like subtype of breast cancer (which is defined by differentiation state and gene expression profile). Luminal II 91 81 (non- III 72 54 HER2+) IV 33 17 TNBC + I 98 95 10% Luminal (non-HER2 ) tumors are typically II 92 86 + HER2+ breast cancers estrogen receptor positive, **HER2 HER2+ III 85 75 have luminal features a 20% displaying high ER levels. and are characterized IV 40 15 Luminal, These tumors are dependent by ERBB2 gene amplifi- non-HER2+ on estrogen for growth and, I 93 90 cation and overexpres- 70% therefore, respond to II 76 70 sion leading to a de- endocrine therapy. TNBC III 45 37 pendency on HER2 sig- naling. IV 15 11 *Preinvasive stage **Estimated overall survival (OS) using HER2-targeted therapies Top 21 most commonly mutated Key signaling pathways in breast cancer genes in breast cancer based on somatic mutation data Gene All (%) Luminal TNBC TP53 35 26 54 USH2A IGF-1R EGFR HER2 FGFR E-cadherin PIK3CA 34 44 8 GATA3 9 13 0 MAP3K1 8 11 0 MLL3 6 8 3 CDH1 6 8 2 USH2A 5 4 8 SRC PTEN 3 3 3 TBL1XR1 NF1 RAS PI3K PTEN RUNX1 3 4 0 NCOR1 RUNX1 MAP2K4 3 4 1 mTORC2 CBFB C NCOR1 3 3 1 M BRAF MAP3K1 Y RB1 3 2 5 CM ERa GATA3 MY mTORC1 AKT TBX3 2 3 1 CY CMY NCOA3 K PIK3R1 2 3 2 MEK1/2 MAP2K4 MDM2 GSK-3 FOXA1 CTCF 2 2 1 MYC NF1 2 2 1 p27Kip1 MYB SF3B1 2 2 0 ERK1/2 JNK p53 Cyclin D1/3 AKT1 2 2 0 CDK4 CBFB 1 2 1 N C E R Ink4A A R p16 C E S FOXA1 1 1 1 G E A N I R STMN2 TBX3 pRB T C C CDKN1B 1 1 0 I I H H C C X X E E Mutation frequencies (%) in all tumors, YEARS OF Colors indicate tumor suppressors (blue), oncogenes (red), or mutant genes with unclear roles (purple), 10S + I N 2 or just within luminal (including HER2 ) C 0 0 and lighter shading marks pathway components in which somatic mutations have not been identified.
    [Show full text]
  • Downloaded from Bioscientifica.Com at 09/26/2021 09:35:42AM Via Free Access
    25 2 Endocrine-Related S Redaelli et al. New treatments for MEN2 25:2 T53–T68 Cancer THEMATIC REVIEW Novel targeted therapeutics for MEN2 Sara Redaelli1, Ivan Plaza-Menacho2 and Luca Mologni1 1School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy 2Spanish National Cancer Research Center (CNIO), Madrid, Spain Correspondence should be addressed to L Mologni: [email protected] This paper is part of a thematic review section on 25 Years of RET and MEN2. The guest editors for this section were Lois Mulligan and Frank Weber Abstract The rearranged during transfection (RET) proto-oncogene was recognized as the Key Words multiple endocrine neoplasia type 2 (MEN2) causing gene in 1993. Since then, much f cell signaling effort has been put into a clear understanding of its oncogenic signaling, its biochemical f multiple endocrine function and ways to block its aberrant activation in MEN2 and related cancers. Several neoplasias small molecules have been designed, developed or redirected as RET inhibitors for the f oncogene treatment of MEN2 and sporadic MTC. However, current drugs are mostly active against f thyroid several other kinases, as they were not originally developed for RET. This limits efficacy and poses safety issues. Therefore, there is still much to do to improve targeted MEN2 treatments. New, more potent and selective molecules, or combinatorial strategies may lead to more effective therapies in the near future. Here, we review the rationale for RET targeting in MEN2, the use of currently available drugs and novel preclinical and clinical Endocrine-Related Cancer RET inhibitor candidates. (2018) 25, T53–T68 MEN2: introduction Mary (fictitious name) is a beautiful and joyful eighteen- features and mucosal neuromas of the lips and the year-old girl who enjoys her life.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8,975,248 B2 Zakn0en Et Al
    US008975248B2 (12) United States Patent (10) Patent No.: US 8,975,248 B2 Zakn0en et al. (45) Date of Patent: Mar. 10, 2015 (54) COMBINATIONS OF THERAPEUTIC (56) References Cited AGENTS FOR TREATING CANCER U.S. PATENT DOCUMENTS (75) Inventors: Sara Zaknoen, Hoboken, NJ (US); 7,105,492 B2 * 9/2006 Dallavalle et al. .............. 514/25 Margaret Ma Woo, Raritan, NJ (US); 2002/0103141 A1* 8, 2002 McKearnet al. ............... 514,43 Richard William Versace, Wanaque, NJ 2004, OO18988 A1 1/2004 Dallavalle et al. (US); Claudio Pisano, Aprilia (IT): 2004/01 16407 A1* 6/2004 Borisy et al. .................. 514,217 Loredana Vesci, Rome (IT) 2005/0272755 A1* 12/2005 Denis et al. ................... 514,283 FOREIGN PATENT DOCUMENTS (73) Assignee: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Rome (IT) EP O715854 9, 2003 JP 2002-539 128 11, 2002 JP 2004-529150 9, 2004 (*) Notice: Subject to any disclaimer, the term of this JP 2008-1698.25 T 2008 patent is extended or adjusted under 35 WO WOOO,536O7 A1 * 9, 2000 CO7D 491?22 WO WO O2/O85459 10, 2002 U.S.C. 154(b) by 1206 days. WO WO-O3,O13541 2, 2003 WO WO-03/037897 5, 2003 (21) Appl. No.: 11/720,776 WO WO-2004/083214 9, 2004 WO WO-2004,103274 12, 2004 WO WO 2004f103358 12, 2004 (22) PCT Filed: Dec. 13, 2005 WO WO-2006/06578O 6, 2006 OTHER PUBLICATIONS (86). PCT No.: PCT/US2OOS/O44993 Petrangolini et al. (Molecular Cancer Research 2003; 1: 863-870).* S371 (c)(1), Kao et al.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • Synthetic and Biological Investigations Into Hypoxia-Activated Anti-Tumour Codrugs
    University of Wollongong Research Online University of Wollongong Thesis Collection 1954-2016 University of Wollongong Thesis Collections 2015 Synthetic and biological investigations into hypoxia-activated anti-tumour codrugs Nicholas Kirk University of Wollongong Follow this and additional works at: https://ro.uow.edu.au/theses University of Wollongong Copyright Warning You may print or download ONE copy of this document for the purpose of your own research or study. The University does not authorise you to copy, communicate or otherwise make available electronically to any other person any copyright material contained on this site. You are reminded of the following: This work is copyright. Apart from any use permitted under the Copyright Act 1968, no part of this work may be reproduced by any process, nor may any other exclusive right be exercised, without the permission of the author. Copyright owners are entitled to take legal action against persons who infringe their copyright. A reproduction of material that is protected by copyright may be a copyright infringement. A court may impose penalties and award damages in relation to offences and infringements relating to copyright material. Higher penalties may apply, and higher damages may be awarded, for offences and infringements involving the conversion of material into digital or electronic form. Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong. Recommended Citation Kirk, Nicholas, Synthetic and biological investigations into hypoxia-activated anti-tumour codrugs, Doctor of Philosophy thesis, School of Chemistry, University of Wollongong, 2015.
    [Show full text]