Table Of ContentANTI-ANGIOGENESIS
STRATEGIES
IN CANCER
THERAPIES
Edited by
SHAKER A. MOUSA
The Pharmaceutical Research Institute
Albany College of Pharmacy and Health Sciences
Rensselaer, New York, United States
PAUL J. DAVIS
Department of Medicine, Albany Medical College
Albany, New York, United States
The Pharmaceutical Research Institute
Albany College of Pharmacy and Health Sciences
Rensselaer, New York, United States
Amsterdam • Boston • Heidelberg • London
New York • Oxford • Paris • San Diego
San Francisco • Singapore • Sydney • Tokyo
Academic Press is an imprint of Elsevier
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, United Kingdom
525 B Street, Suite 1800, San Diego, CA 92101-4495, United States
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
Copyright © 2017 Elsevier Inc. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic
or mechanical, including photocopying, recording, or any information storage and retrieval system,
without permission in writing from the publisher. Details on how to seek permission, further informa-
tion about the Publisher’s permissions policies and our arrangements with organizations such as the
Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.
elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by the Pub-
lisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience
broaden our understanding, changes in research methods, professional practices, or medical treatment
may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and
using any information, methods, compounds, or experiments described herein. In using such informa-
tion or methods they should be mindful of their own safety and the safety of others, including parties
for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume
any liability for any injury and/or damage to persons or property as a matter of products liability,
negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein.
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
ISBN: 978-0-12-802576-5
For information on all Academic Press publications
visit our website at https://www.elsevier.com/
Publisher: Mica Haley
Acquisition Editor: Kristine Jones
Editorial Project Manager: Molly McLaughlin
Production Project Manager: Julia Haynes
Designer: Mark Rogers
Typeset by Thomson Digital
LIST OF CONTRIBUTORS
Maii Abu Taleb
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences,
Rensselaer, NY, United States
Dhruba J. Bharali
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences,
Rensselaer, NY, United States
Noureldien H.E. Darwish
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences,
Rensselaer, NY, United States; Faculty of Medicine, Mansoura University, Mansoura, Egypt
Paul J. Davis
Department of Medicine, Albany Medical College, Albany, NY, United States;
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health
Sciences, Rensselaer, NY, United States
Matthew Leinung
Department of Medicine, Albany Medical College, Albany, NY, United States
Shaker A. Mousa
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences,
Rensselaer, NY, United States
Vandhana Muralidharan-Chari
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences,
Rensselaer, NY, United States
Mehdi Rajabi
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences,
Rensselaer, NY, United States
Domenico Ribatti
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University
of Bari Medical School; National Cancer Institute “Giovanni Paolo II”, Bari, Italy
Thangirala Sudha
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences,
Rensselaer, NY, United States
Angelo Vacca
Department of Biomedical Sciences, and Human Oncology, Section of Internal Medicine
and Clinical Oncology, University of Bari Medical School, Bari, Italy
Murat Yalcin
The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences,
Rensselaer, NY, United States; Department of Physiology, V eterinary Medicine Faculty,
Uludag University, Bursa, Turkey
xi
Introduction
The requirement of aggressive cancers for rapidly growing blood
vessels with unique structures [1,2] has rendered anti-angiogenesis
[3] a highly attractive adjunct to standard chemotherapy or has led
to its consideration as single-agent treatment. Anti-angiogenesis
has been tested against a spectrum of solid tumors, including breast
[4], ovary [5], prostate [6], hepatocellular carcinoma [7], lung can-
cers [8], and colon [9], among others.
However, reviews of anti-angiogenic therapy in cancer
conclude that this approach to-date has been disappointing
[10–14]. Redundancy and upregulation of compensatory pro-
angiogenesis pathways are a hallmark of tumor cell defenses in
general and, not unexpectedly, our appreciation of the scope of
mechanisms of tumor refractoriness to anti-angiogenesis continues
to increase [15–18]. This has led to consideration of new directions
in interventions in cancer-related blood vessel formation. Such
new directions include combinations of anti-angiogenic agents
[12], DNA-based immunotherapy directed at vasculature [19,20],
anti-inflammation [21], anti-platelet therapy [22], and novel small
molecules that serve to regulate the functions of multiple angio-
genic factors [23,24]. Additionally, certain angiogenesis pathways,
such as the integrin αvβ3 receptor complex might serve as a novel
targeting strategy for imaging and targeted delivery for a nanoen-
capsulated payload of various chemotherapies (Chapter 11).
In this book, we summarize a number of mechanisms for
limitations of anti-angiogenic interventions in cancer and have
assembled reviews of a panel of strategies that may serve to improve
effectiveness of anti-angiogenic interventions, alone, in cancer or
in combination with chemotherapy.
xiii
xiv Introduction
REFERENCES
[1] Dvorak HF, Weaver VM, Tlsty TD, Bergers G. Tumor microenvironment
and progression. J Surg Oncol 2011;103(6):468–74.
[2] Nagy JA, Chang SH, Shih SC, Dvorak AM, Dvorak HF. Heterogeneity of
the tumor vasculature. Semin Thromb Hemost 2010;36(3):321–31.
[3] Abdollahi A, Folkman J. Evading tumor evasion: current concepts and
perspectives of anti-angiogenic cancer therapy. Drug Resist Updat
2010;13(1–2):16–28.
[4] Lohmann AE, Chia S. Patients with metastatic breast cancer using bevaci-
zumab as a treatment: is there still a role for it? Curr Treat Options Oncol
2012;13(2):249–62.
[5] Eskander RN, Tewari KS. Incorporation of anti-angiogenesis therapy in
the management of advanced ovarian carcinoma--mechanistics, review of
phase III randomized clinical trials, and regulatory implications. Gynecol
Oncol 2014;132(2):496–505.
[6] Bilusic M, Wong YN. Anti-angiogenesis in prostate cancer: knocked down
but not out. Asian J Androl 2014;16(3):372–7.
[7] Sun H, Zhu MS, Wu WR, Shi XD, Xu LB. Role of anti-angiogenesis
therapy in the management of hepatocellular carcinoma: the jury is still
out. World J Hepatol 2014;6(12):830–5.
[8] Ellis PM. Anti-angiogenesis in personalized therapy of lung cancer. Adv
Exp Med Biol 2016;893:91–126.
[9] Marien KM, Croons V, Martinet W, De Loof H, Ung C, Waelput W,
Scherer SJ, Kockx MM, De Meyer GR. Predictive tissue biomarkers for
bevacizumab-containing therapy in metastatic colorectal cancer: an up-
date. Expert Rev Mol Diagn 2015;15(3):399–414.
[10] Shojaei F. Anti-angiogenesis therapy in cancer: current challenges and fu-
ture perspectives. Cancer Lett 2012;320(2):130–7.
[11] Bellou S, Pentheroudakis G, Murphy C, Fotsis T. Anti-angiogenesis in can-
cer therapy: Hercules and hydra. Cancer Lett 2013;338(2):219–28.
[12] Wang Z, Dabrosin C, Yin X, Fuster MM, Arreola A, Rathmell WK,
Generali D, Nagaraju GP, El-Rayes B, Ribatti D, Chen YC, Honoki K,
Fujii H, Georgakilas AG, Nowsheen S, Amedei A, Niccolai E, Amin A,
Ashraf SS, Helferich B, Yang X, Guha G, Bhakta D, Ciriolo MR, Aqui-
lano K, Chen S, Halicka D, Mohammed SI, Azmi AS, Bilsland A, Keith
WN, Jensen LD. Broad targeting of angiogenesis for cancer prevention
and therapy. Semin Cancer Biol 2015;35:S224–43.
[13] Mitamura T, Gourley C, Sood AK. Prediction of anti-angiogenesis escape.
Gynecol Oncol 2016;141(1):80–5.
Introduction xv
[14] Ye W. The complexity of translating anti-angiogenesis therapy from basic
science to the clinic. Dev Cell 2016;37(2):114–25.
[15] Giuliano S, Pages G. Mechanisms of resistance to anti-angiogenesis thera-
pies. Biochimie 2013;95(6):1110–9.
[16] Ribatti D. Tumor refractoriness to anti-VEGF therapy. Oncotarget 2016.
[17] Huijbers EJ, van Beijnum JR, Thijssen VL, Sabrkhany S, Nowak-Sliwinska
P, Griffioen AW. Role of the tumor stroma in resistance to anti-angiogenic
therapy. Drug Resist Updat 2016;25:26–37.
[18] Pinto MC, Sotomayor P, Carrasco-Avino G, Corvalan AH, Owen GI.
Escaping antiangiogenic therapy: strategies employed by cancer cells. Int
J Mol Sci 2016;17(9.).
[19] Ugel S, Facciponte JG, De Sanctis F, Facciabene A. Targeting tumor vascu-
lature: expanding the potential of DNA cancer vaccines. Cancer Immunol
Immunother 2015;64(10):1339–48.
[20] Wagner SC, Ichim TE, Ma H, Szymanski J, Perez JA, Lopez J, Bogin
V, Patel AN, Marincola FM, Kesari S. Cancer anti-angiogenesis vac-
cines: is the tumor vasculature antigenically unique? J Transl Med
2015;13:340.
[21] Ribatti D, Crivellato E, Vacca A. Inflammation and antiangiogenesis in
cancer. Curr Med Chem 2012;19(7):955–60.
[22] Yan M, Lesyk G, Radziwon-Balicka A, Jurasz P. Pharmacological regula-
tion of platelet factors that influence tumor angiogenesis. Semin Oncol
2014;41(3):370–7.
[23] Mousa SA, Lin HY, Tang HY, Hercbergs A, Luidens MK, Davis PJ.
Modulation of angiogenesis by thyroid hormone and hormone analogues:
implications for cancer management. Angiogenesis 2014;17(3):463–9.
[24] Davis PJ, Sudha T, Lin HY, Mousa SA. Thyroid hormone, hormone
analogs, and angiogenesis. Compr Physiol 2015;6(1):353–62.
CHAPTER 1
Angiogenesis and
Anti-Angiogenesis Strategies
in Cancer
Shaker A. Mousa and Paul J. Davis
Contents
Process of Angiogenesis 2
Angiogenesis in Cancer 3
Strategies 5
Current Examples of Cancer Treatment Agents that Block
Angiogenesis 6
Side Effects of Angiogenesis Inhibitors 7
Angiogenesis and Angiogenesis Inhibitors: Potential
Anti-Cancer Therapeutic Efficacy 7
Targeting of VEGF 7
Additional Anti-Angiogenesis Strategies in Cancers 8
Kininostatin 8
Alpha 3 Chain of Type IV Collagen 9
Matrix Metalloproteinases 9
2-Methoxyestradiol 9
Small Molecule Integrin Antagonists 10
Nutraceutical-Derived Polyphenols 10
Anti-Angiogenesis Therapy in Hematologic Cancer: Multiple Myeloma 10
Anti-Coagulants and Angiogenesis 11
Possible Mechanisms of Acquired Resistance to Anti-Angiogenic Drugs 12
Standard Chemotherapy Versus Angiogenesis Inhibitors 13
Anti-Angiogenesis Agents and Thrombosis 13
Diagnostic Imaging of Angiogenesis 13
microRNA and Angiogenesis Modulation 14
References 14
Anti-Angiogenesis Strategies in Cancer Therapies
http://dx.doi.org/10.1016/B978-0-12-802576-5.00001-2 1
Copyright © 2017 Elsevier Inc. All rights reserved.
2 Anti-Angiogenesis Strategies in Cancer Therapies
PROCESS OF ANGIOGENESIS
Angiogenesis is a complex process in which endogenous local or
systemic chemical signals coordinate functions of endothelial cells
and smooth muscle cells. Both repair of damaged blood vessels
and the formation of new blood vessels can be achieved with these
signals. Another set of chemical signals, angiogenesis inhibitors
(Table 1.1), may systematically disrupt blood vessel formation or
support removal of existing vessels, for example, at the conclusion
of an inflammatory response. In the setting of homeostasis, the
stimulating and inhibiting chemical signals are balanced and blood
vessels form only as they are needed.
Angiogenic support is critical to growth and spread of can-
cer. Growth of localized tumors beyond a few millimeters in size
Table 1.1 Selected list of endogenous angiogenesis inhibitors and
mechanisms of action
Endogenous angiogenesis
inhibitors Mechanisms
Soluble VEGF-1 Decoy receptors for VEGF-B
Angiostatin Suppress EC adhesion, migration,
proliferation
Thrombospondin-1 and -2 Suppress EC adhesion, migration,
proliferation
Angiopoietin-2 Oppose angiopoietin-1
Platelet factor-4 Inhibit bFGF (FGF2) and VEGF
binding
Endostatin Suppress EC adhesion, migration,
proliferation
Anti-thrombin III fragment Suppress EC adhesion, migration,
proliferation
Osteopontin Serve as ligand for integrin binding
Collagen Substrate for MMPs
Kininogen domains Suppress EC adhesion, migration,
proliferation
Tissue factor pathways inhibitor Antagonist for tissue factor
Abbreviations: bFGF, basic fibroblast growth factor; EC, endothelial cell; MMP, matrix metal-
loproteinase; VEGF, vascular endothelial growth factor.
Angiogenesis and Anti-Angiogenesis Strategies in Cancer 3
requires local angiogenesis. Tumor cells generate new blood vessel
formation by releasing proangiogenic chemical signals. Normal
cells proximal to cancer cells may also support a proangiogenic
response via signaling molecules. Local neovascularization supplies
growing tumors with oxygen and essential nutrients, supports tu-
mor extension and invasion into nearby normal tissue, and is es-
sential to distant metastasis [1,2].
ANGIOGENESIS IN CANCER
As in normal tissues, tumor tissue is unable to grow or metasta-
size locally or systemically without angiogenic support. The vessels
supply oxygen and nutrients required for growth [2]. The hypoxic
tumor cell, for example, at the center of a typically spheroid cancer
in situ, will not divide. This state may serve as a survival mechanism
when such cells are exposed to therapeutic measures—radiation or
certain chemotherapeutic agents—that disrupt DNA only when it
is undergoing division.
The walls of blood vessels are endothelial cells that divide and
migrate in response to local signals. The sequential steps of new
blood vessel creation include activation of the endothelial cell wall
of an existing small blood vessel (capillary), secretion of metallo-
proteinase enzymes that degrade the proteinaceous extracellular
matrix (surrounding tissue), invasion of the matrix, and then cell
division. String-like lattices of new endothelial cells organize into
hollow tubes, resulting in new blood vessel networks that enable
surrounding (cancer) tissue growth [2–4].
In nonmalignant tissues, endothelial cells are largely dormant.
In growing cancers, endothelial cells are vigorously active. When
needed in normal tissues or organs, new capillary growth is closely
regulated by release of factors that activate endothelial cells and
factors (Table 1.1) that are inhibitory [2,3]. Such a balance is less
apparent in cancers, where anti-angiogenic factor production is of
course reduced.
Among many proteins, known to activate endothelial cell growth
and motility, are angiogenin, epidermal growth factor (EGF),
