Resistance to Targeted Anti-Cancer Therapeutics 19 Series Editor: Benjamin Bonavida Cristina Maccalli Matilde Todaro Soldano Ferrone E ditors Cancer Stem Cell Resistance to Targeted Therapy Resistance to Targeted Anti-Cancer Therapeutics Volume 19 Series Editor: Benjamin Bonavida More information about this series at http://www.springer.com/series/11727 Cristina Maccalli • Matilde Todaro Soldano Ferrone Editors Cancer Stem Cell Resistance to Targeted Therapy Editors Cristina Maccalli Matilde Todaro Research Department Department of DIBIMIS Sidra Medicine University of Palermo Doha, Qatar Laboratory of Cellular and Molecular Pathophysiology Soldano Ferrone Palermo, Italy Department of Surgery Massachusetts General Hospital Harvard Medical School Boston, MA, USA ISSN 2196-5501 ISSN 2196-551X (electronic) Resistance to Targeted Anti-Cancer Therapeutics ISBN 978-3-030-16623-6 ISBN 978-3-030-16624-3 (eBook) https://doi.org/10.1007/978-3-030-16624-3 © Springer Nature Switzerland AG 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Aims and Scopes Cells with stemness/cancer-initiating properties (CSCs/CICs) have been isolated from tumors with different histological properties. These cells have been shown to be responsible for tumor formation and progression and represent the component of tumor resistance to standard therapies and immunotherapy. During the last decades, targeted cancer therapies have been developed, including drugs, antibod- ies, chemical inhibitors, etc., targeting specific tumor-associated genes, antigens, and blood vessels that regulate tumor growth and progression. More recently, FDA- and EMA-approved immunotherapy agents targeting the host immune responses have shown clinical activity by improving patient’s survival. Targeted cancer therapies are being used alone or in combination either with other targeted therapies or with standard therapies. Tumor cell resistance to targeted therapies remains a major problem, and several strategies are being considered to reverse the resistance to these therapies. The bio- logical, molecular, and immunological characterization of CSCs/CICs contributed to identify key signaling pathways involved in controlling their properties. Therapeutic strategies selectively targeting cancer cells with stemness properties can overcome tumor resistance. The volume “Cancer Stem Cell Resistance to Target Therapy” part of the special series Resistance to Targeted Anti-Cancer Therapeutics will focus on the molecular and biological properties of cancer stem cells rendering these cells resistant to target therapy. Moreover, insights regarding novel CSC-/CIC-specific target molecules and their interaction with the host immune system will be provided, and possible solutions to the problem of tumor resistance to therapies will be discussed. v About the Editors Cristina Maccalli MSc, PhD is a Principal Investi- gator at the Division of Translational Medicine, Sidra Medicine, Doha, Qatar. Cristina obtained in 1990 a Master’s Degree in Biological Sciences and then, in 1996, a PhD in Applied Genetics at the University of Milan, Italy. Her research interest lies in the area of immunology, tumor immunology, and immunotherapy, with main focus on the functional characterization of immune responses, cancer stem cells, and identification of biomarkers pre- dictive of patients’ clinical outcome and responsive- ness to therapies. She has carried out her postdoctoral research pro- grams at the National Cancer Institute in Milan, Italy, and, then, at the Surgery Branch, National Cancer Institute, NIH, Bethesda, MD, USA. From 2003 to mid-2007, she worked as investigator at the Istituto Superiore di Sanita’, Rome, Italy. In 2007, Cristina joined the Unit of Immuno-biotherapy of Melanoma and Solid Tumors at the San Raffaele Foundation Scientific Institute, Milan, Italy, and she has been dedi- cated to novel studies on the immunological character- ization of cancer stem cells from glioblastoma and colorectal cancer patients and to perform monitoring of immune responses in cancer patients undergoing immunotherapy. In 2013, she contributed in the role of senior investigator to set up in the context of the Italian Network for Biotherapy of Tumors (NIBIT), a novel laboratory dedicated to the identification of biomark- ers for cancer patients through the design of standard- ized and validated immune-monitoring assays. In vii viii About the Editors October 2014, Cristina joined the Translational Medicine Department at Sidra Medicine, Doha, Qatar, where she is involved in development of innovative studies in the context of biomarker discovery and immunotherapy. Her principal project areas are (1) the generation of chimeric receptor-engineered T cells to target hematological malignancies, (2) the molecular and functional characterization of cancer stem cells isolated from colorectal and breast cancer patients, and (3) the identification of biomarkers predictive of clini- cal outcome of patients with inflammatory bowel disease. Cristina is author/coauthor of about 60 original peer-reviewed publications and 3 chapter books. She is associate editor of the Journal of Translational Medicine and reviewer of a variety of international sci- entific journals (e.g., The Journal of Immunology, Cancer Research, Clinical Cancer Research, Cancer Immunology, Immunotherapy, Frontiers in Immunology, etc.). She acted as reviewer for fellow- ship programs of the Society for Immunotherapy of Cancer (SITC). She has been involved as lecturer in educational courses in immuno-oncology in the con- text of NIBIT. She is a member of the SITC. In the con- text of SITC, she has served as member of working groups on immunotherapy biomarkers. Matilde  Todaro MD, has contributed to cancer research by developing new anticancer therapies. Recently, her interest has been focused on the most promising and innovative biomedical research, namely, cancer stem cells and their role in the onset and pro- gression of breast cancer. The publication of many of her studies in prestigious journals has granted her inclusion in a national and international research network. Dr. Todaro’s group was one of the first to isolate and propagate cancer stem cells from tumors of epithelial origin. This advanced contribution to the scientific community led her to establish collaborations with prestigious international pharmaceutical companies such as Eli Lilly, Roche, Pfizer, Tristar, Merck, and Trevigen, who have financed part of her research aimed at the development of therapies against cancer stem cells. About the Editors ix She has supervised and mentored many gradu- ate students, and she was the tutor in charge of several postgraduate and postdoctoral fellows. Recently, Dr. Todaro’s scientific activity is aimed at studying the biology of breast cancer in order to identify new molecular targets that facili- tate early diagnosis and to improve the treatment options against breast cancer that nowadays are restricted to conventional therapies. Dr. Todaro is currently an associate professor, SSD MED/04, General Pathology, University of Palermo. She is the medical director and head of Endocrinology and Metabolic Disease, Intensive Metabolic Care Unit, Institute of Clinical Medicine, University of Palermo. She is also responsible for the onco-hematological diagnos- tics laboratory, Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo. Soldano  Ferrone MD, PhD, joined the Massachusetts General Hospital, Harvard Medical School, in 2012 as professor in the Department of Surgery. He has held faculty positions at many Academic Institutions in the United States and at the Medical School of the University of Milan, Milan, Italy. His research program focused on the develop- ment of antibody-based immunotherapeutic strat- egies for the treatment of solid tumors and on the characterization of the role of defects of HLA class I antigen processing machinery as an escape mechanism utilized by tumor cells to avoid immune recognition and destruction. These stud- ies are greatly facilitated by the large panel of HLA antigen- and human tumor antigen-specific monoclonal antibodies he has developed and shared with the scientific community over the years. He has described the results of his studies in more than 600 papers published in peer-reviewed journals. Moreover, he has been the editor of 14 books and the guest editor of 5 special issues of oncology journals. x About the Editors Dr. Ferrone has received many awards and honors. For the last 30 years, he has been the member of many review committees including NIH Study Sections and of the edi- torial boards of many scientific journals. Furthermore, he is the member of several external scientific boards. Preface Cancer represents one of the leading causes of death. Advances on the genetic and molecular characterization of cancer with different histological origins allowed to improve therapeutic treatments such as chemotherapy, radiotherapy-targeted agents, and their combinations. This led to increasing the overall survival for patients with some type of tumors. However, a significant proportion of cancer patients is unre- sponsive or develops resistance to treatments. Factors contributing to failure of therapeutic interventions are genetic and epi- genetic variability, interactions with tumor microenvironment and differences in patient’s genomics, leading to both intratumor and intertumoral heterogeneity. Cancer stem cells or cancer-initiating cells (CSCs/CICs) have been identified in both hematological and solid tumors. They are present with relatively low frequency within tumor lesions and are endowed with self-renewal, multipotency, and tumori- genic features. These rare cells have been shown as tumors’ components responsi- ble for tumor formation, resistance to therapies, and tumor progression and metastatization. The tumorigenic properties of cancer stem cells have been demonstrated through the usage of xenotransplantation in immune-deficient mice. These systems have proven that upon transplantation of cells with “stemness” features, the neoformation of malignant lesions representing the phenocopy of the original tumor is observed. These models have allowed to demonstrate that tumors have a hierarchical organi- zation and following serial transplantation, phenotypically different subpopulation can be identified including stem-like cells. Nevertheless, the biological character- ization of CSCs/CICs provided evidence of their high grade of heterogeneity and plasticity. These properties are influenced by the interaction between CSCs/CICs and tumor microenvironment, in which the CSC-associated niche, which is needed for their survival and maintenance, is localized. Multiple “bona fide” CSC-/CIC- associated markers have been identified depending on the tissue of origins. These markers are mostly overexpressed by CSCs/CICs but also shared with either dif- ferentiated tumor cells or normal stem cells. Nevertheless, some of these markers have been used either to isolate stem-like cells from neoplastic tissues or to localize these cells within tumor tissues. Moreover, the identification of cells positive for xi