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    Understanding Cancer from a Systems Biology Point of View: From Observation to Theory and Back
    Understanding Cancer from a Systems Biology Point of View: From Observation to Theory and Back
    Understanding Cancer from a Systems Biology Point of View: From Observation to Theory and Back
    Ebook215 pages8 hours

    Understanding Cancer from a Systems Biology Point of View: From Observation to Theory and Back

    By Irina Kareva

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    About this ebook

    Understanding Cancer from a Systems Biology Point of View: From Observation to Theory and Back starts with a basic question, why do we sometimes observe accelerated metastatic growth after resection of primary tumors? Next, it helps readers understand the systemic nature of cancer and how it affects treatment approaches and decisions. The book puts together aspects of cancer that many readers have most likely never combined, using unfamiliar, novel methods. It is a valuable resource for cancer researchers, cancer biologists, mathematicians and members of the biomedical field who are interested in applying systems biology methodologies for understanding and treating cancer.

    • Explains the systemic nature of cancer and how it affects decisions on treatment
    • Brings a variety of methods together, showing, in detail, the logical approach to finding answers to complex questions
    • Discusses the theoretical underpinnings of cancer as a systemic disease, providing the reader with valuable information on applicable cases
    LanguageEnglish
    PublisherAcademic Press
    Release dateFeb 7, 2018
    ISBN9780128136744
    Understanding Cancer from a Systems Biology Point of View: From Observation to Theory and Back
    Author

    Irina Kareva

    Dr. Irina Kareva is a theoretical biologist, and the primary focus of her research involves using mathematical modeling to study cancer as an evolving ecosystem within the human body, where heterogeneous populations of cancer cells compete for limited resources (i.e., oxygen and glucose), cooperate with each other to fight off predators (the immune system), and disperse and migrate (metastases). In 2017 Dr. Kareva gave a TED talk on using mathematical modeling for biological research. Dr. Kareva's book Understanding cancer from a systems biology point of view: from observation to theory and back was published by Elsevier in 2018. Dr. Kareva is a Senior Scientist in Simulation and Modeling at EMD Serono, Merck KGaA, where she develops quantitative systems pharmacology (QSP) models to help understand and predict dynamics of new therapeutics.

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    Book preview

    Understanding Cancer from a Systems Biology Point of View - Irina Kareva

    Understanding Cancer from a Systems Biology Point of View

    From Observation to Theory and Back

    Irina Kareva

    Table of Contents

    Cover image

    Title page

    Copyright

    Dedication

    Chapter 1. Introduction

    A Primer on Mathematical Modeling: Predator–Prey

    Estimating Parameters

    Chapter 2. Tumor Dormancy

    Introduction

    Modeling Parametrically Heterogeneous Populations: Parameter Distribution Technique

    Parameters and Distributions

    Primary Dormancy, Metastatic Dormancy, Both or Neither?

    Getting Back to the Question

    Chapter 3. Cancer Immunoediting: A Process Driven by Metabolic Competition as a Predator–Prey-Shared Resource Type Model

    Background

    Model Description

    Model Investigation: Using the Model to Answer Questions

    We Wrote and Analyzed the Model. Now What?

    Pharmacokinetic and Pharmacodynamic Modeling

    Including the Effects of Various Immunotherapeutic Interventions

    Getting Back to the Question

    Chapter 4. Blood Vessel Formation and Pathological Angiogenesis as Mitigated by Competing Angiogenesis Regulators

    Introduction

    Normal Blood Vessel Formation

    What Happens in Tumors?

    Using Mathematical Modeling for Hypothesis Testing

    Model Description

    Parameter Estimation

    Normal Blood Vessel Formation

    Summary

    Chapter 5. Angiogenesis Regulators as a Possible Key to Accelerated Growth of Secondary Tumors Following Primary Tumor Resection

    Introduction

    Sensitivity Analysis

    Results

    Therapeutic Implications

    Chapter 6. Cancer as a Systemic Disease That Requires a Systemic Approach

    Origins of Maximum Tolerated Dose Protocol for Chemotherapy Administration

    What Do We Now Know About Most Solid Tumors?

    Cancer as an Ecosystem: Lessons From Conservation Biology

    Metronomic (Maintenance) Chemotherapy as a Way to Target Tumor Microenvironment

    Decreased Angiogenesis

    Improved Antitumor Immunity

    Decreased Therapeutic Resistance

    Clinical Trials

    Potential Synergy Between Immunotherapy and Chemotherapy

    Cytotoxic T-Lymphocyte Antigen-4 Inhibition

    PD-1, PD-L1, and PD-L2 Inhibition

    Combination: Metronomic Chemotherapy and Checkpoint Inhibitors

    Thinking of Cancer as a Systemic Disease

    Chapter 7. Conclusions

    Acknowledgments

    Supplementary Chapter I: Code, Exercises, and Future Direction

    Glossary

    Index

    Copyright

    Academic Press is an imprint of Elsevier

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    Copyright © 2018 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 information 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 Publisher (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 information 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: 978-0-12-813673-7

    For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

    Publisher: Mica Haley

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    Editorial Project Manager: Lisa Eppich

    Production Project Manager: Kiruthika Govindaraju

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    Typeset by TNQ Books and Journals

    Dedication

    To my family

    Chapter 1

    Introduction

    Contents

    A Primer on Mathematical Modeling: Predator–Prey

    Estimating Parameters

    Research is driven by the interplay of theory and experiment. Experiments give rise to theories, which we test using experiments, which drive theory, until we find answers to questions that interest us. After all, research is first and foremost about satisfying scientific curiosity.

    Some experiments are easy to run. Most are not. Experiments require planning, and for most biological questions, expensive equipment, laboratory space, and abundant resources. Even more importantly, investigating any biological system means trying to unravel the interplay of numerous factors, the influence of which on the final outcome is not always easy to tease out. That is where mathematical modeling can come in very handy.

    The schematic approach for using mathematical modeling for testing hypotheses about biological mechanisms can be summarized as follows:

    In a way, mathematical modeling is like Rosetta Stone, a way to translate back and forth between mathematics and biology. As modelers, we try to (1) understand a biological mechanism, (2) tease out key players that drive the dynamics, (3) formulate assumptions about how these key players interact with each other and their environment, (4) translate these assumptions into equations, (5) analyze them using a very well-developed mathematical apparatus, and (6) translate the results back into the language of biology. If our predictions are consistent with experimental observations, then maybe we got it right, and we can now try to make further predictions about what will happen if we change this or that aspect of the system. Conducting early in silico experiments can save thousands of dollars when planning further experiments, advancing a fiscally responsible way of conducting research.

    And what if the predictions made by the model are not consistent with experimental observations? That may be even more interesting. This means that some of our assumptions are incorrect, and thus our understanding of biology is incomplete. The good news is that since we built the model, we control all the assumptions, and so we can go through them one by one and identify which one is causing the discrepancy. Chances are we just identified a gap in knowledge, which we can now try to close using both theory and experiment.

    However, all of this matters only when there is a question. A question that drives your curiosity, a question that bugs you like a pebble in your shoe. The question driving the work that led to this book stems from the following observation: sometimes after removal of primary tumors, metastases start growing faster. This has been observed particularly in colorectal cancer but in other cancer types as well. And the question is Why? What is going on?

    It is possible that removing a primary tumor can result in some kind of malignant transformation, causing secondary tumors to form and rapidly start growing, but it is not very likely. Although some aggressive tumor types do exist, tumors typically take years and sometimes decades to form and grow. It is more likely that secondary tumors were there all along, either kept at bay or sleeping, and something either about the process of primary tumor removal, such as surgery, or the changes that happen in the body after the removal of the primary tumor woke them up. Cancers that are present but do not grow are known as dormant tumors, cancer without disease. Trying to understand mechanisms that underlie the state of dormancy might hold a key to answering the question underlying this book.

    However, before we dive into that, it is important to gain some understanding about the basic mechanisms of mathematical modeling.

    A Primer on Mathematical Modeling: Predator–Prey

    A key aspect of understanding dynamical systems and writing mathematical models lies in thinking not of what things are but of what they do. This translates into thinking about relationships between individuals (people, animals, or cells), and how they interact with each other and their environment.

    For instance, predator–prey type models have been developed extensively in the literature, starting from the classic Lotka–Volterra models that describe the dynamics of two populations, where the growth of one is dependent on consuming the other. These models were used to explain the dynamics of natural populations of lynx and snowshoe hare in Canada, for instance. However, predator–prey type models are also the classic framework for describing tumor–immune interactions, where tumor is the prey and immune system is predator. We will use this framework as an example for describing how to

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