Targeted Therapy in Translational Cancer Research E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Fachliteratur
• Serie: Translational Oncology
• Sprache: Englisch

Seitenzahl: 1597

Veröffentlichungsjahr: 2015

Beschreibung

Targeted Therapy in Translational Cancer Research for the Translational Oncology series provides a comprehensive overview of recent developments in our understanding of tumor biology, elucidates the roles of targets and pathways involved in carcinogenesis, and describes current state-of-the-art anticancer therapy, as well as the most promising areas of translational research and targeted therapy. * Introduces cutting-edge 'bench to bedside and back' breakthroughs which have transformed the diagnosis, prognosis, and treatment of cancer * Covers basic principles of targeted therapy, including immunotherapy and the roles of cancer stem cells, the microenvironment, angiogenesis, epigenetics, microRNAs, and functional imaging in precision medicine * Summarises major advances in therapeutic management of hematologic malignancies and solid tumors using conventional therapy, targeted therapy, immunotherapy, or novel treatment modalities

Leseprobe

TRANSLATIONAL ONCOLOGY

SERIES EDITORS

ROBERT C. BAST, MD

Vice President for Translational Research The University of Texas MD Anderson Cancer Center Houston, TX, USA

MAURIE MARKMAN, MD

Senior Vice President for Clinical Affairs Cancer Treatment Centers of AmericaClinical Professor of Medicine Drexel University College of Medicine Philadelphia, PA, USA

ERNEST HAWK, MD, MPH

Vice President, Division of OVP, Cancer Prevention and Population Sciences The University of Texas MD Anderson Cancer Center Houston, TX, USA

Targeted Therapy in Translational Cancer Research

EDITED BY

Apostolia-Maria Tsimberidou, MD, PhD

Department of Investigational Cancer Therapeutics The University of Texas MD Anderson Cancer Center Houston, TX, USA

Razelle Kurzrock, MD

Center for Personalized Cancer Therapy UC San Diego Moores Cancer Center La Jolla, CA, USA

Kenneth C. Anderson, MD, PhD

LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center Department of Medical Oncology, Dana-Farber Cancer Institute Harvard Medical School Boston, MA, USA

Copyright © 2016 by John Wiley & Sons, Inc. All rights reserved.

Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Targeted therapy in translational cancer research / edited by Apostolia-Maria Tsimberidou, Razelle Kurzrock, Kenneth C. Anderson.   p. ; cm. – (Translational oncology)  Includes bibliographical references and index.  ISBN 978-1-118-46857-9 (cloth)  I. Tsimberidou, Apostolia-Maria, editor. II. Kurzrock, Razelle, editor. III. Anderson, Kenneth C., editor. IV. Series: Translational oncology (Series)  [DNLM: 1. Molecular Targeted Therapy. 2. Neoplasms–drug therapy. 3. Immunotherapy. 4. Individualized Medicine. 5. Translational Medical Research. QZ 267]  RC271.I45  616.99′4061–dc23

2015015320

CONTENTS

List of Contributors

Series Foreword

Foreword

Preface: Bench to Bedside and Back

PART I: Principles of Targeted Therapies

CHAPTER 1: Toward Personalized Therapy for Cancer

Introduction

Personalized Targeted Therapy

Prognostic Stratification and Prediction of Chemotherapy Benefit in Hormone Receptor-Positive Breast Cancer

HER2-Targeted Therapy in Breast Cancer

BRAF Inhibitors in BRAF Mutant Melanoma

Strategies for Comprehensive Molecular Characterization

A Personalized Approach to Investigational Therapy Selection

Challenges to Personalized Cancer Therapy

Summary

References

CHAPTER 2: Combining Targeted Therapies

Rationale for Drug Combination of Targeted Agents

Principles and Strategies for Combining Agents Targeting Signaling Pathways

Combining Targeted and Immune Therapies

Preliminary Data: Building the Hypothesis and Rationale for the Trial

First Step, Regulatory Issues to Consider Before a Hands-On Approach

Clinical Scenarios and Clinical Trial Design

Conclusions

References

CHAPTER 3: Principles of Targeted Immunotherapy

Introduction

Principles of Immunotherapy

Conclusion

References

CHAPTER 4: Cancer Stem Cell Principles

Background

Historical Perspective

Cancer Stem Cells in Hematologic Malignancies

Cancer Stem Cells in Solid Tumors

Controversy and Clinical Relevance

Targeting Cancer Stem Cells

Conclusions

Note

References

CHAPTER 5: The Tumor Microenvironment as a Target for Therapeutic Intervention

Introduction

Components of the TME

Complex Communication Between Tumor Cells and Their Microenvironment

Lessons Learned and Conclusions

Final Remarks

Acknowledgment

References

CHAPTER 6: The Role of Angiogenesis in Cancer

How Vessels Are Formed

Angiogenesis Pathways

Therapies Targeting the VEGF Pathway

Toxicities

Resistance to Antiangiogenic Therapy

Biomarkers

Concluding Remarks

References

CHAPTER 7: Epigenetics and Epigenetic Therapy of Cancer

Structure of the Genetic Code

DNA Methylation

DNA Demethylation

TET Proteins

Histone Modifications

Noncoding RNA

Polycomb Repressive Complex

IDH1/2

Epigenetic Perturbations in Hematologic Malignancies

Epigenetic Perturbations in Breast Cancer

Epigenetic Perturbations in Lung Cancer

Epigenetic Perturbations in Colon Cancer

Epigenetics in Diagnostics

Role of Epigenetics in Therapeutics

Histone Deacetylase Inhibitors

EZH2 Inhibitors

Conclusions

References

CHAPTER 8: The Role of microRNAs in Cancer

Introduction

miRNAs Dysregulation in Cancer

miRNAs in Therapy

Conclusion

References

CHAPTER 9: Acute Myeloid Leukemia

Introduction

Monoclonal Antibodies

Targeting Drivers of Proliferation in AML

Targeting Apoptotic Pathways, Cell Cycle Regulation, and Cancer Cell Metabolism

Chimeric Antigen Receptors and Vaccines

Summary

References

CHAPTER 10: Targeted and Functional Imaging

Introduction

Functional Imaging of Tumor Physiology

Functional Imaging of Tumor Molecular Targets and Processes

Conclusion

Note

References

PART II: Targeted Therapy in Hematological Malignancies

CHAPTER 11: Targeted Therapies in Chronic Myeloid Leukemia

Introduction

CML Frontline Treatment Options

Other Strategies

Choice of Frontline Therapy

Management of TKI Resistance

Second Generation TKI

Third Generation TKI

Definition of Response and Failure to TKI Therapy and Choice of Therapy

Can TKIs Be Safely Discontinued?

Conclusions and Future Perspectives

References

CHAPTER 12: Targeted Therapy for Acute Lymphoblastic Leukemia

Introduction

Prognostication in ALL

Surface Antigen as a Therapeutic Target

BCR-ABL-Positive ALL

Ph-Like ALL

PI3K/AKT/mTOR Signaling Pathway Inhibitors and B-Cell Receptor Inhibitors

Chimeric Antigen Receptor Therapy

T-Cell ALL

Notch Inhibition in T-Cell ALL

Early T-Cell Precursor ALL

Conclusions

References

CHAPTER 13: Chronic Lymphocytic Leukemia

Background

Biologic and Molecular Aspects of CLL

Targeted Therapeutic Agents in the Treatment of CLL

Clinical Results with BCR Signaling Kinase Inhibitors

Other Novel Therapeutic Agents in CLL

Conclusions

References

CHAPTER 14: Multiple Myeloma

MM as a Neoplastic Factory of Immunoglobulins: Biologic and Clinical Implications

A Broader View: MM in the Context of the BM Niche

Distinct Molecular Targets of MM Cells

Conclusions and Future Perspective

References

CHAPTER 15: The Impact of Genomics on Targeted Therapy in Multiple Myeloma and Lymphomas

Genomics of Hematologic Neoplasms and Their Potential to Inform Rationale Therapies

Targeted Agents in Clinical Trials for Patients with MM and DLBCL

New Therapeutic Challenges Revealed by Genomics

References

CHAPTER 16: Targeted Therapy in Myelodysplastic Syndromes

Biological Hallmarks of Myelodysplasia

Current Standard of Care in MDS

New Therapeutic Targets in MDS

Conclusions

References

CHAPTER 17: Lymphoma and Targeted Therapies

Overview

Summary

References

PART III: Targeted Therapy in Solid Tumors

CHAPTER 18: Targeted Therapy in Solid Tumors: Brain

Introduction

Predictive and Prognostic Factors

Targets for Therapy

Future Perspectives

Concluding Remarks

References

CHAPTER 19: Targeted Therapy for Breast Cancer

Targeting ER in Breast Cancer

Targeting HER2 in Breast Cancer

Novel Targeted Treatments in ER Positive Breast Cancer

BRCA-Associated Tumors and PARP Inhibitors

Genomic Profiling

References

CHAPTER 20: Targeted Therapy in Solid Tumors: Colorectal Cancer

Overview

Targeted Therapy, Receptors, and Signaling Networks

Conclusion

References

CHAPTER 21: Endometrial Cancer

Endometrial Cancer

PI3K/PTEN/AKT/mTOR

EGFR and HER2

IGF-1R

FGFR2

E-cadherin

Conclusions

References

CHAPTER 22: Targeted Therapy in Solid Tumors: Head and Neck

Introduction

Genetic Alterations in Head and Neck Squamous Cell Carcinoma

Current Treatment for Head and Neck Squamous Cell Carcinoma

Targeted Therapy in Head and Neck Squamous Cell Carcinoma

Targeting the Epidermal Growth Factor Receptor

Targeting the Vascular Endothelial Growth Factor Receptor

Targeting the Proteasome

Targeting TP53a

Conclusions

References

CHAPTER 23: Targeted Therapy in Solid Tumors: Lung Cancer

Angiogenesis

Epidermal Growth Factor Receptor

ALK

ROS1

RET

BRAF

HER2

KRAS

Other Mutations in Adenocarcinomas

Squamous Cell Lung Cancer

Comprehensive Genomic Studies

Future Perspectives

References

CHAPTER 24: Targeted Therapy in Melanoma

Introduction

The MAP Kinase Pathway

BRAF as a Therapeutic Target

Paradoxical MAP Kinase Pathway Activation

MEK Inhibitors in BRAF-Mutant Melanoma

NRAS

CKIT

Acquired Resistance to BRAF-Targeted Therapy

Mechanisms of

de novo

BRAF Inhibitor Resistance

Intersection Between Targeted Therapy and Immune Therapy

Summary

References

CHAPTER 25: Ovarian Cancer

Introduction

Ovarian Cancer Histology

Molecular Aberrations in Ovarian Cancer

Targeting Angiogenesis

Targeting DNA Repair with Poly-ADP-Ribose Polymerase Inhibition

Targeting the RAS/RAF Pathway

Targeting the PI3K/AKT Pathway

Targeting the Epidermal Growth Factor Receptor Pathway

Targeting Folate

Targeting Other Pathways of Interest

Conclusion

References

CHAPTER 26: Molecular Therapeutics: Pancreatic Cancer

Introduction

Therapeutics Currently in Development

Conclusions

References

CHAPTER 27: Targeted Therapies for Pediatric Solid Tumors

Introduction

Neuroblastoma

Gliomas

Osteosarcoma

Ewing's Sarcoma

Rhabdomyosarcoma

Wilms' Tumor

Hepatoblastoma

Ependymomas

Medulloblastoma

Retinoblastoma

Conclusions

References

CHAPTER 28: Prostate Cancer

Introduction

Molecular Pathogenesis of Prostate Cancer

Systemic Prostate Cancer Treatments Targeting Androgen Signaling

Non-androgen Signaling-Targeted Systemic Treatments

Bone-Targeted Systemic Treatments

Immunotherapy

Future Perspectives

References

CHAPTER 29: Renal Cell Carcinoma and Targeted Therapy

Introduction

Molecular Pathogenesis of RCC

Important Signaling Pathways in RCC

Targeted Therapies in RCC

Conclusion

References

CHAPTER 30: Targeted Therapy in Solid Tumors: Sarcomas

Introduction

KIT

Conclusion

References

PART IV: Targeted Therapy for Specific Molecular Aberrations

CHAPTER 31: RAS-RAF-MEK Pathway: Aberrations and Therapeutic Possibilities

Introduction

The RAS Family: HRAS, KRAS, and NRAS

The Congenital RAS-opathies: Germline Mutations of

RAS

The Acquired RAS-opathies: Melanoma and NRAS

The RAF Family: ARAF, BRAF, and CRAF

BRAF Inhibitors

Management of Metastatic Melanoma in the Era of BRAF Inhibitors

The CRAF Story

MEK Inhibitors—The MEK Family: MEK1 and MEK2

Future Directions: Big Results for Small Molecules

References

CHAPTER 32: The Phosphatidylinositol 3-Kinase Pathway in Human Malignancies

Introduction

Phosphatidylinositol 3-Kinases

PI3K Effectors: AKT/mTOR

PI3K/AKT/mTOR Mutations

PI3K/AKT/mTOR as a Therapeutic Target

From Rational Drug Design to Clinical Efficacy: Lessons and Challenges

References

CHAPTER 33: Current Status and Future Direction of PARP Inhibition in Cancer Therapy

Introduction

BRCA1, BRCA2

, and Breast and Ovarian Cancer

DNA Damage and Repair

Role of PARP in DNA Repair

Molecular Mechanism of HRR

Clinical Development of PARP Inhibitors

Epithelial Ovarian Cancer

Maintenance Therapy

Other PARPi in Epithelial Ovarian Cancer

Breast Cancer

Prostate Cancer

Pancreatic Cancer

PARPi Therapy in Other Cancers

Other PARP Inhibitors in Development

Toxicity Profile of PARPi Monotherapy

PARPi as Combination Therapy

Predictive Biomarkers of Response to PARPi

Resistance to PARPi

Platinum Sensitivity Following PARPi Resistance

Conclusion and Future Directions

References

CHAPTER 34: Targeting the c-Met Kinase

Role of c-Met in Carcinogenesis and Tumor Progression

c-Met Expression in Various Tumor Types

Cross Talk Among Signaling Pathways

c-Met Pathways as Therapeutic Targets

HGF/c-Met-Targeted Therapies Now in Development

Mechanisms of Resistance

Future Perspectives

References

CHAPTER 35: KIT Kinase

KIT Biology

KIT in Cancer

KIT as a Therapeutic Target

KIT Future Strategies

References

CHAPTER 36: TP53

Introduction

p53 Pathway Abnormalities in Malignancies

Targeting p53 for Cancer Therapy

Concluding Remarks

Acknowledgments

References

PART V: Future Perspectives

CHAPTER 37: Future Perspectives

Introduction

Study of Tumor Biology

Molecular Testing for Clinical Use

Tumor Monitoring

Use of Bioinformatics

Innovative Clinical Trials

Optimal Access to Drugs

Drug Development Regulations

Economic Considerations

Value of Cancer Care

Centralized Big Data

References

Index

EULA

List of Tables

Chapter 1

Table 1.1

Chapter 2

Table 2.1

Table 2.2

Chapter 3

Table 3.1

Chapter 5

Table 5.1

Chapter 6

Table 6.1

Table 6.2

Chapter 8

Table 8.1

Table 8.2

Chapter 9

Table 9.1

Chapter 11

Table 11.1

Table 11.2

Table 11.3

Chapter 13

Table 13.1

Table 13.2

Table 13.3

Chapter 14

Table 14.1

Table 14.2

Table 14.3

Chapter 15

Table 15.1

Chapter 16

Table 16.1

Chapter 18

Table 18.1

Chapter 20

Table 20.1

Table 20.2

Chapter 21

Table 21.1

Chapter 22

Table 22.1

Table 22.2

Chapter 23

Table 23.1

Chapter 24

Table 24.1

Chapter 25

Table 25.1

Table 25.2

Table 25.3

Chapter 26

Table 26.1

Chapter 27

Table 27.1

Chapter 28

Table 28.1

Chapter 29

Table 29.1

Table 29.2

Chapter 30

Table 30.1

Table 30.2

Chapter 32

Table 32.1

Chapter 33

Table 33.1

List of Illustrations

Chapter 1

Figure 1.1 The cancer care continuum for personalized medicine.

Figure 1.2 Biomarker-driven clinical trials. (a, b) Biomarker-selected single arm trials may deliver targeted therapy to patients selected for a specific genomic alteration or other biomarker or may randomize patients with a biomarker to investigational therapy or standard of care therapy. (c, d) Patients may be stratified based on the biomarker status, and patients with or without the biomarker may receive the investigational therapy or they may be randomized between standard of care therapy and the investigational arm. (e) In umbrella trials, multiple biomarkers may be simultaneously assessed, and patients allocated to treatment based on biomarker status. (f) In adaptive trials, initially patients can be randomly allocated between treatment arms, but subsequently the allocation is adaptive, based on disease control or other short-term endpoints in each biomarker subtype for each therapy. (g) In N-of-1 trials, patients are given a therapeutic regimen assessed to match their genomic/molecular profile most closely.

Chapter 2

Figure 2.1 Proposal of novel trial designs exploring combinations of targeted therapies. Combining two drugs depicts a 2D matrix of possible dose levels (a). In some cases, dose escalation can proceed without exploring all those potential dose levels; dose escalation can proceed in a diagonal orientation (b), by increasing the dose of each drug, one at a time like a staircase (c) or by starting at full doses of one drug and escalating the dose of the other (e). In case side effects are seen, dose escalation can diverge and several alternative cohorts can be opened (d), allowing exploration of multiple MTDs. In the case of combining 3 drugs, the matrix of dose levels is in 3D (f). In looking for synergy, one could begin with one drug, and after an assessment, the other one is added (g). When exploring the role of one drug for overcoming drug-resistance of the principal one, patients could be treated with the principal one and at disease progression, the second drug is added (h). Multiple combinations or schedules can be compared in a single study with or without an adaptive randomization methodology (i and j).

Chapter 3

Figure 3.1 Antibody-based immunotherapy. Various iterations of monoclonal antibodies (mAbs) have been developed for the treatment of cancer. Unconjugated mAbs bind to their target and engage NK cells, macrophages, dendritic cells as well as soluble complement components via the Fc-component of the mAb. These resulting effector functions include ADCC (antibody-dependent cellular cytotoxicity), CMC (complement-mediated cytotoxicity—not depicted), and ADCP (antibody-dependent phagocytosis—not depicted). Bispecific mAbs and BiTEs are engineered to bind to the TAA (tumor-associated antigen) and engage CD3 on CTLs (cytotoxic lymphocytes), thereby activating CTLs against tumor cells, independent of their TCR (T-cell receptor) specificity. TriomAbs additionally recruit NK cells and macrophages via their Fc-receptor. Immunoconjugates such as ADC (antibody-drug conjugates), RIT (radioimmunotherapies), immunotoxins, or ADEPT (antibody-dependent enzyme prodrug therapies) deliver cytotoxic agents directly to the target cell. Antagonistic mAbs to CTLA-4, PD1 or PD1-L block ligand–receptor interactions that otherwise deliver inhibitory signals to the T cell and allow targeted cellular cytotoxicity to ensue.

Figure 3.2 Chimeric antigen-receptor (CARs) T cells. T cells can be transduced to express chimeric antigen-receptors (CARs) that endow them with specificity to a particular TAA. Although many iterations have been developed, the CAR commonly consists of a sFcv (single-chain variable fragment) derived from an mAb against a TAA which is linked to an ITAM (immunoreceptor tyrosine-based activation motif) such as the CD3ζ-chain. Frequently, additional intracellular co-stimulatory domains are included (not depicted here). CAR+ T-cells can recognize TAAs independent of their MHC-presentation and become activated upon binding to the TAA.

Chapter 4

Figure 4.1 Cancer stem cell concept versus stochastic model of tumor growth. The cancer stem cell concept proposes that most cancers are broadly organized in a similar hierarchical structure to their tissue of origin: relatively rare populations of stem-like cells, termed cancer stem cells (depicted in red), give rise to more prevalent differentiated cells. It further hypothesizes that current treatment methods eliminate the differentiated cells, but leave behind the drug-resistant cancer stem cells that eventually regenerate the tumor and lead to relapse; accordingly, cure requires treatments that target the drug-resistant cancer stem cells. Conversely, the stochastic model suggests that some cancer cells will escape therapy as a result of chemotherapy response following first order kinetics, and any remaining cancer cell can regenerate the tumor. Under this model, it would not be necessary to specifically target a subset of cells, but rather better targeting of the total population is needed.

Chapter 5

Figure 5.1 Evolution of the concept of the tumor microenvironment in cancer biology: some milestone discoveries.

Chapter 8

Figure 8.1 miRNAs biology. (a) Phylogenetic tree indicating conserved genomic clustering of miR-100, let-7, and miR-125/lin-4 microRNAs. Note that the human genome contains three miR-100, let-7, and miR-125/lin-4 clusters on chromosomes 9, 11, and 21 respectively. (b) Alignments of the human let-7 family members. The seed region of let-7 is highlighted in red: it is identical for all the paralogs. (c) Genomic organization of miRNA genes in human. Intergenic and intronic monocistronic or multicistronic miRNA genes are represented; miRtrons are also shown. (d) miRNAs are transcribed in the nucleus mainly by the RNA polymerase II producing a primary-miRNA (pri-miRNA). The primary step of miRNA biogenesis and maturation is the nuclear cleavage of the pri-miRNA by a ribonuclease III enzyme called Drosha liberating a ∼60–70 nt stem–loop intermediate known as the miRNA precursor called pre-miRNA (cropping). After this cleavage the pre-miRNA is transported into the cytoplasm by Exportin 5 (Exp 5), a Ran-GTP-dependent nucleo/citoplasmic cargo transporter (export). Once exported into the cytoplasm, pre-miRNAs are processed into short double-strand miRNA duplex by Dicer (dicing). Mature miRNA of 19–25 nt in length is incorporated into the RNA-induced silencing complex (RISC) where they target specific mRNAs for translational repression or mRNA cleavage therefore regulating gene expression.

Chapter 10

Figure 10.1 Glucose metabolism and cell proliferation PET imaging. Whole-body FDG-PET and FLT-PET in 73-year-old man with mantle cell lymphoma for pre- and post-therapy evaluation. Coronal maximal intensity projection (MIP) images reveal multiple FDG and FLT avid lesions in lymph node chains. Pre-therapy FDG (a) and FLT (b) scans were performed within 24 hours of each other, as well as the post-therapy FDG (c) and FLT (d) scans. Note interval decrease in metabolism and cell proliferation in tumor sites following therapy.

Figure 10.2 Glucose metabolism and hypoxia PET imaging. Whole-body FDG-PET (a) and whole-body

18

F-HX4-PET (b) coronal images of 76-year-old man with laryngeal cancer status post combined chemoradiation therapy. Note mild FDG uptake in mid neck (arrow) due to post-treatment inflammation and lack of

18

F-HX4 uptake indicating lack of tumor hypoxia. Patient is currently alive for approximately 3 years since PET imaging.

Figure 10.3 Glucose metabolism and angiogenesis PET imaging. Whole-body FDG-PET (a) and whole-body

18

F-RGD-K5-PET (b) coronal MIP images of 60-year-old man with metastatic gastrointestinal stromal tumor to liver. Note multiple FDG avid hepatic metastases and lack of

18

F-RGD-K5 uptake within metastatic lesions indicating lack of angiogenesis. The patient did not respond to anti-angiogenesis therapy and subsequently passed away several months after PET imaging due to tumor progression.

Chapter 12

Figure 12.1 Monoclonal antibodies in B-cell ALL.

Chapter 13

Figure 13.1 B-cell receptor (BCR) signaling pathways and therapeutic targets in CLL B cell (shown with a lightning bolt symbol). BCR signaling pathways and therapeutic targets: BCR signaling in CLL can occur in the presence of an external antigen (Ag) or by recognizing an internal epitope on light chain FR3 with HCDR3 region on heavy chain of the surface immunoglobulin (sIg). Autonomous stimulation activates the phosphatidylinositol 3-kinase (PI3K) pathway directly while antigen-dependent signaling stimulates other signaling molecules as shown in the figure (see the main text for details). Chemokines, chemokine receptors, endothelial cells, and interactions of nurse-like cells (NLC) are shown. (a) Kinase inhibitors of BCR signaling. The lightning bolt symbol (pink) indicates major kinases LYN, SYK, BTK, p110PI3Kδ, and p110PI3K, and other isoforms (γ, α, β) as therapeutic targets across the BCR signaling pathway. Signaling cascade and specific inhibitors of each class are discussed in the main text. (b) Monoclonal antibodies (mAbs) (in yellow)—common surface epitopes used for developing therapeutic mAbs include CD20, CD52, CD37, and CD40. Other targets of potential relevance include inhibitors of mTOR/AKT pathway depicted in bolt (green), inhibitors of CXCR4 receptors depicted in bolt (white), inhibitors of RAS/MAP kinase pathway depicted in bolt (black), inhibitors of protein kinase C beta (PKCβ), and NFkB depicted in bolt (blue and brown, respectively).

Chapter 14

Figure 14.1 Pathogenesis of MM. MM is the cancer transformation of BM-resident long-lived PC and evolves from the premalignant conditions MGUS and smoldering MM. Initial oncogenic events are hypothesized to take place during the process of immunoglobulin isotype switch and somatic hypermutation in the GC. Genetic, epigenetic, and biologic events are outlined along with the neoplastic evolution. Diverse patterns of clonal evolution have been recently identified in MM and are outlined here and are overall characterized by a progressive increase in genomic complexity culminating at the leukemic stage of MM.

105

Abbreviations: GC: germinal center; PC: plasma cell; MGUS: monoclonal gammopathy of undetermined significance; SMM: smoldering MM; MM: multiple myeloma; F: founder clone; S: subclone. Modified with permission from Reference 106.

Figure 14.2 Molecular targets in MM involved in protein synthesis, folding and disposal. The cartoon synthesizes the molecular targets identified along the processes of protein synthesis, folding and disposal, in particular along the ubiquitin-proteasome pathway and alternative proteolytic pathways. Green boxes outline FDA-approved while red boxes signify drugs currently being evaluated in clinical trials. Abbreviations: E1: ubiquitin-activating enzymes; E2: ubiquitin-conjugating enzymes; E3: ubiquitin ligase enzymes; Ub: ubiquitin; DUBs: deubiquitinating enzymes.

Figure 14.3 The large blue cell in the center is a MM cell with nucleus, endoplasmic reticulum and proteolytic pathways outlined. The close interplay with bone marrow stromal cells (BMSC) in light brown, osteoclasts (in red) and osteblasts (in green) is outlined. Immune cells relevant for immunologic escape of MM are also represented. Key signaling molecules and cytokines are represented in pale pink ovals while in pale pink squares are molecules targeted by currently approved therapies. Modified with permission from Reference 106.

Chapter 16

Figure 16.1 Treatment algorithm for the current standard of care in MDS. Low-risk MDS: Consider ESAs +/– G-CSF if EPO levels predict possibility of response (<500 mUI/mL). In patients with del(5q) treatment with lenalidomide should be initiated. If loss of response appears, consider treatment with hypomethylating agents or inclusion in clinical trial. High-risk MDS: Standard treatment should involve HMA treatment followed by alloSCT if candidate to transplantation. Inclusion in a clinical trial if relapse or loss of response should be considered if available.

Figure 16.2 Main molecular targets of new transduction inhibitors in MDS.

Chapter 17

Figure 17.1 Antibody-drug conjugates (ADC).

Source:

Reproduced from Sievers and Senter 2013, Reference 1 with permission of Annual Reviews.

Figure 17.2 Antigen-dependent B-cell receptor (BCR) signaling and its targeting by small-molecule inhibitors. Antigen binding induces the aggregation of the BCR with its co-receptors CD79 A and B, which become phosphorylated by the tyrosine kinases LYN and SYK. SYK activates phosphoinositide 3

–

kinase (PI3Kδ), which in turn converts phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate PIP3. PIP3 serves as a docking site for the cytoplasmic kinases Bruton's tyrosine kinase (BTK) and AKT. BTK phosphorylates and thereby activates phospholipase C gamma 2 (PLCγ2), which in turn generates a set of second messengers to activate protein kinase C beta (PKCβ). PKCβ phosphorylates IκB kinase (IKK) to activate nuclear factor κB (NF-κB) transcription factors that regulate gene expression of several survival factors. The kinases inhibited by small molecules with promising clinical activity are indicated.

Source:

Reproduced from Wiester 2013, © 2013, Reference 15 with permission of the American Society of Clinical Oncology.

Figure 17.3 Potential effects of immunomodulatory agents in lymphomas.

Source:

Reproduced from Chanan-Khan and Cheson 2008, Reference 78 with permission of the American Society of Clinical Oncology.

Chapter 18

Figure 18.1 Molecular subclasses of GBM and their genomic molecular correlates. Genomic alterations and survival associated with five molecular subtypes of GBM. Expression and DNA methylation profiles were used to classify 332 GBMs with available (native DNA and whole genome amplified DNA) exome sequencing and DNA copy-number levels. The most significant genomic associations were identified through Chi-Square tests, with

p

-values corrected for multiple testing using the Benjamini-Hochberg method. Reproduced from Brennan et al., 2013, Reference 14 with permission from Elsevier.

Figure 18.2 Pathway alterations in GBM. Overall alteration rate summarized for canonical PI3K/MAPK, TP53 and RB regulatory pathways. Reproduced from Brennan et al., 2013, Reference 14 with permission from Elsevier.

Chapter 20

Figure 20.1 Epidermal growth factor receptor (EGFR) targeting using monoclonal antibodies (mAbs), cetuximab and panitumumab. Epithelial cells are stimulated by EGF to activate multiple signaling cascades that initiate mRNA transcription and translation to protein that leads to migration, invasion, survival and proliferation. EGFR is inhibited by these mAbs. The proteins in these signaling cascades are defined as folows: (1) growth factor receptor-bound protein 2 (Grb2) → son of sevenless (SOS) → rat sarcoma (Ras) → rapidly accelerated fibrosarcoma (RAF) → microtubule-associated protein kinase (MAPK)-extracellular signal regulated kinase (ERK and MEK); (2) sarcoma (Src) → signal transducer and activator of transcription (STAT); (3) Janus kinase (JAK) → STAT; (4) phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) → v-akt murine thymoma viral oncogene homolog 1 (AKT) → mammalian target of rapamycin (mTOR) that is inhibited by phosphatase and tensin homolog (PTEN).

Figure 20.2 Vascular endothelial growth factor (VEGF) targeting uses monoclonal antibodies (mAbs), bevacizumab and aflibercept. Vascular endothelial cells are stimulated by VEGF to activate multiple signaling cascades that initiate mRNA transcription and translation to protein that initiate migration, invasion, survival and proliferation and alter vascular permeability along with angiogenesis. The key signaling cascades are defined in Figure 20.1. Regorafennib is a potent multi-target kinase inhibitor that prevents the phosphorylation and activation of multiple VEGFR isoforms 1–3 along with numerous other targets.

Chapter 21

Figure 21.1 Relevant pathways and druggable targets in endometrial cancer. Abbreviations: PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate; PI3K, phosphatidylinositol 3 kinase; PTEN, phosphatase and tensin homolog deleted on chromosome 10; AKT, v-akt murine thymoma viral oncogene homolog 1; mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; S6K, ribosomal protein S6kinase beta-1; Ras, rat sarcoma gene; Raf, v-raf-1 murine leukemia viral oncogene homolog 1; MEK, mitogen activated protein kinase kinase; ERK, mitogen activated protein kinase; IRS-1, insulin receptor substrate 1; LKB1, liver kinase B1; AMPK, adenosine monophosphate kinase; ATP, adenosine triphosphate; AMP, adenosine, monophosphate; EGFR, epidermal growth factor receptor; HER2, epidermal growth factor 2 receptor; IGF-1R, insulin-like growth factor 1 receptor; FGFR2, fibroblast growth factor receptor 2; VEGFR, vascular endothelial growth factor receptor; PDGFR, platelet-derived growth factor receptor; EGF, epidermal growth factor; FGF, fibroblast growth factor; IGF, insulin-like growth factor; TGFα, transforming growth factor α; VEGF, vascular endothelial growth factor; PDGF, platelet-derived growth factor; MLH1, mutL homolog 1; PARP, poly ADP-ribose polymerase; ER, estrogen receptor. Asterisks indicate druggable targets that have been or are currently being evaluated in clinical trials for the treatment of endometrial cancer. Highly prevalent alterations, such as p53 and E-cadherin, remain major obstacles for conventional drug design.

Chapter 23

Figure 23.1 Trial design by Lung Cancer Mutation Consortium. LCMC trials are designed to match a targeted agent to the specific mutation. Crizotinib is an inhibitor of MET, ALK, and ROS1. Dacomitinib is a second-generation EGFR TKI. Both dabrafenib and trametinib are MEK inhibitors. ERL is erlotinib and ARQ197 is a MET inhibitor.

Chapter 24

Figure 24.1 Physiologic MAP kinase signaling and constitutively active BRAF in the setting of a V600 mutation. RTK, receptor tyrosine kinase; B-/CRAF, BRAF or CRAF.

Figure 24.2 Mechanisms of resistance to BRAF inhibitor therapy.

Chapter 28

Figure 28.1 A model for DNA double strand breaks (DSBs) generated by androgen receptor (AR) recruitment of TOP2B during initiation of transcription at target genes. DHT, dihydrotestosterone; DNA-PK, DNA-dependent protein kinase; PARP1, poly(ADP-ribose) polymerase 1; ATM, ataxia-telangiectasia mutated; ROS, reactive oxygen species.

Source:

Reproduced from Haffner et al., 2011, Reference

13

with permission of American Association for Cancer Research (AACR).

Figure 28.2 Abiraterone, a CYP17 inhibitor, further reduces androgen levels when used to treat CRPC. Prostate cancers can progress despite abiraterone therapy, becoming androgen independent, either via maintained addiction to AR signaling (androgen-receptor dependent) or by abandoning AR signaling (androgen-receptor independent).

Source:

Reproduced from Nelson et al., 2011, Reference

166

with permission from Elsevier.

Figure 28.3 Mechanisms of resistance to AR-directed therapies. Progression to CRPC after initial treatments targeting androgen action often reflects persistent addiction to AR signaling, permitting the successful use of second-generation anti-androgens. Ultimately, both AR-dependent and -independent clones can emerge.

Source:

Reproduced from Reference

21

.

Chapter 29

Figure 29.1 Signaling pathways and targeted agents in the treatment of renal cell carcinoma.

Chapter 30

Figure 30.1 Proposed integration of molecular analysis/next-generation sequencing into clinical practice.

Chapter 31

Figure 31.1 Simplified diagram of the MAPK signaling pathway. Following stimulation of a cell-surface receptor (e.g., KIT), intracellular proteins become activated while recruiting SOS1 which exchanges GTP-GDP in RAS (GDP is the inactive form). RAS activation subsequently stimulates RAF (BRAF, RAF1), MEK (MEK1A1, MEK1A2), and, ERK (ERK1, ERK2). The GDP-GTP balance is regulated by guanine nucleotide exchange factors (GEF) and GTPase activating proteins (GAPs).

Figure 31.2 Genotypes and phenotypes in malignant melanomas.

Figure 31.3 Primary and secondary resistance to BRAF inhibitors.

Chapter 32

Figure 32.1 The frequency of mutations in major PI3K pathway components across common cancers. Data from the COSMIC database (http://www.sanger.ac.uk/genetics/CGP/cosmic/) and the Memorial Sloan Kettering cbio database (http://cbio.mskcc.org/gdac-portal/index.do). Carcinoma categories are not separated by subtype. The tumor suppressor TP53 (p53), the most mutated gene in cancer, is shown for comparison. Deletions and chromosomal rearrangements in PTEN are not included.

Figure 32.2 Canonical Class I PI3K activation. RTK ligand binding leads to RTK autophosphorylation and recruitment of class IA PI3K heterodimers via interaction between RTK phosphotyrosine residues and SH2 domains on p85. Binding releases the basal p85 inhibition of the catalytic p110 PI3K subunit, thereby freeing p110 to catalyze the conversion of PIP2 to PIP3. Also shown is an alternate activation mechanism through adaptor proteins whereby PI3K is bound to activated RAS which stabilizes PI3K plasma membrane localization and activation of the p110 catalytic domain.

Figure 32.3 AKT as a primary class I PI3K effector. Following PI3K-mediated conversion of PI-4,5-P2 to PIP3 AKT becomes localized to the plasma membrane via binding of the PH domain of AKT to PIP3. AKT is then fully activated by T308 and S473 phosphorylation by PDK1 and mTORC2, respectively. Numerous AKT substrates are outlined. Source: Vanhaesebroeck et al., 2012.

30

Reproduced with permission from Nature Publishing Group.

Figure 32.4 The importance of mTOR in cancer. Panel A shows the major cellular processes regulated by mTORC1 and mTORC2 demonstrating their role in tumorigenesis and progression. Panel Ba depicts the PI3K/AKT/mTOR pathway in the absence of mTOR inhibitors and panel Bb, Bc, and Bd demonstrate effects of rapamycin, mTOR catalytic inhibitors, and dual PI3K/mTOR inhibitors. Source: Zoncu et al., 2011.

31

Reproduced with permission from Nature Publishing Group.

Chapter 33

Figure 33.1 Repair of double-strand breaks. (a) Double-strand break is rejoined end-to-end. (b) A double-strand break is repaired with the help of a homologous undamaged DNA (shown in orange). Strand invasion allows resynthesis on complementary sequence, followed by a resolution of the strands and rejoining.

Figure 33.2 Synthetic lethality. Single-strand DNA breaks can be repaired by BER. PARPi block BER leading to conversion of SSB to DSBs. In

BRCA wt

cells, HR repair DSBs. However, BRCA1/2-mutant cells are deficient in HRR and unable to repair DSBs. Treating cancer cells with mutations in

BRCA1/2

with PARPi causes cell death via synthetic lethality.

Chapter 35

Figure 35.1 Activation of the KIT tyrosine kinase receptor. The natural ligand for KIT, stem cell factor (SCF, orange oval) binds to the extracellular region of KIT resulting in dimerization and autophosphorylation of intracellular tyrosine residues. The conformational change resulting from autophosphorylation perpetuates the further phosphorylation of other tyrosine residues that serve as sites that initiate downstream signaling. Activating mutations in the KIT gene result in the constitutive activation (not needing SCF initiation) of the KIT protein.

Chapter 36

Figure 36.1 Inactivation of wild-type p53 in cancer. p53 inactivation may be achieved at least by MDM2/MDMX overexpression, reduced ATM/ARF expression, HPV infection, and nuclear exclusion of p53. HPV-E6, human papillomavirus E6 protein.

Figure 36.2 Agents targeting wild-type p53, MDM2, or MDMX. p53 binding, p53-binding domain; AD, acidic domain; Zn2+, zinc finger domain; RING, RING domain; TA, transactivation domain; DBD, DNA-binding domain; NES, nuclear export signal; RITA, reactivation of p53 and induction of tumor cell apoptosis.

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List of Contributors

James Abbruzzese, MD

Division of Medical Oncology

Duke Cancer Institute

Durham, NC, USA

Maen Abdelrahim, MD, PhD

Department of Internal Medicine

Baylor College of Medicine

Houston, TX, USA

Abass Alavi, MD, MD(Hon.), PhD(Hon.), DSc(Hon.)

Department of Radiology

Hospital of the University of Pennsylvania

Philadelphia, PA, USA

Kenneth C. Anderson, MD, PhD

LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center

Department of Medical Oncology, Dana-Farber Cancer Institute

Harvard Medical School

Boston, MA, USA

Michael Andreeff, MD, PhD

Section of Molecular Hematology and Therapy

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Analia Azaro, MD

Early Clinical Drug Development Group

Vall d'Hebron Institute of Oncology

Universitat Autonoma de Barcelona

Barcelona, Spain

Susana Banerjee, MBBS, MA, MRCP, PhD

The Royal Marsden Hospital

London, UK

Robert C. Bast, MD

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Susanne H. C. Baumeister, MD

Department of Pediatric Oncology

Dana-Farber Cancer Institute

Boston, MA

Division of Hematology-Oncology

Boston Children's Hospital

Harvard Medical School

Boston, MA

Giada Bianchi, MD

LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center

Department of Medical Oncology, Dana-Farber Cancer Institute

Harvard Medical School

Boston, MA, USA

Patrick Boland, MD

Department of Medicine

Temple University School of Medicine

Philadelphia, PA, USA

Jessica L. Bowser, PhD

Department of Pathology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Russell R. Broaddus, MD, PhD

Department of Pathology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Harold J. Burstein, MD, PhD

Dana-Farber Cancer Institute

Brigham and Women's Hospital

Harvard Medical School

Boston, MA, USA

Lewis C. Cantley, PhD

Meyer Cancer Center at Weill Cornell Medical College

New York, NY, USA

Robert L. Coleman, MD

Department of Gynecologic Oncology and Reproductive Medicine

Center for RNA Interference and Non-Coding RNA

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Anthony P. Conley, MD

Department of Sarcoma Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Jorge Cortes, MD

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

M. Angelica Cortez, PhD

Department of Experimental Radiation Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Carlo M. Croce, MD

Department of Molecular Virology, Immunology and Medical Genetics

Comprehensive Cancer Center

Ohio State University

Columbus, OH, USA

Jasmine Quynh Dao, MD

Children's Cancer Hospital

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

John F. de Groot, MD

Department of Neuro-Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Yves A. DeClerck, MD

Division of Hematology-Oncology

Department of Pediatrics and Department of Biochemistry and Molecular Biology

The Saban Research Institute of Children's Hospital Los Angeles

Los Angeles, CA, USA

Department of Medicine

Committee on Clinical Pharmacology and Pharmacogenomics

The University of Chicago

Chicago, IL, USA

Gianpiero Di Leva, PhD

Department of Molecular Virology, Immunology and Medical Genetics

Comprehensive Cancer Center

Ohio State University

Columbus, OH, USA

Glenn Dranoff, MD, PhD

Department of Medicine, Harvard Medical School

Human Gene Transfer Laboratory Core, Dana-Farber Cancer Institute

Boston, MA, USA

Hua Fang, PhD

Division of Hematology-Oncology

The Saban Research Institute of Children's Hospital Los Angeles

Los Angeles, CA, USA

Department of Medicine

Committee on Clinical Pharmacology and Pharmacogenomics

The University of Chicago

Chicago, IL, USA

Omotayo Fasan, MRCP

Department of Medicine

Temple University School of Medicine

Philadelphia, PA, USA

Department of Hematologic Oncology and Blood Disorders

Levine Cancer Institute

Charlotte, NC, USA

Keith T. Flaherty, MD

Massachusetts General Hospital Cancer Center

Boston, MA, USA

David Fogelman, MD

Department of Gastrointestinal Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Matthew D. Galsky, MD

Division of Hematology and Medical Oncology

The Tisch Cancer Institute

Mount Sinai School of Medicine

New York, NY, USA

Guillermo García-Manero, MD

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Benjamin A. Gartrell, MD

Department of Medical Oncology

Montefiore Medical Center

The Albert Einstein College of Medicine

Bronx, NY, USA

Gabriel Ghiaur, MD, PhD

The Sidney Kimmel Comprehensive Cancer Center

The Johns Hopkins University School of Medicine

Baltimore, MD, USA

Michael C. Haffner, MD

The Sidney Kimmel Comprehensive Cancer Center and Brady Urological Institute

The Johns Hopkins University School of Medicine

Baltimore, MD, USA

Roy S. Herbst, MD, PhD

Department of Medicine

Division of Medical Oncology

Yale Comprehensive Cancer Center

New Haven, CT, USA

Ashley M. Holder, MD

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

David Hong, MD

Department of Investigational Cancer Therapeutics

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Jean-Pierre J. Issa, MD

Fels Institute for Cancer Research and Molecular Biology

Temple University School of Medicine

Philadelphia, USA

Elias Jabbour, MD

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Nitin Jain, MD

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Preetesh Jain, MD, DM, PhD

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Filip Janku, MD, PhD

Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program)

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Milind Javle, MD

Department of Gastrointestinal Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Richard J. Jones, MD

The Sidney Kimmel Comprehensive Cancer Center

The Johns Hopkins University School of Medicine

Baltimore, MD, USA

Stan Kaye, MD

The Royal Marsden hospital and The Institute of Cancer Research

London, UK

Samuel J. Klempner, MD

Division of Hematology/Oncology

University of California Irvine Health

Orange, CA, USA

Birgit Knoechel, MD, PhD

Boston Children's Hospital

Dana-Farber Cancer Institute

Harvard Medical School

Boston, MA, USA

Kensuke Kojima, MD, PhD

Section of Molecular Hematology and Therapy

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Scott Kopetz, MD, PhD, FACP

Department of Gastrointestinal Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Patricia Kropf, MD

Department of Medicine

Temple University School of Medicine

Philadelphia, PA, USA

Razelle Kurzrock, MD

Center for Personalized Cancer Therapy

UC San Diego Moores Cancer Center

La Jolla, CA, USA

Jens G. Lohr, MD, PhD

Dana-Farber Cancer Institute

Boston, MA, USA

Harvard Medical School

Boston, MA, USA

David Menter, PhD

Department of Gastrointestinal Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Funda Meric-Bernstam, MD

Department of Investigational Cancer Therapeutics

Institute for Personalized Cancer Therapy

Department of Surgical Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Larissa A. Meyer, MD, MPH

Department of Gynecologic Oncology and Reproductive Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Marcus M. Monroe, MD

Department of Otolaryngology

University of Utah School of Medicine

Salt Lake City, UT

Guillermo Montalbán-Bravo, MD

Department of Hematology

Hospital Universitario La Paz

Madrid, Spain

Daniel Morgensztern, MD

Department of Medicine

Division of Medical Oncology

Washington University School of Medicine

St. Louis, MO, USA

Javier Munoz, MD, FACP

Division of Hematology/Oncology

Banner MD Anderson Cancer Center

Gilbert, AZ, USA

Andrea P. Myers, MD, PhD

Novartis Pharmaceuticals

Cambridge, MA, USA

Jeffrey N. Myers, MD, PhD

Department of Head and Neck Surgery

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

William G. Nelson, MD, PhD

The Sidney Kimmel Comprehensive Cancer Center and Brady Urological Institute

The Johns Hopkins University School of Medicine

Baltimore, MD, USA

Barbara J. O'Brien, MD

Department of Neuro-Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Susan O'Brien, MD

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

William K. Oh, MD

Division of Hematology and Medical Oncology

The Tisch Cancer Institute

Mount Sinai School of Medicine

New York, NY, USA

Shreyaskumar Patel, MD

Department of Sarcoma Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Saeed Rafii, MD, PhD, MRCP

Institute of Cancer Sciences

The University of Manchester and The Christie Hospital

Manchester, UK

Farhad Ravandi-Kashani, MD

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Vinod Ravi, MD

Department of Sarcoma Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Jordi Rodon, MD

Early Clinical Drug Development Group

Vall d'Hebron Institute of Oncology

Universitat Autonoma de Barcelona

Barcelona, Spain

Rabih Said, MD, MPH

Department of Investigational Cancer Therapeutics

The University of Texas MD Anderson Cancer Center

Department of Internal Medicine

The University of Texas Health Science Center

Houston, TX, USA

Allison C. Sharrow, PhD

Department of Pathology

Johns Hopkins University School of Medicine

Baltimore, MD, USA

Department of Cancer Immunotherapeutics and Tumor Immunology

Beckman Research Institute

City of Hope Comprehensive Cancer Center

Duarte, CA, USA

Alexander C. Small, MD

Division of Hematology and Medical Oncology

The Tisch Cancer Institute

Mount Sinai School of Medicine

New York, NY, USA

Sonali M. Smith, MD

Department of Medicine

The University of Chicago

Chicago, IL, USA

Anil K. Sood, MD

Department of Gynecologic Oncology and Reproductive Medicine

Center for RNA Interference and Non-Coding RNA

Department of Cancer Biology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Richard M. Stone, MD

Department of Medical Oncology

Dana-Farber Cancer Institute

Boston, MA, USA

Chad Tang, MD

Department of Radiation Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Morgan Taylor, MD

Department of Gynecologic Oncology and Reproductive Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Drew A. Torigian, MD, MA, FSAR

Department of Radiology

Hospital of the University of Pennsylvania

Philadelphia, PA, USA

Davis Torrejon, MD

Early Clinical Drug Development Group

Vall d'Hebron Institute of Oncology

Universitat Autonoma de Barcelona

Barcelona, Spain

Apostolia-Maria Tsimberidou, MD, PhD

Department of Investigational Cancer Therapeutics

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Thanh-Trang Vo, PhD

Department of Molecular Biology and Biochemistry

University of California Irvine

Irvine, CA, USA

Julie M. Vose, MD, MBA

Division of Hematology/Oncology

University of Nebraska Medical Center

Omaha, NE, USA

Saiama N. Waqar, MBBS, MSCI

Department of Medicine

Division of Medical Oncology

Washington University School of Medicine

St. Louis, MO, USA

Shiao-Pei Weathers, MD

Department of Neuro-Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

James W. Welsh, MD

Department of Radiation Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Shannon N. Westin, MD, MPH

Department of Gynecologic Oncology and Reproductive Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Ofir Wolach, MD

Adult Leukemia Program

Department of Medical Oncology

Dana-Farber Cancer Institute

Boston, MA, USA

Scott E. Woodman, MD, PhD

Departments of Melanoma Medical Oncology and Systems Biology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Srinivasan Yegnasubramanian, MD, PhD

The Sidney Kimmel Comprehensive Cancer Center and Brady Urological Institute

The Johns Hopkins University School of Medicine

Baltimore, MD, USA

Jian Q. (Michael) Yu, MD, FRCPC

Department of Diagnostic Imaging

Fox Chase Cancer Center

Philadelphia, PA, USA

W. K. Alfred Yung, MD

Department of Neuro-Oncology

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Patrick A. Zweidler-McKay, MD, PhD

Children's Cancer Hospital

The University of Texas MD Anderson Cancer Center

Houston, TX, USA

Series Foreword

While our knowledge of cancer at a cellular and molecular level has increased exponentially over the last decades, progress in the clinic has been more gradual, largely depending upon empirical trials using combinations of individually active anti-cancer drugs to treat the average patient. The challenge for the immediate future is to accelerate the pace of progress in clinical cancer care by enhancing the bidirectional interaction between laboratory and clinic. Our new understanding of human cancer biology and the heterogeneity of cancers at a molecular level must be used to identify novel targets for therapy, prevention, and detection focused on each individual. Barriers must be removed to facilitate the flow of targeted agents and fresh approaches from the laboratory to the clinic, while returning relevant human specimens, images, and data from the clinic to the laboratory for further analysis.

An Introduction to Translational Cancer Research provides a brief overview of current understanding of human cancer biology that is driving interests in targeted therapy and personalized management. Further development of molecular diagnostics should facilitate earlier detection, more precise prognostication, and prediction of response across the spectrum of cancer development. Targeted therapy has already had a dramatic impact on several forms of cancer and strategies are being developed to identify small groups of patients who would benefit from novel targeted drugs in combination with each other or with more conventional surgery, radiotherapy, or chemotherapy. Development of personalized interventions—whether preventive or therapeutic in nature—will require multidisciplinary teams of investigators and the infrastructure to match patient samples and agents in real time.

To accelerate translational cancer research, greater alignment will be required between academic institutions, the National Cancer Institute, the Food and Drug Administration, foundations, pharma, and community oncologists. Ultimately, new approaches to prevention, detection, and therapy must be sustainable. In the long run, translational research and personalized management can reduce the cost of cancer care, which has escalated in recent years. More accurate and specific identification of at-risk members and risk stratification will be helpful to minimize the risks of over-diagnosis and over-treatment, while maximizing the benefits of screening, early detection, and preventive intervention. Patients who would benefit most can be identified and funds saved by avoiding treatment in those whose cancers would not respond. Participation and education of community oncologists will be required, as will modification of practice patterns. For progress in the clinic to occur at an optimal pace, leaders of translational teams must envision a clear path to bring new concepts and new agents from the laboratory to the clinic, to complete pharmaceutical or biological development, to obtain regulatory approval and to bring new strategies for detection, prevention, and treatment to patients in the community.

In a series of additional volumes regarding translational cancer research, several topics are explored in greater depth, including gene therapy by viral and non-viral vectors, biomarkers, immunotherapy, and this volume concerning targeted therapy. The purpose of these books has been not only to describe different strategies for controlling particular forms of cancer but also to identify some of the barriers to translation using different reagents or different strategies around common therapeutic or diagnostic modalities. Potential barriers are many and include the need for a deeper understanding of science, methods to overcome the challenge of tumor heterogeneity, the development of targeted therapies, the availability of patients with an appropriate phenotype and genotype within a research center with the investigators, research teams and infrastructure required for clinical/translational research and the design of novel trials, adequate financial support, a viable connection to diagnostic and pharmaceutical development, and a strategy for regulatory approval as well as for dissemination in the community.

Targeted Therapy in Translational Cancer Research considers many of these areas. Principles are beginning to emerge for identifying therapeutic targets. A critical issue is how best to combine therapies against different targets within the same cancer if we are to develop effective personalized care. Tumor initiating cells must be eliminated as well as their progeny. Not only the cancer cells but tumor vessels and microenvironment can be targeted. While a separate volume will consider immunotherapy, a chapter on principles of immunotherapeutic targeting has been included, because of the rapid progress in this area. A better understanding of epigenetic and miRNA regulation has suggested new approaches to targeted therapy. The current status of targeted therapy for individual hematologic neoplasms and solid cancers has been reviewed extensively. As several major molecular targets and signaling pathways—TP53, PARP, Met, Kit, PI3K, and Ras/MAP—are important to cancers at multiple sites, chapters have also been devoted to strategies for their inhibition. Overall, this volume includes substantial perspective regarding the translational potential of targeted therapy that should provide useful information for investigators and clinicians.

Robert C. Bast

Maurie Markman

Ernest Hawk

Foreword

As a busy clinical oncologist/hematologist striving to be current in preparing to see a new patient, or as a clinical investigator trying to determine what might be the best new approach for the patient with advanced refractory cancer, this volume titled Targeted Therapy in Translational Cancer Research can be of enormous help. In addition, for the young or experienced bench scientist this offering gives both a basic background and an important grounding in the current field of clinical targeted therapies.

The above comments should come as no surprise given the deep experience of the editors and the contributors to this volume.

In a review of the parts of this volume there is excellent coverage of (a) the principles of targeted therapies; (b) specific targeted therapies in the hematologic and solid malignancies; and (c) coverage of targeted therapies for specific molecular aberrations. As one drills down into the well-written individual chapters there is excellent coverage of the current state of the art plus meaningful coverage of how the field is evolving.

It is gratifying to see chapters on functional imaging, the issue of combining targeted therapies, targeted immunotherapies, the microenvironment, microRNAs, and tackling tough targets such as Ras and TP53.

The chapter on specific organ types of cancer are both practical for us to catch up on the best treatments and yet comprehensive enough to see how the treatments are evolving.

All in all, this is a wonderful volume to aid all of us in a practical and deeper understanding of targeted therapies. Congratulations to the contributors and editors of this special volume.

Daniel D. Von Hoff, MD, FACP

Preface: Bench to Bedside and Back

In the last decade, emergent technologies have enhanced our understanding of genomic, transcriptional, proteomic, epigenetic, and immune mechanisms in carcinogenesis. This improved understanding has enabled the development of targeted cancer therapies and transformed conventional treatment paradigms; it has provided the framework for the discovery of new targets, for validation of novel agents, for combination therapies predicated upon scientific rationale, and for clinical trials that have already markedly improved the prognosis and outcome of patients with cancer. Excitingly, the implication of immunomodulatory targets in carcinogenesis has led to the development of new promising drugs based on the central principle that breaking tolerance using immune checkpoint blockers can achieve durable responses. Moreover, although distinct pathways are initially analyzed independently, interdependent and compensatory mechanisms have derived innovative combinations of targeted, immunomodulating, antiangiogenic, and/or chemotherapeutic agents, which have additive or synergistic cytotoxicity and can overcome resistance to conventional therapies. Continued progress will require improved genomic classification of the various tumor types, delineation of the mechanisms of resistance to treatment and disease progression, and improved understanding of metastasis, ultimately allowing for provision of therapies designed to target tumor heterogeneity early in the disease course.

This edition of Targeted Therapy in Translational Cancer Research