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 Preface

Prostate cancer is the most common malignancy in men and its incidence will dra-
matically increase over the next several decades due to the ‘‘baby boomers’’
reaching maturity. While the majority of patients can be cured with local radio-
therapy or surgical modalities, many will progress with metastatic disease for
which there is, currently, a limited number of treatment options. However, research
in prostate cancer has made significant progress over the last decade, providing us
with a better understanding of the critical events that lead to the development and
progression of this disease and novel targets for therapies. This book will provide
state-of-the-art information on evolving translational therapies in prostate cancer,
which will translate into better outcomes for our patients.
It is appropriate that Drs. Nelson and De Marzo set the stage and describe the
initial events of the development and progression of prostate cancer and identify
the key elements that could be potential targets for preventing prostate cancer.
However, identifying the target does not always lead to an effective therapy, as
Dr. Sausville illustrates, and clinical investigations with these new targeted thera-
pies require the integration of unique tumor markers, imaging modalities, and trial
designs to show the clinical or biologic effect of the drug. Many therapies have
overcome these hurdles and are now showing clinical benefit in patients.
Some agents that have shown promise include the endothelial receptor
antagonists, vitamin D analogs, monoclonal antibodies to the prostate-specific
membrane antigen, angiogenesis inhibitors, and many other small molecules such
as the tyrosine kinase inhibitors. Drs. Qian and Pili and his colleagues describe a
new class of agents called posttranscription modifiers, which include the histone
deacetylase inhibitors and demethylation agents, while others have been investi-
gating antisense oligonuclitides to inhibit specific proteins and kinases such as
Bcl-2, clusterin, and other vital proteins that are critical in the growth of prostate
cancer. Therapies that inhibit telomerase, proteasomes, and heat shock proteins
have been promising avenues for the treatment of prostate cancer and these thera-
pies are described by Drs. Burger, Dreicer, and Solit.
Immunologic and gene therapy approaches continue to be pursued and the
data showing that these therapies may one day be a standard treatment is stren-
gthening. Dr. Small and his researchers update us on the exciting data of several
novel vaccine approaches and other new modalities that modify the immune
response.
Investigators are also developing a better understanding of the pathophysiol-
ogy of osteoblastic metastasis and androgen receptor. Dr. Hamdy and associates
have reviewed the advancements in bone-targeted therapies and new agents that
will be entering into the clinics while Dr. Mellinghoff highlights novel therapies
that will inhibit the androgen receptor.

iii
iv Preface

For decades, hormone-refractory prostate cancer was thought to be resistant

to chemotherapy; however recent data has shown that prostate cancer is sensitive
to chemotherapy and improves survival, which has renewed the interest in
identifying novel cytotoxic drugs for this disease. Dr. Hussain reviews this ongoing
research and highlights the new agents that are in clinical trials—many of which
are in Phase III testing.
Compared to a decade ago, we have made great advancements in the under-
standing of prostate cancer and the targets that may treat this disease, but this was
only possible from the strong support of dedicated researchers and patients.

Nancy A. Dawson
W. Kevin Kelly
 Contents

Preface . . . . iii
Contributors . . . . xiii

1. The Molecular Pathogenesis and Pathophysiology of

Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
William G. Nelson and Angelo M. De Marzo
Introduction . . . . 1
Anatomy and Function of the Human Prostate . . . . 1
The Cellular Origin of Prostate Cancer . . . . 3
Genetic Susceptibility to Prostate Cancer . . . . 4
Epidemiology of Prostate Cancer . . . . 6
Inflammation and Prostate Cancer . . . . 7
Somatic Genome Changes in Prostate Cancer Cells . . . . 8
Gene Expression Changes in Prostate Cancer . . . . 11
Prostate Cancer Progression to Metastasis . . . . 12
Conclusions . . . . 13
References . . . . 13

2. Targeted Therapies for Cancer: Definitions

and Attributes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
Edward A. Sausville
Empirical vs. Targeted Agents for Cancer . . . . 27
Qualification of Cancer Targets . . . . 29
Agent/Target Discovery Strategies . . . . 30
Pathogenic Targets: Issues . . . . 31
Ontogenic Targets: Issues . . . . 32
Pharmacological Targets: Issues . . . . 32
Stromal Targets: Issues . . . . 32
Targeted Therapeutics: Differences
In Development Strategy . . . . 33
Special Issues with Prostate Cancer . . . . 36
References . . . . 37

v
vi Contents

3. Novel Biomarkers for Disease Diagnosis, Prognosis,

and Prediction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
James V. Tricoli
Introduction . . . . 39
A Brief History of Prostate Cancer Diagnostics . . . . 39
Genes and Proteins Correlating with Prostate
Cancer . . . . 40
Criteria for Biomarker Selection . . . . 41
Prostate Cancer Biomarkers of Interest . . . . 45
Future Directions . . . . 50
References . . . . 51

4. The Endothelin Pathway and its Modulation

in Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Antonio Jimeno and Michael Carducci
Introduction . . . . 59
The Endothelin Axis . . . . 59
Leading Compound in Cancer: Atrasentan . . . . 64
Other Compounds Undergoing Evaluation in Cancer:
ZD4054 . . . . 69
Conclusions . . . . 69
Summary . . . . 71
References . . . . 71

5. Targeting Extracellular Molecules in Prostate

Cancer—Mechanisms to Inhibit Entry into the
Cell-Signaling Abyss . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Susan F. Slovin
Introduction . . . . 75
Potential Role of Cluster-Defined Molecules . . . . 76
PSCA—What Role does it Play as a Cell
Surface Molecule? . . . . 78
Mediators of Receptor Tyrosine Kinase Pathways . . . . 79
Platelet-Derived Growth Factor as a
Target for Therapy . . . . 81
Inhibitors of PDGFR . . . . 82
Targets of Immunologic Recognition: Enhancing
immunogenicity Through Vaccines by Enhancing T cell
function . . . . 82
Studies in Men . . . . 83
Manipulation of the T Cell—Can Changing Expression
of Cell Surface Molecules Affect Function? . . . . 84
Contents vii

Conclusions . . . . 85
References . . . . 85

6. Immunologic Approaches to Prostate Cancer . . . . . . . . . . . . . 91

Lawrence Fong and Eric J. Small
Introduction . . . . 91
Detecting Responses to Immunotherapy . . . . 92
Prostate Antigens Recognized by T-Cells . . . . 93
Prostate Antigens Targeted by Antibodies . . . . 95
Tumor Vaccines Utilizing Prostate Cancer as a Source of
Antigen . . . . 97
Cytokine Therapy . . . . 98
Immunomodulatory Treatment . . . . 98
Future Directions . . . . 99
References . . . . 99

7. Gene Therapy and Novel Clinical Trial Design . . . . . . . . . . 103

Henry T. Tsai and Jonathan W. Simons
Introduction . . . . 103
Gene Vector . . . . 104
Strategies in PCA Gene Therapy . . . . 112
Combined Modalities . . . . 115
Novel Clinical Trial Design . . . . 116
Future Directions . . . . 121
References . . . . 121

8. Angiogenesis Inhibitors in Prostate Cancer . . . . . . . . . . . . . 127

William D. Figg, Michael C. Cox, Tania Alachalabi, and
William L. Dahut
Introduction . . . . 127
Biologic Control of Angiogenesis . . . . 127
Proangiogenic Factors . . . . 128
Hypoxia Inducible Factor-1 . . . . 128
Angiopoietin . . . . 128
Platelet-Derived Growth Factor . . . . 128
Vascular Endothelial Growth Factor . . . . 129
Prostate Cancer and the Dependence on Angiogenesis . . . . 130
Anti-angiogenic Therapy for Prostate Cancer . . . . 131
TNP-470 . . . . 131
Carboxytriamidazole (CAI) . . . . 132
SU5416 . . . . 132
SU101 . . . . 132
2-Methoxyestradiol (Panzam, 2ME2) . . . . 132
viii Contents

Imatinib . . . . 132
Bevacizumab (rhuMab.VEGF) . . . . 133
Thalidomide . . . . 133
Single-Agent Thalidomide . . . . 134
Thalidomide in Combination with Anticancer Agents . . . . 134
Summary and Future Directions . . . . 135
References . . . . 135

9. What Antisense Oligonucleotides

Have Promise in Prostate Cancer . . . . . . . . . . . . . . . . . . . . . 143
Kim N. Chi and Martin E. Gleave
Introduction . . . . 143
Antisense Oligonucleotides . . . . 143
ASOs in Prostate Cancer . . . . 146
Summary . . . . 154
References . . . . 155

10. Novel Approaches to Androgen Receptor Blockade . . . . . . 163

Ingo K. Mellinghoff
Introduction . . . . 163
The Structural Basis of AR Function . . . . 163
Activation of AR Signaling . . . . 165
Mechanisms of Hormone-refractory Prostate Cancer
Growth . . . . 167
Therapeutic Implications . . . . 170
References . . . . 171

11. Can Post-Transcription Modifiers Change the

Course of Prostate Cancer? . . . . . . . . . . . . . . . . . . . . . . . . . 179
David Z. Qian and Roberto Pili
Introduction . . . . 179
Targeting MRNA . . . . 179
Targeting Protein Synthesis . . . . 182
Targeting Protein Modification . . . . 183
Conclusions and Future Perspectives . . . . 190
References . . . . 191

12. Telomere Targeting Agents . . . . . . . . . . . . . . . . . . . . . . . . . 195

Angelika M. Burger and Lloyd R. Kelland
Introduction . . . . 195
Telomerase and Telomeres in Prostate Cancer
Development . . . . 200
TTA and Prostate Cancer . . . . 202
Contents ix

Future and Clinical Perspectives . . . . 205

References . . . . 206

13. Expanding the Role of EGFR Inhibitors

in Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Srikala S. Sridhar and Malcolm J. Moore
Introduction . . . . 209
EGFRs and Their Ligands . . . . 209
EGFRs and Prostate Cancer . . . . 211
Targeting the EGFR Family in Prostate Cancer . . . . 212
Tyrosine Kinase Inhibitors . . . . 212
Monoclonal Antibodies . . . . 215
Discussion . . . . 217
References . . . . 218

14. Bone-Directed Therapy in Prostate Cancer:

Rationale and Novel Approaches . . . . . . . . . . . . . . . . . . . . 223
Colby L. Eaton, Kate D. Linton, and Freddie C. Hamdy
Abstract . . . . 223
Primary Considerations in the Evaluation of New
Treatments in Prostate Cancer . . . . 223
Treatment of Established Bone Metastases:
Targeting the ‘‘Vicious Cycle’’ . . . . 224
Prevention of Metastasis: Targeting the Establishment
of Bone Metastases . . . . 229
Concluding Remarks . . . . 233
References . . . . 233

15. Inhibiting the Proteasome in Advanced

Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
Robert Dreicer
Overview of the Proteasome and Its Function . . . . 237
Bortezomib . . . . 237
Inhibiting the Proteasome in Prostate
Cancer . . . . 238
Clinical Experience of Bortezomib in Prostate
Cancer . . . . 239
Docetaxel þ Bortezomib . . . . 240
Summary . . . . 242
References . . . . 242
x Contents

16. Hsp90: A Target for Prostate Cancer Therapy . . . . . . . . . . . 245

David B. Solit, Howard I. Scher, and Neal Rosen
Introduction . . . . 245
AR Stability and Activity Are Regulated by HSP90 . . . . 245
HSP90 as a Target for Cancer Therapy: Basis for a
Therapeutic Index . . . . 246
Clinical Experience with 17-AAG . . . . 249
Novel HSP90 Inhibitors That Bind the N-Terminal
ATP Pocket . . . . 250
HSP90 Inhibitors That Bind the C-Terminal Domain . . . . 251
HDAC Inhibitors . . . . 251
Conclusions . . . . 251
References . . . . 252

17. Vitamin D Analogs and Their Role in Prostate Cancer . . . . 257

Tomasz M. Beer and Anne Myrthue
Introduction . . . . 257
Epidemiology of Vitamin D and Prostate Cancer . . . . 257
Mechanisms of Antineoplastic Activity in Preclinical
Systems . . . . 258
Vitamin D in Combination with Other Antineoplastic Agents in
Preclinical Models . . . . 261
Clinical Trials of Calcitriol in Prostate Cancer . . . . 262
Calcitriol Analogs . . . . 266
Conclusions . . . . 268
References . . . . 268

18. Other Novel Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281

Arif Hussain and Richard Schraeder
Introduction . . . . 281
Epothilones . . . . 281
Satraplatin . . . . 284
Conclusion . . . . 286
References . . . . 287

19. Molecular Imaging, Clinical Trial Design, and the

Development of Emerging Therapies for
Metastatic Prostate Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . 291
Michael J. Morris, Neeta Pandit-Taksar, Chaitanya Divgi,
Steven Larson, and Howard I. Scher
Introduction . . . . 291
Contents xi

Prostate Cancer, Standard Imaging, and Clinical Trial

Design . . . . 292
Tracers That Demonstrate Metabolism and Growth . . . . 296
Imaging Individual Proteins Relevant to
Prostate Cancer . . . . 302
Summary and Future Directions . . . . 305
References . . . . 306

Index . . . . 315
 Contributors

Tania Alachalabi Medical Oncology Branch, Center for Cancer Research,

National Cancer Institute, National Institutes of Health, Bethesda,
Maryland, U.S.A.

Tomasz M. Beer Division of Hematology & Medical Oncology and the OHSU
Cancer Insitute, Oregon Health & Science University, Portland, Oregon, U.S.A.

Angelika M. Burger Department of Pharmacology and Experimental

Therapeutics, Marlene and Stewart Greenebaum Cancer Center, University of
Maryland School of Medicine, Baltimore, Maryland, U.S.A.

Michael Carducci The Sidney Kimmel Comprehensive Cancer Center, The

Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

Kim N. Chi BC Cancer Agency, Vancouver, British Columbia, Canada

Michael C. Cox Medical Oncology Branch, Center for Cancer Research,

National Cancer Institute, National Institutes of Health, Bethesda,
Maryland, U.S.A.

William L. Dahut Medical Oncology Branch, Center for Cancer Research,

National Cancer Institute, National Institutes of Health, Bethesda,
Maryland, U.S.A.

Angelo M. De Marzo Department of Pathology, The Sidney Kimmel

Comprehensive Cancer Center and Brady Urological Institute, The Johns Hopkins
University School of Medicine, Baltimore, Maryland, U.S.A.

Chaitanya Divgi Nuclear Medicine Service, Department of Radiology,

Memorial Sloan-Kettering Cancer Center, New York, New York, U.S.A.

Robert Dreicer Department of Solid Tumor Oncology, The Glickman Urologic

Institute and The Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland,
Ohio, U.S.A.

Colby L. Eaton Academic Urology, University of Sheffield, Royal Hallamshire

Hospital, Sheffield, U.K.

xiii
xiv Contributors

William D. Figg Medical Oncology Branch, Center for Cancer Research,

National Cancer Institute, National Institutes of Health, Bethesda,
Maryland, U.S.A.

Lawrence Fong University of California, San Francisco, California, U.S.A.

Martin E. Gleave Vancouver Hospital D-9, Vancouver, British Columbia,

Canada

Freddie C. Hamdy Academic Urology, University of Sheffield, Royal

Hallamshire Hospital, Sheffield, U.K.

Arif Hussain University of Maryland Greenebaum Cancer Center, Baltimore,

Maryland, U.S.A.

Antonio Jimeno The Sidney Kimmel Comprehensive Cancer Center,

The Johns Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

Lloyd R. Kelland Antisoma Research Laboratories, St. Georges Hospital

Medical School, Cranmer Terrace, London, U.K.

Steven Larson Nuclear Medicine Service, Department of Radiology, Memorial

Sloan-Kettering Cancer Center, New York, New York, U.S.A.

Kate D. Linton Academic Urology, University of Sheffield, Royal Hallamshire

Hospital, Sheffield, U.K.

Ingo K. Mellinghoff Department of Pharmacology, University of California,

Los Angeles, California, U.S.A.

Malcolm J. Moore Department of Medicine and Pharmacology, Princess

Margaret Hospital, University of Toronto, Toronto, Ontario, Canada

Michael J. Morris Genitourinary Oncology Service, Department of Medicine,

Memorial Sloan-Kettering Cancer Center, New York, New York, U.S.A.

Anne Myrthue Division of Hematology & Medical Oncology and the OHSU
Cancer Insitute, Oregon Health & Science University, Portland, Oregon, U.S.A.

William G. Nelson The Sidney Kimmel Comprehensive Cancer Center and

Brady Urological Institute, The Johns Hopkins University School of Medicine,
Baltimore, Maryland, U.S.A.

Neeta Pandit-Taksar Nuclear Medicine Service, Department of Radiology,

Memorial Sloan-Kettering Cancer Center, New York, New York, U.S.A.

Roberto Pili The Sidney Kimmel Comprehensive Care Center, The Johns
Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.
Contributors xv

David Z. Qian The Sidney Kimmel Comprehensive Care Center, The Johns
Hopkins University School of Medicine, Baltimore, Maryland, U.S.A.

Neal Rosen Department of Medicine, Pharmacology and Chemistry, Memorial

Sloan-Kettering Cancer Center, New York, New York, U.S.A.

Edward A. Sausville University of Maryland, Marlene and Stewart

Greenebaum Cancer Center, Baltimore, Maryland, U.S.A.

Howard I. Scher Genitourinary Oncology Service, Department of Medicine,

Memorial Sloan-Kettering Cancer Center, New York, New York, U.S.A.

Richard Schraeder University of Maryland Greenebaum Cancer Center,

Baltimore, Maryland, U.S.A.

Jonathan W. Simons Department of Hematology and Oncology, Winship

Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, U.S.A.

Susan F. Slovin Genitourinary Oncology Service, Department of Medicine,

Memorial Sloan-Kettering Cancer Center, New York, New York, U.S.A.

Eric J. Small University of California, San Francisco, California, U.S.A.

David B. Solit Department of Medicine and the Human Oncology and

Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York,
New York, U.S.A.

Srikala S. Sridhar Department of Medicine, Juravinski Cancer Center,

McMaster University, Hamilton, Ontario, Canada

James V. Tricoli Diagnostic Biomarkers and Technology Branch, Division of

Cancer Treatment and Diagnosis, Cancer Diagnosis Program, National Cancer
Institute, Rockville, Maryland, U.S.A.

Henry T. Tsai Department of Hematology and Oncology, Winship Cancer

Institute, Emory University School of Medicine, Atlanta, Georgia, U.S.A.