Table Of ContentCancer Drug Discovery and Development
Volume 82
Series Editor
Beverly A. Teicher
Bethesda, Maryland, USA
Cancer Drug Discovery and Development, the Springer series headed by Beverly
A. Teicher, is the definitive book series in cancer research and oncology. Volumes
cover the process of drug discovery, preclinical models in cancer research, specific
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Ryan J. Sullivan
Editor
BRAF Targets in Melanoma
Biological Mechanisms, Resistance,
and Drug Discovery
Editor
Ryan J. Sullivan
Center for Melanoma
Massachusetts General Hospital Cancer Center
Boston
Massachusetts
USA
ISSN 2196-9906 ISSN 2196-9914 (electronic)
ISBN 978-1-4939-2142-3 ISBN 978-1-4939-2143-0 (eBook)
DOI 10.1007/978-1-4939-2143-0
Springer New York Heidelberg Dordrecht London
Library of Congress Control Number: 2014955080
© Springer Science+Business Media New York 2015
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Contents
1 Melanoma: Historical Context ................................................................ 1
Suraj Venna, Sekwon Jang and Michael Atkins
2 Melanoma Pathogenesis .......................................................................... 25
Jennifer A. Lo and David E. Fisher
3 Molecular Diagnostics and Tumor Mutational Analysis ...................... 47
Melissa A. Wilson and Katherine L. Nathanson
4 Clinical Utility of BRAF-Targeted Therapy in Melanoma .................. 67
Jeffrey A. Sosman and Douglas B. Johnson
5 T he Ethics of Randomized Trials in Oncology ...................................... 85
Pallavi Kumar and Ryan J. Sullivan
6 Parallel and Serial Blockade Strategies in
BRAF-Mutant Melanoma ....................................................................... 105
Michael A. Davies
7 T argeting the Cell Cycle and p53 in Combination with
BRAF-Directed Therapy ......................................................................... 137
Dale Han and Keiran SM Smalley
8 Combination BRAF-Directed Therapy and Immunotherapy ............. 163
Zachary A. Cooper, Zain Ahmed and Jennifer A. Wargo
9 M oving Forward: Making BRAF-Targeted Therapy Better ............... 183
Keith T. Flaherty
Index ................................................................................................................ 203
v
Contributors
Zain Ahmed Cleveland Clinic Lerner College of Medicine of Case Western
Reserve University, Cleveland, OH, USA
Michael B. Atkins Medstar Washington Cancer Institute, Lombardi
Comprehensive Cancer Center, Medstar Georgetown University Hospital,
Washington DC, USA
Zachary A. Cooper Department of Surgical Oncology, University of Texas MD
Anderson Cancer Center, Houston, TX, USA
Department of Genomic Medicine, University of Texas MD Anderson Cancer
Center, Houston, TX, USA
Michael A. Davies Departments of Melanoma Medical Oncology, University of
Texas MD Anderson Cancer Center, Houston, TX, USA
Departments of Systems Biology, University of Texas MD Anderson Cancer Center,
Houston, TX, USA
David E. Fisher Program in Biological and Biomedical Sciences, Harvard
Medical School, Boston, MA, USA
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown,
MA, USA
Department of Dermatology, Massachusetts General Hospital, Boston, MA, USA
Keith T. Flaherty Massachusetts General Hospital Cancer Center, Boston, MA,
USA
Dale Han Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa,
FL, USA
Sekwon Jang Medstar Washington Cancer Institute, Lombardi Comprehensive
Cancer Center, Medstar Georgetown University Hospital, Washington DC, USA
vii
viii Contributors
Douglas B. Johnson Vanderbilt University School of Medicine, Vanderbilt-
Ingram Cancer Center, Nashville, TN, USA
Pallavi Kumar Center for Melanoma, Massachusetts General Hospital Cancer
Center, Boston, MA, USA
Jennifer A. Lo Program in Biological and Biomedical Sciences, Harvard Medical
School, Boston, MA, USA
Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown,
MA, USA
Katherine L. Nathanson Division of Translational Medicine and Human
Genetics, Department of Medicine Perelman School of Medicine at the University
of Pennsylvania, Philadelphia, PA, USA
Keiran SM Smalley Department of Cutaneous Oncology, Moffitt Cancer Center,
Tampa, FL, USA
Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL, USA
Jeffrey A. Sosman Vanderbilt University School of Medicine, Vanderbilt-Ingram
Cancer Center, Nashville, TN, USA
Ryan J. Sullivan Center for Melanoma, Massachusetts General Hospital Cancer
Center, Boston, MA, USA
Suraj Venna Medstar Washington Cancer Institute, Lombardi Comprehensive
Cancer Center, Medstar Georgetown University Hospital, Washington DC, USA
Jennifer A. Wargo Department of Surgical Oncology, University of Texas MD
Anderson Cancer Center, Houston, TX, USA
Department of Genomic Medicine, University of Texas MD Anderson Cancer
Center, Houston, TX, USA
Melissa A. Wilson Division of Hematology/Oncology, Department of Medicine,
Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA,
USA
Chapter 1
Melanoma: Historical Context
Suraj Venna, Sekwon Jang and Michael Atkins
Abstract We are in the midst of a therapeutic revolution for patients with mela-
noma. This chapter reviews several topics on melanoma from epidemiologic trends,
to the evolution of the surgical approach, to adjuvant treatment of melanoma, and
also reviews various systemic therapies for metastatic melanoma. Each component
of this chapter describes advances from a historical perspective, beginning with
the first descriptions of melanoma in the literature, to the discovery of activating
B-raf mutations in melanoma, and concluding with the current immune and targeted
based therapies for advanced melanoma. It serves as a segue to the more detailed
therapies and advances in the ensuing chapters.
Keywords B-raf · Checkpoint inhibition · Adjuvant therapy · Chemotherapy ·
Biochemotherapy · Immunotherapy · MC1R · Risk factors · Sentinel lymph node
biopsy · Vaccines
1.1 Introduction
John Hunter in 1787 excised a tumor from the jaw of a young man and aptly
described it as a “cancerous fungous excrescence.” Hunter detailed that the tumor
recurred on the patients chin several years later, thought to perhaps have been in-
cited by trauma as this young gentleman had partaken in a bar room brawl at that
time. This specimen was preserved for nearly 200 years in the Hunterian Museum
of the Royal College of Surgeons in London and is now specimen number 219 [1].
In 1968 the specimen was examined and verified to be melanoma. Rene Laennec in
1806 is credited as the first physician in modern times to describe melanoma as a
disease and published this while still a medical student [2]. William Norris in 1820
M. B. Atkins ()
New Research Building, Rm E501, 3970 Reservoir Rd, NW, Washington DC 20056, USA
e-mail: [email protected]
S. Venna · S. Jang · M. B. Atkins
Medstar Washington Cancer Institute, Lombardi Comprehensive Cancer Center, Medstar
Georgetown University Hospital, Washington DC, USA
© Springer Science+Business Media New York 2015 1
R. J. Sullivan (ed.), BRAF Targets in Melanoma,
Cancer Drug Discovery and Development 82, DOI 10.1007/978-1-4939-2143-0_1
2 S. Venna et al.
published his post-mortem description of a patient with atypical nevi who devel-
oped and died of metastatic melanoma: “On making an incision through the origi-
nal tumour, I found the texture to be heterogeneous; it was of a reddish and whitish
brown tint throughout, not very unlike the internal structure of a nutmeg. The newly
formed tumour, and the tubera around, though during life they wore a very dif-
ferent aspect, after death both exhibited the same dark-coloured appearance. On
puncturing a considerable number of the different tubercles, a thick dark fluid was
discharged from them [3].” The first formal acknowledgement that melanoma, in
advanced stages, is untreatable and a death sentence, was documented in 1844 by
Samuel Cooper in his textbook First lines of theory and practice of surgery [4]. He
published that the only chance for survival was early removal of the disease, stating
that “No remedy is known of, for melanosis….the only chance of benefit depends
upon the early removal of the disease by operation….” However, the earliest ex-
ample of melanoma has been suggested to come from Mummified skeletal remains
of Peruvian Incas dating to 2400 BC [5]. Over time, we have moved from simple
descriptive terms such as cancerous fungous excrescence, to defining the molecular
pathways responsible for the development of melanoma. This has elegantly been
now translated into targeted therapies for melanoma that provide the expectation
of controlling this often devastating disease in significant subsets of patients for
increasingly extended periods of time.
After a nearly 15 year stand-still for the treatment of metastatic melanoma, we
are in the midst of a virtual revolution in systemic treatment of patients with mela-
noma. The targeted therapy era for melanoma was initiated by the finding that a
significant proportion of melanomas carry activating mutations in a component of
the mitogen activated protein kinase (MAPK) signaling pathway. Activating muta-
tions in B-raf were identified in 2002 and also found to occur in the vast majority of
benign nevi (80 %) [6, 7]. These findings led to a resurgence of interest in melanoma
but also led to continued interrogation of the MAPK pathway and other pathways.
The discovery of B-raf mutations in benign nevi made it clear that this may be a
necessary but early step in melanoma progression and other critical targets must
also be involved.
1.2 Epidemiologic Trends
Melanoma accounts for 5 % of all skin cancers but is the major cause of death from
skin cancer. In the year 2013, there were an estimated 76,690 new cases of invasive
melanoma in the United States and over 9480 deaths attributable to melanoma [8].
This equates to one melanoma-specific death every hour. The number of annual
new cases is likely underestimated given that in-situ lesions and thin invasive mela-
nomas (Stage 1a) are not consistently reported to tumor registries, being excised in
the outpatient and private practice settings [9]. The lifetime incidence of develop-
ing melanoma in the United States was 1/1500 for individuals born in the early
1900’s [10]. Between 1950 and 2000, there was an explosive increase in melanoma
