Tài liệu MELANOMA - FROM EARLY DETECTION TO TREATMENT docx

MELANOMA - FROM

EARLY DETECTION TO

TREATMENT

Edited by Guy Huynh Thien Duc

Melanoma - From Early Detection to Treatment

http://dx.doi.org/10.5772/50853

Edited by Guy Huynh Thien Duc

Contributors

Lee Cranmer, Sherif Morgan, Joanne Jeter, Evan Hersh, Sun Yi, Paul Mosca, Paul Speicher, Douglas Tyler, Hinrich

Abken, Jennifer Makalowski, Laura Hutchins, Konstantinos Arnaoutakis, Dorothy Graves, Jianli Dong, Lester Davids,

Kazuya Murata, Hideaki Matsuda, Megumi Masuda, Yumi Abe, Akemi Uwaya, Palmieri, Maria Colombino, Paolo

Antonio Ascierto, Amelia Lissia, Corrado Rubino, Antonio Cossu, Jose Neptuno Rodriguez-Lopez, Luis Sanchez-del￾Campo, Magali Saez-Ayala, Maria F. Montenegro, Maria Piedad Fernandez-Perez, Juan Cabezas-Herrera, Gloria Ribas,

Maider Ibarrola-Villava, Maria Peña-Chilet, Lara P. Fernandez, Conrado Martinez-Cadenas, Andrea Zangari, Elisabetta

Cerigioni, Annachiara Contini, Mercedes Romano, Federico Zangari, Maria Giovanna Grella, Ascanio Martino, David

Weber, Kira Hartman, Ruth Prichard, Denis Evoy, Zahraa Al-Hilli, Enda McDermott, James Geraghty, Yasuhiro

Nakamura, Rizos, Roger Chammas, Guilherme Francisco, Priscila Cirilo, Fernanda Gonçalves, Tharcisio Tortelli Jr, John

Ogden Mason, Emine Kilic, Mario Santinami, Roberto Patuzzo, Roberta Ruggeri, Carlotta Tinti, Giulia Baffa, Gianpiero

Castelli, Andrea Maurichi, Alexeev, Miriam Jasiulionis, Jonathan Castillo Arias, Duane Miller, Victoria De Los Ángeles

Bustuoabad, Lucia Speroni, Arturo Irarrázabal, Storkus, Sakuhei Fujiwara, Yoshitaka Kai

Published by InTech

Janeza Trdine 9, 51000 Rijeka, Croatia

Copyright © 2013 InTech

All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to

download, copy and build upon published articles even for commercial purposes, as long as the author and publisher

are properly credited, which ensures maximum dissemination and a wider impact of our publications. After this work

has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they

are the author, and to make other personal use of the work. Any republication, referencing or personal use of the

work must explicitly identify the original source.

Notice

Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those

of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published

chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the

use of any materials, instructions, methods or ideas contained in the book.

Publishing Process Manager Ana Pantar

Technical Editor InTech DTP team

Cover InTech Design team

First published January, 2013

Printed in Croatia

A free online edition of this book is available at www.intechopen.com

Additional hard copies can be obtained from [email protected]

Melanoma - From Early Detection to Treatment, Edited by Guy Huynh Thien Duc

p. cm.

ISBN 978-953-51-0961-7

free online editions of InTech

Books and Journals can be found at

www.intechopen.com

Contents

Preface IX

Section 1 Fundamental Aspects of the Melanoma Biology 1

Chapter 1 Overcoming Resistance to BRAF and MEK Inhibitors by

Simultaneous Suppression of CDK4 3

Jianli Dong

Chapter 2 Targeted Therapies in Melanoma: Successes and Pitfalls 29

Giuseppe Palmieri, Maria Colombino, Maria Cristina Sini, Paolo

Antonio Ascierto, Amelia Lissia and Antonio Cossu

Chapter 3 Low-Penetrance Variants and Susceptibility to Sporadic

Malignant Melanoma 59

G. Ribas, M. Ibarrola-Villava, M.C. Peña-Chilet, L.P. Fernandez and C.

Martinez-Cadenas

Chapter 4 Melanoma Genetics: From Susceptibility to Progression 83

Guilherme Francisco, Priscila Daniele Ramos Cirilo, Fernanda Toledo

Gonçalves, Tharcísio Citrângulo Tortelli Junior and Roger Chammas

Chapter 5 Diagnosis, Histopathologic and Genetic Classification of Uveal

Melanoma 137

J.G.M. van Beek, A.E. Koopmans, R.M. Verdijk, N.C. Naus, A. de Klein

and E. Kilic

Chapter 6 Recombinant DNA Technology in Emerging Modalities for

Melanoma Immunotherapy 175

Vitali Alexeev, Alyson Pidich, Daria Marley Kemp and Olga

Igoucheva

Chapter 7 Acquired Resistance to Targeted MAPK Inhibition in

Melanoma 197

Kavitha Gowrishankar, Matteo S. Carlino and Helen Rizos

Chapter 8 Pars Plana Vitrectomy Associated with or Following Plaque

Brachytherapy for Choroidal Melanoma 219

John O. Mason and Sara Mullins

Chapter 9 Combination Therapies to Improve Delivery of Protective T

Cells into the Melanoma Microenvironment 231

Devin B. Lowe, Jennifer L. Taylor and Walter J. Storkus

Section 2 Melanoma Treatment Approaches 253

Chapter 10 Management of In-Transit Malignant Melanoma 255

Paul J. Speicher, Douglas S. Tyler and Paul J. Mosca

Chapter 11 Management of Brain Metastasis in Melanoma Patients 275

Sherif S. Morgan*, Joanne M. Jeter, Evan M. Hersh, Sun K. Yi and

Lee D. Cranmer*

Chapter 12 Surgical Treatment of Nevi and Melanoma in the

Pediatric Age 329

Andrea Zangari, Federico Zangari, Mercedes Romano, Elisabetta

Cerigioni, Maria Giovanna Grella, Anna Chiara Contini and Martino

Ascanio

Chapter 13 Adoptive Cell Therapy of Melanoma: The Challenges of

Targeting the Beating Heart 365

Jennifer Makalowski and Hinrich Abken

Chapter 14 Cellular and Molecular Mechanisms of Methotrexate Resistance

in Melanoma 391

Luis Sanchez del-Campo, Maria F. Montenegro, Magali Saez-Ayala,

María Piedad Fernández-Pérez, Juan Cabezas-Herrera and Jose

Neptuno Rodriguez-Lopez

Chapter 15 Surgery and the Staging of Melanoma 411

Z. Al-Hilli, D. Evoy, J.G. Geraghty, E.W. McDermott and R.S. Prichard

Chapter 16 Melanoma: Treatments and Resistance 439

Jonathan Castillo Arias and Miriam Galvonas Jasiulionis

VI Contents

Chapter 17 Management of Acral Lentiginous Melanoma 475

Yoshitaka Kai and Sakuhei Fujiwara

Chapter 18 Sentinel Lymph Node Biopsy for Melanoma and Surgical

Approach to Lymph Node Metastasis 499

Yasuhiro Nakamura and Fujio Otsuka

Chapter 19 Cutaneous Melanoma − Surgical Treatment 523

Mario Santinami, Roberto Patuzzo, Roberta Ruggeri, Gianpiero

Castelli, Andrea Maurichi, Giulia Baffa and Carlotta Tinti

Chapter 20 Therapeutic Agents for Advanced Melanoma 537

Zhao Wang, Wei Li and Duane D. Miller

Chapter 21 Update in Ocular Melanoma 565

Victoria de los Ángeles Bustuoabad, Lucia Speroni and Arturo

Irarrázabal

Section 3 Melanoma Related Features 581

Chapter 22 The Menace of Melanoma: A Photodynamic Approach to

Adjunctive Cancer Therapy 583

L.M. Davids and B. Kleemann

Chapter 23 Study of the Anti-Photoaging Effect of Noni (Morinda

citrifolia) 629

Hideaki Matsuda, Megumi Masuda, Kazuya Murata, Yumi Abe and

Akemi Uwaya

Chapter 24 Inhibiting S100B in Malignant Melanoma 649

Kira G. Hartman, Paul T. Wilder, Kristen Varney, Alexander D. Jr.

MacKerell, Andrew Coop, Danna Zimmer, Rena Lapidus and David

J. Weber

Chapter 25 Immunomodulation 669

Konstantinos Arnaoutakis, Dorothy A. Graves, Laura F. Hutchins and

Thomas Kieber-Emmons

Contents VII

Preface

The link of melanoma risk to ultraviolet (UV) radiation exposure is widely recognized, but

UV radiation independent events account also for a significant number of cases which high‐

lights the need for analysing further the mechanism(s) underlying melanomagenesis. There‐

fore, the essential aspects to be considered would be related to the balance between Mc1R

(melanocortin 1 receptor)-inherited background and the mutated BRAF (BRAF V600E) con‐

veying stresses caused either by UV radiation or oxydative damage in the context of defined

pheomelanin/eumelanin ratio.

Concerning the treatment of metastatic melanoma, overall results so far obtained still re‐

mained poor, although significant response rate has been observed with vemurafenib

(PLX4032). However resistance to this remarkable small molecule is beginning to emerge

and it is known that only patients with relevant mutation respond to this agent.

In this context, it is worth noting the development of new technologies, following the advent

of human genome sequencing allowing to identify important somatic driver mutations that

harness most aggressive cancer types. Progress gained in sequencing thousands of individu‐

al cancer genomes has already provided an invaluable insight into activating mutations and

surrogate signalling pathways sustaining deregulated proliferation, invasiveness and resist‐

ance to apoptosis as well as to inhibitors. On the other hand, the throughout deep sequenc‐

ing will also help development of other active inhibitors like PLX4032 specifically adapted

for targeting defined activating mutations. Needless to say that personalized medicine

based on patient’s genetic background represents also important aspect for taking in consid‐

eration. Overall, the huge effort provided by scientists in many areas along with that of

physicians recently will open, beyond doubt, the ways to development of appropriate and

efficient strategies in the treatment of metastatic melanoma in particular and other cancer

types in general.

As such, the book “Melanoma - From Early Detection to Treatment” assembles data and

knowledge from most experienced experts in the field. It covers sections from fundamental

aspects of the melanoma biology to various treatment approaches including melanoma re‐

lated features.

Acknowledgements: We thank Chaobin Zhu for his helpful assistance.

Guy Huynh Thien Duc

Research Director emeritus from the CNRS (Centre National de la Recherche Scientifique),

INSERM, U-1014, Université Paris XI – Groupe hospitalier Paul-Brousse,

Villejuif, France

Section 1

Fundamental Aspects of the Melanoma Biology

Chapter 1

Overcoming Resistance to BRAF and MEK Inhibitors by

Simultaneous Suppression of CDK4

Jianli Dong

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/53620

1. Introduction

Melanoma is one of the most prevalent malignancies and has a very poor prognosis. Muta‐

tions in v-raf murine sarcoma viral oncogene homolog B1 (BRAF) occur in approximately

50% of melanomas [4]. While the response to selective BRAF inhibitors (BRAFi) in BRAF￾mutant melanoma is encouraging, virtually all patients rapidly develop secondary resist‐

ance [6, 7]. Based on the finding that the mitogen activated protein kinase/ERK kinase

(MEK)-extracellular signal regulated kinase (ERK) pathway is frequently reactivated by var‐

ious BRAFi resistance mechanisms, a combination trial of a selective mutant BRAF inhibitor

(dabrafenib, GSK2118436) with a MEK inhibitor (trametinib, GSK1120212) is underway and

has achieved clinical responses in 17% and disease control in 67% in patients who failed pri‐

or single-agent treatment with a BRAF inhibitor [9]. While these results are promising, there

is a critical need to overcome resistance to BRAF and MEK inhibitors. The clinical efficacy of

BRAFi and MEKi therapy is believed to rely on a functional retinoblastoma (RB) axis to in‐

hibit cell proliferation. The inhibitor of cyclin-dependent kinase 4A (INK4A) gene encode the

p16 protein, a critical cell cycle regulator that interacts with cyclin dependent kinase (CDK)

4, inhibiting its ability to phosphorylate and inactivate RB [12, 13]. Genetic disruption of

INK4A occurs in approximately 50% of melanomas irrespective of BRAF mutation and has

been detected in melanoma cells that developed resistance to BRAFi. Of note, cyclin D is still

expressed even in the setting of maximum tolerance dosing of BRAF inhibitor [7]. We have

reported that combination of BRAFi or MEKi with the expression of wild-type INK4A or a

CDK4 inhibitor (CDK4i) significantly suppresses growth and enhances apoptosis in melano‐

ma cells [1-3]. Currently, CDK4 inhibitors are in active clinical development (http://clinical‐

trials.gov/). Based on our previous work and recent insights into molecular mechanisms of

resistance to BRAF and MEK inhibitors, we hypothesize that simultaneous suppression of

© 2013 Dong; licensee InTech. This is an open access article distributed under the terms of the Creative

Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

CDK4 is an effective strategy to overcome resistance to BRAF and MEK inhibitors. BRAF

mutation assays have been used to guide treatment with BRAF and MEK inhibitors, devel‐

opment of sensitive and specific INK4A/p16 assays may serve as predictive biomarkers for

treatment with CDK4 inhibitors.

2. Body

Constitutive activation of RAS-RAF-MEK-ERK signaling pathway in melanomas.NRAS

and BRAF mutations were found respectively in 10-20% and 60-80% melanomas [4]. NRAS

and BRAF are components of the RAS-RAF-mitogen activated protein kinase/ERK kinase

(MEK)-extracellular signal regulated kinase (ERK) signaling pathway (Fig. 1) [5]. This sig‐

naling pathway plays an essential role in cell proliferation, differentiation and survival [5,

14, 15]. Constitutive activation of the ERK pathway has been shown to mediate the trans‐

forming activity of mutant BRAF in melanoma cells [16-18]. Suppression of mutant BRAF

expression has been shown to inhibit ERK pathway activation and subsequent suppression

of melanoma cell proliferation and survival in vitro and in vivo [19-21]. Our previous data

revealed that the inhibition of mutant BRAF decreased levels of phospho-ERK (p-ERK), a

marker of ERK pathway activation in melanoma cells [5, 14, 15].

The high frequency of BRAF mutation in melanomas makes it an ideal target for therapy.

Because normal cells require wild-type BRAF for survival [22], specifically inhibiting mu‐

tant, but not wild-type BRAF in tumor cells could avoid toxic side effects generated by tar‐

geting normal cells. The finding that mutations in v-raf murine sarcoma viral oncogene

homolog B1 (BRAF) occur in approximately 50% of melanomas led to extensive investiga‐

tion of targeting BRAF for melanoma treatment, resulting in the first approved mutant spe‐

cific BRAF inhibitor for treatment of advanced melanoma.

Combine BRAF and MEK inhibitors with chemotherapeutic agents. Intrinsic therapy re‐

sistance is a major limitation in the treatment of malignant melanomas. The mechanisms in‐

volved in the resistance of melanomas are largely unknown [23, 24]. It is believed that

apoptosis and cytostasis (growth arrest/differentiation) are two of the main cellular respons‐

es to anticancer agents and loss of either process promotes treatment failure [25-27]. Activat‐

ing BRAF mutations could drive cell proliferation and increase the cell death threshold

through ERK pathway or alternative mechanisms [28-30], resulting in the blockage of both

cytotoxic and cytostatic effects of therapeutic drugs [14, 31, 32]. It has been shown that inhib‐

ition of ERK pathway sensitizes melanoma cells to apoptosis induced by DNA damaging

agents including cisplatin and ultra-violate (UV) irradiation [32, 33]. Rational combination of

BRAF and MEK inhibitors with selective chemotherapeutic agents, for example, dacarbazine

(DTIC), may generate additive/synergistic therapeutic effects.

ERK pathway activation and p16 in melanocytic lesions. Melanocytic lesions can be group‐

ed into two main categories: nevi and melanomas. Nevi are divided into several different

types based on histology. These include acquired melanocytic nevi, congenital melanocytic

nevi, blue nevi, Spitz nevi, and dysplastic nevi. Melanoma can be further divided based on

4 Melanoma - From Early Detection to Treatment

clinical and traditional histological methods as superficial spreading melanoma, lentigo ma‐

ligna melanoma, acral lentiginous melanoma, and nodular melanoma. In early stages of

melanomas, neoplastic cells are confined to the epidermis or with microinvasion into the

dermis. In advanced melanomas, cancer cells expand in the dermis and generate tumor nod‐

ules and have a high potential for metastatic spread. In the metastatic phase, cancer cells dis‐

seminate to lymph nodes or distant organs [34, 35]. For the early diagnosed and localized

melanomas, surgery is the choice of treatment. But there is currently no effective treatment

for invasive and metastatic melanomas. Patients with late stage melanomas have a high

mortality rate and life expectancy averages approximately 6-8 months after diagnosis.

Figure 1. p16-cyclin D/CDK4 modifies the outcome of RAS/RAF/MEK/ERK signaling activation. RAF relays RAS signals

through MEK to ERK. The activation of this pathway has multiple effects on cell proliferation, differentiation, and sur‐

vival depending on the cellular contexts [5]. Constitutive activation of growth factor signaling pathways or NRAS and

BRAF activating mutations can trigger over-expression of p16 leading to proliferative senescence, which manifest as

benign nevus [10, 11]. Loss of p16 by genetic and epigenetic changes allows activation of cyclin D/CDK4 and inactiva‐

tion of RB, leading to E2F activation, cell cycle progression from G1 to S phase, cell proliferation and tumor formation

[12, 13]. Further genetic changes cause tumor progression to malignant melanoma. Of the three RAS and three RAF

genes, NRAS and BRAF are mutated in melanoma [4].

Of note, in addition to melanomas, BRAF mutations are found at high frequencies (70-80%)

in benign melanocytic nevi [36, 37]. There are a large numbers of melanocytic nevi in the

general population compared to the relatively low incidence of melanomas [34, 35]. Clinical‐

ly, it is known that nevi often regress over time. This suggests that BRAF mutations alone

are insufficient to induce malignant transformation in nevus cells. The growth arrest of nevi

is believed to result from oncogene-induced senescence, which is known as a protective

mechanism against unlimited proliferation that could result from BRAF mutations and acti‐

vation of the ERK signaling pathway (nevus in Fig. 1) [10, 11]. Tumor suppressor genes have

been found to be involved in senescence process. For example, p16 is one tumor suppressor

Overcoming Resistance to BRAF and MEK Inhibitors by Simultaneous Suppression of CDK4

http://dx.doi.org/10.5772/53620

5