Preface

**Section 3 Non-melanoma Skin Cancers 133**

**Therapeutic Targets 135**

**Optical Methods 161**

Monica Neagu

**VI** Contents

Chapter 6 **Squamous Cell Carcinoma: Biomarkers and Potential**

Chapter 7 **Correlation between Porcine and Human Skin Models by**

and Priscila Fernanda Campos de Menezes

Adriana T. Lopez, Liang Liu and Larisa Geskin

Chapter 8 **Molecular Mechanisms and Biomarkers of Skin**

**Photocarcinogenesis 175**

Vlad-Mihai Voiculescu, Constantin Caruntu, Iulia Solomon, Mihai Lupu, Mihaela Adriana Ilie, Daniel Boda, Carolina Constantin and

Alessandra Keiko Lima Fujita, Rozana Wendler da Rocha, André Escobar, Andrigo Barboza de Nardi, Vanderlei Salvador Bagnato The annual incidence of all forms of human skin cancer are increasing, representing a grow‐ ing public concern. Human skin cancers are by far the most common type of tumors and so represent a significant health burden to the society: it is estimated that the annual cost is \$8.1 billion for all skin cancers combined, of which some \$3.3 billion is devoted to melanoma1 . Nearly 5 million people are treated in the United States each year for various skin cancers, with melanoma, the deadliest, killing nearly 9,000 people yearly2 . Skin cancer is a disease of the elderly and it has been estimated that half of all Americans who live to age 65 develop skin cancer at least once.

The deadliest skin cancer is unquestionably melanoma. If detected early it is curable by re‐ section, however at later stages it is often deadly3 . Melanoma stages 0 – 4 are described as: Stage 0: Melanoma in situ, the cancer is only in the epidermis. Stage 1: Up to 2 millimeters (mm) deep, not spread to lymph nodes or other sites. Stage 2: Melanoma thicker than 1 mm, may be thicker than 4 mm, not spread to lymph nodes or other sites, may or may not be ulcerated. Stage 3: Spread to local lymph nodes or nearby lymphatics, but not spread to dis‐ tant sites. The primary cancer may be thicker than 4 mm, and it may be ulcerated. Stage 4: Metastatic melanoma has reached distant lymph nodes or metastasized to additional organs; most commonly liver, lungs, bones and brain are affected by these metastases.

It is estimated that 50% of all melanomas have an activating mutation in the *BRAF* gene, which promotes unrestrained melanocyte proliferation4 . Novel drugs have been developed to specifically target mutated BRAF proteins. Two such drugs, vemurafenib and dabrafe‐ nib, have been approved by FDA for the treatment of late-stage melanomas. MEK is a BRAF effector protein, it acts downstream from BRAF, and therefore is another attractive target for melanoma therapy. Drugs that block MEK proteins, trametinib (Mekinist) and cobimetinib (Cotellic),have been shown to shrink some melanomas with mutated BRAF changes. Gener‐ ally, they are used in combination therapy, with BRAF inhibitors, because they are expected to delay the development of resistance to BRAF-targeting monotherapies5 .

A very promising new approach for melanoma treatment is immunotherapy, an approach that boosts patient's own immune system to identify and defeat cancer cells more effective‐ ly. These drugs work by eliminating the restraints from the body's immune system. Pembro‐ lizumab (Keytruda) and nivolumab (Opdivo) inhibit PD-1, a protein that prevents immune cells from attacking other cells in the body6 . Blocking PD-1boosts the immune response against melanoma cells, leading to diminished tumors and prolonged lives. These drugs of‐ ten cause serious side effects. Ipilimumab (Yervoy) also boosts the immune response, but it targets a different protein, CTLA-4, another immunity check point7 .

Alternatively, interferon-alfa and interleukin-2 are proteins that boost the immune system in a general way8 . They were shown to shrink advanced melanomas in about 10% to 20% of patients and may be given together.

Interferon-alfa is sometimes be used as adjuvant therapy after surgery to delay the melano‐ ma recurrence.

**KIT** is a proto-oncogene receptor tyrosine-protein kinase (CD117).

**MEK, ERK** are members of a cascade of protein kinases that convey signal from cell surface

**CDK4, 6** are cell division protein kinases whose activity is required for G1/S transition of the

**RAC, Rho** and **Cdc42** are small GTPase of the Rho family that regulate cytoskeleton in cell

**PI3K** is phosphatidylinositol-3-kinase, an enzyme involved in cell proliferation, survival,

**AKT** (a.k.a. PKB) is a serine/threonine protein kinase that regulates glucose metabolism,

**mTOR** is a member of the PI3K-related kinases family regulates cell proliferation, motility,

**S6K** is the Ribosomal protein **S6** kinase; phosphorylation of S6 stimulates ribosomal protein

[1] Medical Expenditure Panel Survey. Rockville, MD: Agency for Healthcare Re‐ search and Quality; http://meps.ahrq.gov/mepsweb/data\_stats/down‐

[2] U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2010 Incidence and Mortality Web-based report. Atlanta, GA: Centers for Disease Con‐ trol and Prevention, U.S. Dept of Health and Human Services and National Can‐

cer Institute, National Institutes of Health; 2013; http://www.cdc.gov/uscs. [3] The Emerging Therapeutic Landscape of Advanced Melanoma. Henriques V, Martins T, Link W, Ferreira BI. Curr Pharm Des. 2018; doi:

10.2174/1381612824666180125093357. PMID: 29366407.

**Miroslav Blumenberg, PhD., Associate Professor** The R.O.Perelman Department of Dermatology and Department of Biochemistry and Molecular Pharmacology

NYU School of Medicine

New York, USA

Preface IX

**CCND1** encodes cyclin D1, a cyclin that regulates subunit of CDK4 or CDK6.

**MITF** is a lineage-specific transcription factor found in melanocytes.

**PTPN11** is a non-receptor tyrosine-protein phosphatase. **NRAS** Neuroblastoma RAS viral oncogene homolog. **BRAF** proto-oncogene serine/threonine-protein kinase.

to the nucleus pathway.

adhesion and migration.

differentiation, and motility.

survival and other processes.

apoptosis, proliferation and cell migration.

load\_data\_files.jsp.

cell cycle.

synthesis.

**References**

Public is urged to use the simple ABCDE rule when noticing the presence of malignant mel‐ anoma. These stand for asymmetry of the lesion - A, border, irregular - B, color, non-uni‐ form - C, diameter >6 mm - D and evolving, changing in size, shape, or color - E 9.

Less deadly but more common than melanoma common human skin cancers are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC, the most common type of skin cancer, is caused by ultraviolet part of the sunlight, Usually it occurs on sun-exposed areas, such as the face, neck, or forearms. BCC is usually treated with surgical excision often using Mohs micrographic surgery to spare the nonmalignant tissue10.

SCC, the second most common skin cancer, also occurs in chronically sun-exposed areas. Environmental agents, including papillomaviruses, can be contributing risk factors. SSCs may present as an ulcer, lump or red patch on the skin with scaling or crusting. Common in elderly, SCC often originates in actinic keratosis lesions. Squamous cell carcinoma is usually surgically treated, using Mohs micrographic surgery. Treating actinic keratosis may be a preventive procedure for SCC.

In this volume we focus on pathways, mechanisms, targets and treatments of human skin cancers, with particular emphasis on the new developments in the research on melanomas.

**Figure 1.**The important signaling pathways causing melanoma and potential objects for targeted therapies. Adapted from reference11

**KIT** is a proto-oncogene receptor tyrosine-protein kinase (CD117).

**PTPN11** is a non-receptor tyrosine-protein phosphatase.

**NRAS** Neuroblastoma RAS viral oncogene homolog.

**BRAF** proto-oncogene serine/threonine-protein kinase.

**MEK, ERK** are members of a cascade of protein kinases that convey signal from cell surface to the nucleus pathway.

**CCND1** encodes cyclin D1, a cyclin that regulates subunit of CDK4 or CDK6.

**CDK4, 6** are cell division protein kinases whose activity is required for G1/S transition of the cell cycle.

**RAC, Rho** and **Cdc42** are small GTPase of the Rho family that regulate cytoskeleton in cell adhesion and migration.

**MITF** is a lineage-specific transcription factor found in melanocytes.

**PI3K** is phosphatidylinositol-3-kinase, an enzyme involved in cell proliferation, survival, differentiation, and motility.

**AKT** (a.k.a. PKB) is a serine/threonine protein kinase that regulates glucose metabolism, apoptosis, proliferation and cell migration.

**mTOR** is a member of the PI3K-related kinases family regulates cell proliferation, motility, survival and other processes.

**S6K** is the Ribosomal protein **S6** kinase; phosphorylation of S6 stimulates ribosomal protein synthesis.

> **Miroslav Blumenberg, PhD., Associate Professor** The R.O.Perelman Department of Dermatology and Department of Biochemistry and Molecular Pharmacology NYU School of Medicine New York, USA

#### **References**

Interferon-alfa is sometimes be used as adjuvant therapy after surgery to delay the melano‐

Public is urged to use the simple ABCDE rule when noticing the presence of malignant mel‐ anoma. These stand for asymmetry of the lesion - A, border, irregular - B, color, non-uni‐

Less deadly but more common than melanoma common human skin cancers are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC, the most common type of skin cancer, is caused by ultraviolet part of the sunlight, Usually it occurs on sun-exposed areas, such as the face, neck, or forearms. BCC is usually treated with surgical excision often using

SCC, the second most common skin cancer, also occurs in chronically sun-exposed areas. Environmental agents, including papillomaviruses, can be contributing risk factors. SSCs may present as an ulcer, lump or red patch on the skin with scaling or crusting. Common in elderly, SCC often originates in actinic keratosis lesions. Squamous cell carcinoma is usually surgically treated, using Mohs micrographic surgery. Treating actinic keratosis may be a

In this volume we focus on pathways, mechanisms, targets and treatments of human skin cancers, with particular emphasis on the new developments in the research on melanomas.

**Figure 1.**The important signaling pathways causing melanoma and potential objects for targeted therapies. Adapted

form - C, diameter >6 mm - D and evolving, changing in size, shape, or color - E 9.

Mohs micrographic surgery to spare the nonmalignant tissue10.

ma recurrence.

VIII Preface

preventive procedure for SCC.

from reference11


[4] Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. Cheng L, Lopez-Beltran A, Massari F, Ma‐ cLennan GT, Montironi R. Mod Pathol. 2018;24-38. doi: 10.1038/modpathol. 2017.104. PMID: 29148538.

**Section 1**

**Melanoma: Pathways and Mechanisms**


**Melanoma: Pathways and Mechanisms**

[4] Molecular testing for BRAF mutations to inform melanoma treatment decisions: a move toward precision medicine. Cheng L, Lopez-Beltran A, Massari F, Ma‐ cLennan GT, Montironi R. Mod Pathol. 2018;24-38. doi: 10.1038/modpathol.

[5] Mitogen-activated protein kinase (MEK) inhibitors to treat melanoma alone or in combination with other kinase inhibitors. Faghfuri E, Nikfar S, Niaz K, Faramarzi MA, Abdollahi M. Expert Opin Drug Metab Toxicol. 2018;14:317-330. doi:

[6] Anti-programmed cell death-1 (PD-1) monoclonal antibodies in treating ad‐ vanced melanoma -- a clinical update.Trinh VA, Joseph J, Hwu WJ. Discov Med.

[7] Long-term survival with modern therapeutic agents against metastatic melano‐ ma-vemurafenib and ipilimumab in a daily life setting. Lang BM, Peveling-Ober‐ hag A, Faidt D, Hötker AM, Weyer-Elberich V, Grabbe S, Loquai C. Med Oncol.

[8] IL2 Inducible T-cell Kinase, a Novel Therapeutic Target in Melanoma. Carson CC, Moschos SJ, Edmiston SN, Darr DB, Nikolaishvili-Feinberg N, Groben PA, Zhou X, Kuan PF, Pandey S, Chan KT, Jordan JL, Hao H, Frank JS, Hopkinson DA, Gibbs DC, Alldredge VD, Parrish E, Hanna SC, Berkowitz P, Rubenstein DS, Mill‐ er CR, Bear JE, Ollila DW, Sharpless NE, Conway K, Thomas NE. Clin Cancer

Res. 2015;21:2167-76. doi: 10.1158/1078-0432.CCR-14-1826. PMID: 25934889 [9] A series of melanomas smaller than 4 mm and implications for the ABCDE rule. Goldsmith SM, Solomon AR. J Eur Acad Dermatol Venereol. 2007;21:929-34.

[10] Clinical Characteristics of Non-Melanoma Skin Cancers Recurring within 5 years after Mohs Micrographic Surgery: Single Institution Retrospective Chart Review. Vajdi T, Eilers R, Jiang SIB. J Clin Investig Dermatol. 2017 5. doi:

[11] The molecular pathology of melanoma: an integrated taxonomy of melanocytic neoplasia. Bastian BC. Annu Rev Pathol. 2014;9:239-71. doi: 10.1146/annurev-

2017.104. PMID: 29148538.

X Preface

2018;25:31-40. PMID: 29466692.

PMID: 17659002.

10.1080/17425255.2018.1432593. PMID: 29363351.

10.13188/2373-1044.1000036.. PMID: 28936477

pathol-012513-104658. PMID: 24460190

2018;35:24. doi: 10.1007/s12032-018-1084-9. PMID: 29387968

**Chapter 1**

**Provisional chapter**

**Epigenetics in Melanoma Development and Drug**

**Epigenetics in Melanoma Development and Drug** 

DOI: 10.5772/intechopen.70983

Melanomas, which originate from melanocytic cells, mainly develop in the skin but can also arise at other body sites. The disease accounts for approximately 90% of deaths related to cutaneous tumors with late stage metastatic melanoma having a very poor prognosis of 6–9 month median survival for untreated patients. Research in the last decades resulted in ground-breaking discoveries of melanoma genetics and biology. High frequency mutations in genes like *BRAF*, *NRAS* and *KIT*, which lead to hyper-activation of the MAPK signaling pathway, drive melanoma progression. Targeting the MAPK signaling pathway has successfully been translated into effective therapies that significantly improve patient survival. Despite the unquestionable importance of such genetic events, the involvement of epigenetic alterations for melanoma development, and resistance to aforementioned therapies is becoming increasingly apparent. In this chapter, epigenetic alterations commonly found in melanoma are introduced, with a focus on histone and DNA modifications and their relevance for melanoma development, progression and therapy response. Detailed knowledge about this emerging aspect of melanoma research will help to understand the plastic nature of melanoma and set the foundation for novel treatment strategies that target aberrant gene regulation on genetic and epigenetic levels.

**Keywords:** biomarker, drug resistance, histone modifications, DNA methylation,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2018 The Author(s). Licensee IntechOpen. This chapter is 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.

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

The grim prognosis for metastatic melanoma patients and the steadily increasing rates of melanoma incidents, that are projected to continuously rise within the next decades [1], represent a challenge for healthcare systems worldwide and highlight the importance of developing and optimizing prevention strategies, diagnostic approaches and treatment regimes.

**Resistance**

**Abstract**

**Resistance**

Heinz Hammerlindl and Helmut Schaider

Heinz Hammerlindl and Helmut Schaider

http://dx.doi.org/10.5772/intechopen.70983

melanoma, targeted therapy

**1. Introduction**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

**Provisional chapter**
