**Author details**

Jane O'Sullivan1 \* and Donal O'Connor<sup>2</sup>


### **References**

[1] Gershenwald J, Scolyer R, Hess K, Sondak V, Long G, Ross M, Lazar A, Faries M, Kirkwood J, McArthur G, Haydu L, Eggermont A, Flaherty K, Balch C, Thompson J. Melanoma staging: Evidence-based changes in the American joint committee on cancer eight edition cancer staging manual. CA: A Cancer Journal for Clinicians. 2017;**67**(6):472-492

[2] Dummer R, Hauschild A, Lindenblatt N, Pentheroudakis G, Keilholz U. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology. 2015;**26**(5):126-132

[12] Eggermont A, Chiarion-Sileni V, Grob J, Dummer R, Wolchok J, Schmidt H, Hamid O, Robert C, Ascierto P, Richards J, Lebbé C, Ferraresi V, Smylie M, Weber J, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel J, Hodi F, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. New England Journal of Medicine. 2016;**375**(19):1845-1855

The Modern Approach to Targeting Melanoma http://dx.doi.org/10.5772/intechopen.73489 103

[13] Weber J, Mandala M, Del Vecchio M, Gogas H, Arance A, Cowey C, Dalle S, Schenker M, Chiarion-Sileni V, Marquez-Rodas I, Grob J, Butler M, Middleton M, Maio M, Atkinson V, Queirolo P, Gonzalez R, Kudchadkar R, Smylie M, Meyer N, Mortier L, Atkins M, Long G, Bhatia S, Lebbé C, Rutkowski P, Yokota K, Yamazaki N, Kim T, de Pril V, Sabater J, Qureshi A, Larkin J, Ascierto P. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. New England Journal of Medicine. 2017;**377**(19):1824-1835

[14] Long G, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Schadendorf D, Lesimple T, Plummer R, Ji R, Zhang P, Mookerjee B, Legos J, Kefford R, Dummer R, Kirkwood J. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma.

[15] Richman J, Martin-Liberal J, Diem S, Larkin J. BRAF and MEK inhibition for the treatment of advanced BRAF mutant melanoma. Expert Opinion on Pharmacotherapy.

[16] Dossett L, Kudchadkar R, Zager J. BRAF and MEK inhibition in melanoma. Expert

[17] Flaherty KT, Lee SJ, Zhao F, et al. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. Journal of Clinical Oncology. 2013;**31**(3):373-379

[18] Queirolo P, Picasso V, Spagnolo F. Combined BRAF and MEK inhibition for the treatment of BRAF-mutated metastatic melanoma. Cancer Treatment Reviews. 2015;**41**(6):519-526

[19] Massey P, Prasad V, Figg W, Fojo T. Multiplying therapies and reducing toxicity in meta-

[20] Germann U, Furey B, Markland W, Hoover R, Aronov A, Roix J, Hale M, Boucher D, Sorrell D, Martinez-Botella G, Fitzgibbon M, Shapiro P, Wick M, Samadani R, Meshaw K, Groover A, DeCrescenzo G, Namchuk M, Emery C, Saha S, Welsch D. Targeting the MAPK signaling pathway in cancer: Promising preclinical activity with the novel selective ERK1/2 inhibitor BVD-523 (ulixertinib). Molecular Cancer Therapeutics. 2017;

[21] Larkin J, Ascierto P, Dreno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. The New England Journal of

[22] Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. The New England

static melanoma. Cancer Biology & Therapy. 2015;**16**(7):1014-1018

The New England Journal of Medicine. 2017;**377**(19):1813-1823

2015;**16**(9):1285-1297

**16**(11):2351-2363

Medicine. 2014;**371**(20):1867-1876

Journal of Medicine. 2014;**371**(20):1877

Opinion on Drug Safety. 2015;**14**(4):559-570


[12] Eggermont A, Chiarion-Sileni V, Grob J, Dummer R, Wolchok J, Schmidt H, Hamid O, Robert C, Ascierto P, Richards J, Lebbé C, Ferraresi V, Smylie M, Weber J, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel J, Hodi F, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. New England Journal of Medicine. 2016;**375**(19):1845-1855

[2] Dummer R, Hauschild A, Lindenblatt N, Pentheroudakis G, Keilholz U. Cutaneous melanoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up.

[3] Thomas J, Newton-Bishop J, A'Hern R, Coombes G, Timmons M, Evans J, Cook M, Theaker J, Fallowfield M, O'Neill T, Ruka W, Bliss J. Excision margins in high-risk malig-

[4] Bichakjian C, Halpern A, Johnson T, Foote Hood A, Grichnik J, Swetter S, Tsao H, Barbosa V, Chuang T, Duvic M, Ho V, Sober A, Beutner K, Bhushan R, Smith Begolka W. Guidelines of care for the management of primary cutaneous melanoma. American

[5] Veronesi U, Cascinelli N. Narrow excision (1-cm margin). A safe procedure for thin cuta-

[6] Balch C, Soong S, Ross M, Urist M, Karakousis C, Temple W, Mihm M, Barnhill R, Jewell W, Wanebo H, Harrison R. Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Annals of Surgical Oncology.

[7] Sladden M, Balch C, Barzilai D, Berg D, Freiman A, Handiside T, Hollis S, Lens M, Thompson J. Surgical excision margins for primary cutaenous melanoma. Cochrane

[8] Cascinelli N, Belli F, Santinami M, Fait V, Testori A, Ruka W, Cavaliere R, Mozzillo N, Rossi CR, MacKie RM, Niewag O, Pace M, Kirov K. Sentinel lymph node biopsy in cutaenous melanoma: The WHO melanoma program experience. Annals of Surgical

[9] Morton D, Thompson J, Cochran A, Mozzillo N, Nieweg O, Roses D, Hoekstra H, Karakousis C, Puleo C, Coventry B, Kashani-Sabet M, Smithers B, Paul E, Kraybill W, McKinnon J, Wang H, Elashoff R, Faries M. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. The New England Journal of Medicine. 2014;

[10] Leiter U, Stadler R, Mauch C, Hohenberger W, Brockmeyer N, Berking C, Sunderkötter C, Kaatz M, Schulte K, Lehmann P, Vogt T, Ulrich J, Herbst R, Gehring W, Simon J, Keim U, Martus P, Garbe C. Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): A multicentre ran-

[11] Eggermont A, Chiarion-Sileni V, Grob J, Dummer R, Wolchok J, Schmidt H, Hamid O, Robert C, Ascierto P, Richards J, Lebbé C, Ferraresi V, Smylie M, Weber J, Maio M, Konto C, Hoos A, de Pril V, Gurunath RK, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma(EORTC 18071): A randomised, double-blind, phase 3 trial. The Lancet Oncology. 2015 May;**16**(5):

domised, phase 3 trial. The Lancet Oncology. 2016;**17**(6):757-767

522-530. DOI: 10.1016/S1470-2045(15)70122-1

nant melanoma. New England Journal of Medicine. 2004;**350**(8):757-766

Annals of Oncology. 2015;**26**(5):126-132

102 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

Academy of Dermatology. 2011;**65**(5):1032-1047

2000;**7**(2):87-97

**370**(7):599-609

Oncology. 2000 Jul;**7**(6):469-474

neous melanoma. Archives of Surgery. 1991;**126**(4):438-441

Database of Systematic Reviews. 2009;**7**(4):CD004835


[23] Flaherty K, Infante J, Daud A, Gonzalez R, Kefford R, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. The New England Journal of Medicine. 2012;**367**(18):1694-1703

Tian J, Yellin M, Nichol G, Hoos A, Urba W. Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine. **363**(8):711-723

The Modern Approach to Targeting Melanoma http://dx.doi.org/10.5772/intechopen.73489 105

[35] Fellner C. Ipilimumab (yervoy) prolongs survival in advanced melanoma: Serious side effects and a hefty price tag may limit its use. PT Journal. 2012;**37**(9):503-530

[36] Schadendorf D, Hodi F, Robert C, Weber J, Margolin K, Hamid O, Patt D, Chen T, Berman D, Wolchok J. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in unresectable or metastatic melanoma. Journal of Clinical Oncology.

[37] Robert C, Long G, Brady B, Dutriaux C, Maio M, Mortier L, Hassel J, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage K, Hernberg M, Lebbé C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman I, Atkinson V, Ascierto P. Nivolumab in previously untreated melanoma without BRAF mutation. New England Journal of

[38] Topalian S, Sznol M, McDermott D, Kluger H, Carvajal R, Sharfman W, Brahmer J, Lawrence D, Atkins M, Powderly J, Leming P, Lipson E, Puzanov I, Smith D, Taube J, Wigginton J, Kollia G, Gupta A, Pardoll D, Sosman J, Hodi F. Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab.

[39] Weber J, D'Angelo S, Minor D, Hodi F, Gutzmer R, Neyns B, Hoeller C, Khushalani N, Miller W Jr, Lao C, Linette G, Thomas L, Lorigan P, Grossmann K, Hassel J, Maio M, Sznol M, Ascierto P, Mohr P, Chmielowski B, Bryce A, Svane I, Grob J, Krackhardt A, Horak C, Lambert A, Yang A, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): A randomised, controlled, open-label, phase 3 trial. The Lancet Oncology. 2015;**16**(4):375-384

[40] Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A, KEYNOTE-006 investigators. Pembrolizumab versus ipilimumab in advanced melanoma. The New England Journal

[41] Schachter J, Ribas A, Long G, Arance A, Grob J, Mortier L, Daud A, Carlino M, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank C, Petrella T, Hamid O, Zhou H, Ebbinghaus S, Ibrahim N, Robert C. Pembrolizumab versus ipilimumab for advanced melanoma: Final overall survival results of a multicentre, randomised, open-label phase

[42] Hamid O et al. Preliminary clinical safety, tolerability and activity of atezolizumab (anti-PD-L1) combined with Zelboraf in BRAFv600 metastatic melanoma. In: Presented at the Society for Melanoma Research 2015 International Congress; November 18-21,

2015;**33**(17):1889-1894

Medicine. 2014;**372**(4):320-330

Journal of Clinical Oncology. 2014;**32**(10):1020-1030

of Medicine. 2015 Jun 25;**372**(26):2521-2532

2015; San Francisco, CA

3 study (KEYNOTE-006). Lancet. 2017;**390**(10105):1853-1862


Tian J, Yellin M, Nichol G, Hoos A, Urba W. Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine. **363**(8):711-723

[35] Fellner C. Ipilimumab (yervoy) prolongs survival in advanced melanoma: Serious side effects and a hefty price tag may limit its use. PT Journal. 2012;**37**(9):503-530

[23] Flaherty K, Infante J, Daud A, Gonzalez R, Kefford R, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. The New England Journal

[24] Buschow S, Ramazzotti M, Reinieren-Beeren I, Heinzerling L, Westdorp H, Stefanini I, Beltrame L, Hato S, Ellebaek E, Gross S, Nguyen V, Weinlich G, Ragoussis J, Baban D, Schuler-Thurner B, Svane I, Romani N, Austyn J, De Vries I, Schuler G, Cavalieri D, Figdor C. Survival of metastatic melanoma patients after dendritic cell vaccination correlates with expression of leukocyte phosphatidylethanolamine binding protein 1/Raf

[25] Perica K, Varela J, Oelke M, Schneck J. Adoptive T cell immunotherapy for cancer.

[26] Sharpe A, Pauken K. The diverse functions of the PD1 inhibitory pathway. Nature

[27] Sakaguchi S, Yamaguchi T, Nomura T, Ono M. Regulatory T cells and immune tolerance.

[28] Hall B. T cells: Soldiers and spies—The surveillance and control of effector T cells by regulatory T cells. Clinical Journal of the American Society of Nephrology. 2015;**10**(11):

[29] Kim T, Amaria R, Spencer C, Reuben A, Cooper Z, Wargo J. Combining targeted therapy and immune checkpoint inhibitors in the treatment of metastatic melanoma. Cancer

[30] Ott P, Hodi F, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clinical Cancer Research.

[31] Furness A, Vargas F, Peggs K, Quezada S. Impact of tumour microenvironment and Fc receptors on the activity of immunomodulatoryantibodies. Trends in Immunology.

[32] Ascierto PA, Simeone E, Sileni VC, et al. Clinical experience with ipilimumab 3 mg/ kg: Real-world efficacy and safety data from an expanded access programme cohort.

[33] Simpson T, Li F, Montalvo-Ortiz W, Sepulveda M, Bergerhoff K, Arce F, Roddie C, Henry J, Yagita H, Wolchok J, Peggs K, Ravetch J, Allison J, Quezada S. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy

[34] Hodi F, O'Day S, McDermott D, Weber R, Sosman J, Haanen J, Gonzalez R, Robert C, Schadendorf D, Hassel J, Akerley W, van den Eertwegh A, Lutzky J, Lorigan P, Vaubel J, Linette G, Hogg D, Ottensmeier C, Lebbé C, Peschel C, Quirt I, Clark J, Wolchok J, Weber J,

against melanoma. Journal of Experimental Medicine. 2013;**210**(9):1695-1710

kinase inhibitory protein. Oncotarget. 2017;**8**(40):67439-67456

Rambam Maimonides Medical Journal. 2015;**6**(1):e0004

Reviews. Immunology. 2017. DOI: 10.1038/nri.2017.108

of Medicine. 2012;**367**(18):1694-1703

104 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

Cell. 2008;**133**(5):775-787

2013;**19**(19):5300-5309

Biology & Medicine. 2014;**11**(4):237-246

2014;**35**(7):290-298. DOI: 10.1016/j.it.2014.05.002

Journal of Translational Medicine. 2014;**12**:116

2050-2064


[43] Khoja L, Day D, Wei-Wu Chen T, Siu L, Hansen A. Tumour- and class-specific patterns of immune-related adverse events of immune checkpointinhibitors: A systematic review. Annals of Oncology. 2017;**28**(10):2377-2385

[54] Kohlhapp F, Kaufman H. Molecular pathways: Mechanism of action for talimogene laherparepvec, a new oncolytic virusimmunotherapy. Clinical Cancer Research.

The Modern Approach to Targeting Melanoma http://dx.doi.org/10.5772/intechopen.73489 107

[55] Harrington K, Andtbacka R, Collichio F, Downey G, Chen L, Szabo Z, Kaufman H. Efficacy and safety of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in patients with stage IIIB/C and IVM1a melanoma: Subanalysis

[56] Boudewijns S, Bloemendal M, Gerritsen W, de Vries I, Schreibelt G. Dendritic cell vaccination in melanoma patients: From promising results to future perspectives. Human

[57] Luke J, Schwartz G. Chemotherapy in the management of advanced cutaneous malig-

of the phase IIIOPTiM trial. OncoTargets and Therapy. 2016;**16**(9):7081-7093

Vaccines & Immunotherapeutics. 2016;**12**(10):2523-2528

nant melanoma. Clinics in Dermatology. 2013;**31**(3):290-297

2016;**22**(5):1048-1054


[54] Kohlhapp F, Kaufman H. Molecular pathways: Mechanism of action for talimogene laherparepvec, a new oncolytic virusimmunotherapy. Clinical Cancer Research. 2016;**22**(5):1048-1054

[43] Khoja L, Day D, Wei-Wu Chen T, Siu L, Hansen A. Tumour- and class-specific patterns of immune-related adverse events of immune checkpointinhibitors: A systematic review.

[44] Jochems C, Fantini M, Fernando R, Kwilas A, Donahue R, Lepone L, Grenga I, Kim Y, Brechbiel M, Gulley J, Madan R, Heery C, Hodge J, Newton R, Schlom J, Tsang K. The IDO1 selective inhibitor epacadostat enhances dendritic cell immunogenicity and lytic

[45] Liu X, Shin N, Koblish H, Yang G, Wang Q, Wang K, Leffet L, Hansbury M, Thomas B, Rupar M, Waeltz P, Bowman K, Polam P, Sparks R, Yue E, Li Y, Wynn R, Fridman J, Burn T, Combs A, Newton R, Scherle P. Selective inhibition of IDO1 effectively regulates

[46] Gangadhar T, Hamid O, Smith D, Bauer T, Wasser J, Olszanski J, Luke J, Balmanoukian A, Kaufman D, Zhao Y, Maleski J, Jones M, Leopold L, Gajewski T. Epacadostat plus pembrolizumab in patients with advanced melanoma and select solid tumors: Updated phase 1 results from ECHO-202/KEYNOTE-037. Annals of Oncology. 2016;**27**(6):1 [47] Gibney G, Hamid O, Lutzky J, Olszanski A, Gangadhar T, Gajewsk T, Chmielowski B, Hanks B, Boasberg P, Zhao Y, Newton R, Bowman J, Maleski J, Leopold L Weber. Updated results from a phase 1/2 study of epacadostat (INCB024360) in combination

[48] Wolchok J, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob J, Cowey C, Lao C, Wagstaff J, Schadendorf D, Ferrucci P, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino M, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow M, Callahan M, Walker D, Rollin L, Bhore R, F1 H, Larkin J. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. The New England Journal of Medicine. 2017;**377**(14):1345-1356

[49] Yee C, Adoptive T. Cell therapy: Addressing challenges in cancer immunotherapy.

[50] Dudley M, Yang J, Sherry R, Hughes M, Royal R, Kammula U, Robbins P, Huang J, Citrin D, Leitman S, Wunderlich J, Restifo N, Thomasian A, Downey S, Smith F, Klapper J, Morton K, Laurencot C, White D, Rosenberg S. Adoptive cell therapy for patients with metastatic melanoma: Evaluation of intensive myeloablativechemoradiation preparative

[51] Pol J, Kroemer G, Galluzzi L. First oncolytic virus approved for melanoma immuno-

[52] Dharmadhikari N, Mehnert J, Kaufman H. Oncolytic virus immunotherapy for mela-

[53] Fukuhara H, Ino Y, Todo T. Oncolytic virus therapy: A new era of cancer treatment at

ability of tumor antigen-specific T cells. Oncotarget. 2016;**7**(25):37762-37772

mediators of antitumor immunity. Blood. 2010 Apr 29;**115**(17):3520-3530

with ipilimumab in patients with metastatic melanoma. 2016

Journal of Translational Medicine. 2005 Apr 28;**3**(1):17

therapy. Oncoimmunology. 2016;**5**(1):e1115641

Dawn. Cancer Science. 2016;**107**(10):1373-1379

regimens. Journal of Clinical Oncology. 2008;**26**(32):5233-5239

noma. Current Treatment Options in Oncology. 2015;**16**(3):326

Annals of Oncology. 2017;**28**(10):2377-2385

106 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments


**Chapter 5**

**Provisional chapter**

**Possibilities for the Therapy of Melanoma: Current**

This chapter presents an overview of possibilities for the therapy of melanoma, current knowledge and future direction. Skin cancer is one of the most frequent types of cancers. Melanoma is much less common than basal cell and squamous cell skin cancers, but it is far more dangerous. Detailed knowledge of melanoma at the molecular level allows to develop new treatment alternatives and to design effective new drugs. There are two approaches in therapy of melanoma in the present based on immunotherapy and targeted therapy or their combination. Immunotherapy includes immune checkpoint blockades, whereas targeted therapy is represented by protein kinase inhibitors, such as BRAF inhibitors, MEK inhibitors, and NRAS inhibitors. Detailed knowledge of protein structure and the understanding of its role in key signaling pathways in melanoma development lead to the designation of new protein kinase inhibitors in targeted therapy. **Keywords:** melanoma, chemotherapy, immunotherapy, targeted therapy, protein kinase

**Possibilities for the Therapy of Melanoma: Current** 

DOI: 10.5772/intechopen.70368

© 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 incidence of melanoma is increasing worldwide. Melanomas represent 3% of all skin cancers but 65% of skin cancer deaths [1]. Melanoma is currently the fifth and sixth most common solid malignancy diagnosed in men and women, respectively [2]. The rates of melanoma have been rising for at least 30 years [3]. Although melanoma is no longer considered just 'one disease', pathologists will continue to have important role in identifying and describing tumor subtypes [4]. More detailed understanding of melanoma allows the development

**Knowledge and Future Directions**

**Knowledge and Future Directions**

Marcela Valko-Rokytovská, Jana Šimková, Mária Milkovičová and Zuzana Kostecká

Marcela Valko-Rokytovská, Jana Šimková, Mária Milkovičová and Zuzana Kostecká

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70368

**Abstract**

inhibitors

**1. Introduction**

**Provisional chapter**
