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New Insights and Therapeutıc Implicatıons in Cutaneous Melanoma Pinar Ozuguz*, Serap Karatas and Seval Dogruk Kacar

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New Insights and Therapeutıc Implicatıons in Cutaneous Melanoma Pinar Ozuguz*, Serap Karatas and Seval Dogruk Kacar Ozuguz et al. J Dermatol Res Ther 2016, 2:020 Volume 2 | Issue 2 ISSN: 2469-5750 Journal of DOI: 10.23937/2469-5750/1510020 Dermatology Research and Therapy Review Article: Open Access New Insights and Therapeutıc Implicatıons in Cutaneous Melanoma Pinar Ozuguz*, Serap Karatas and Seval Dogruk Kacar Check for Department of Dermatology, Afyon Kocatepe University, Afyon, Turkey updates *Corresponding author: Pinar Ozuguz, Department of Dermatology, Afyon Kocatepe University, Izmir Yolu 8 km Afyon, Turkey, Tel: +905055210335, E-mail: [email protected] adolescents and young adults between the ages of 15-29 [5]. Abstract Melanoma is a highly aggressive tumour with poor prognosis in By the time, the increase in the incidence of MM has necessitated the metastatic stage that arises and evolves due to a myriad of new treatment approaches. As factors in the pathogenesis were genetic and epigenetic events. Among these, the interaction understood more clearly, targeted therapies have been raised and the between epigenetic alterations (i.e., DNA methylation, histone studies have increased [3,5]. Although a new viewpoint does not modifications, mRNA silencing by miRNAs and nucleosome mean an increase in survival, it may shed light on treatment desicion repositioning) has been recently identified as playing an important and better treatment alternatives. role in melanoma development and progression by affecting key cellular pathways such as cell cycle regulation, DNA repair, Traditional therapeutics and immunomodulatory agents have apoptosis, invasion and immune recognition. A number of new not shown much efficacy against metastatic melanoma. Agents that oncogene candidates such as MAPK1/2, ERBB4, GRIN2A, target the RAS/RAF/MEK/ERK (MAPK) signaling pathway - the GRM3, RAC1, and PREX2 were identified. Their particular role in BRAF inhibitors vemurafenib and dabrafenib, and the MEK1/2 melanoma biology is currently under investigation. However, with inhibitor trametinib - have increased survival in patients with the development of new immunotherapies (monoclonal antibodies metastatic melanoma. Further, the combination of trametinib and specific for cytotoxic T lymphocyte-associated antigen 4 [anti- CTLA-4] and programmed death protein-1 [anti-PD1]) and small dabrafenib has been shown to be superior to single agent therapy molecules interfering with intracellular pathways (BRAF inhibitors for the treatment of metastatic melanoma. However, resistance and mitogen-activated protein kinase kinase [MEK] inhibitors) to these agents develops rapidly. Studies of additional agents and the use of this approach is becoming a viable treatment strategy combinations targeting the MAPK, c-kit, PI3K/AKT/mTOR (PI3K), for locally advanced melanoma. In this review, the risk factors, and other signaling pathways are currently underway. Furthermore, pathogenesis, and innovations in treatment of melanoma, synthetic studies of phytochemicals have yielded promising results against small molecule inhibitors, combined therapies and current progress proliferation, survival, invasion, and metastasis by targeting signaling in the development of phytochemical therapies and new targets will pathways with established roles in melanomagenesis. The relatively be mentioned. low toxicities of phytochemicals make their adjuvant use an attractive Keywords treatment option [6]. Malignant melanoma, Immunomodulatory agents, BRAF inhibitor, The survival rates of melanoma, like any type of cancer, become MEK inhibitor, C-Kit inhibitor worse with advancing stage. Spectrum theory is most consistent with the progression of melanoma from the primary site to the in- Introduction transit locations, regional or sentinel lymph nodes and beyond to the distant sites. Therefore, early diagnosis and surgical treatment Malignant melanoma (MM) is a mainly tumor of cutaneous before its spread is the most effective treatment. In addition to origin which develops from melanocytes. Although it constitutes genomic profiling and sequencing will form the basis for molecular 5% of skin cancer, it is responsible for 75% of skin cancer-related taxonomy for more accurate subgrouping of melanoma patients in deaths [1]. It also originates from oral, conjunctival or vaginal mucosa, the future. Sentinel lymph node biopsy has become a standard of care uveal tract and leptomeninx [2]. Developmentally, melanocytic for staging primary melanoma without the need for a more morbid progenitor cells migrate from neural crest to the skin and malignant complete regional lymph node dissection. With recent developments melanocytes forming melanoma also have migratory feature. High in molecular biology and genomics, novel molecular targeted therapy metastatic potential of melanoma could be explained by this feature is being developed through clinical trials [7]. [3]. Besides, it is known that large numbers of melanocytes are also arise from Schwann cell precursors of nerves innervating the skin Risk Factors of Malignant Melanoma [4]. Melanoma is diagnosed 10-15 years earlier with respect to more Ultraviolet radiation (UVR) common cancers such as breast, lung and colon cancer. More than 35% of melanoma patients are below 45 years of age. In the United Intermittent excessive sunlight exposure and severe sunburns States, it is the most common type of cancer in young adults between especially in childhood are major risk factors. Especially UVB the ages of 25-29 and the second most frequent type of cancer in radiation is more potent cause, its evidence is higher rates of Citation: Ozuguz P, Karatas S, Kacar SD (2016) New Insights and Therapeutıc Implicatıons in Cutaneous Melanoma. J Dermatol Res Ther 2:020 ClinMed Received: November 27, 2015: Accepted: April 09, 2016: Published: April 11, 2016 International Library Copyright: © 2016 Ozuguz P, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. DOI: 10.23937/2469-5750/1510020 ISSN: 2469-5750 melanoma around the equator receives the most intense UVB. MITF (Microphthalmia associated transcription factor) gene: Artificial UV sources are also hazardous. The long-term cumulative MITF protein is the main regulator of melanocyte differentiation. UVR play a role in development of lentigo maligna melanoma. It has Amplification of MITF gene contributes to "lineage addiction", a been showed that the regular use of sunscreens reduces the incidence novel mechanism to drive oncogenesis. of melanoma [2]. MC1R (Melanocortin-1 receptor) gene: MC1R polymorphisms Skin phototypes cause to the synthesis of a high level of carcinogenic pheomelanin and lead to decreased eumelanin/pheomelanin ratio. These People with skin phototype I or II, red or blond hair, blue or green polymorphisms of MC1R are clinically associated with red hair eyes, or freckles are at increased risk [2]. colour, fair skin and 2 to 4-fold increased risk for development of History of melanoma or multiple nevi melanoma and also contribute to the risk of non-melanoma skin cancer. MC1R variants have been associated with melanoma cells Individuals with personal or family history of melanoma, high which contain BRAF-V600E. number of nevi or dysplastic nevi, or large congenital melanocytic nevi, have higher risk [2]. XP (xeroderma pigmentosum) genes: Genetic defects in seven XP repair genes lead to increased mutagenesis and early carcinogenesis. Genetics XP is an autosomal recessive genodermatosis. XP patients are at 600 to 1000-fold increased risk of skin cancer, including melanoma. Germline mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A) located at chromosome 9p21 are responsible BRCA2 (breast cancer susceptibility gene): BRCA2 mutation for about 40% of hereditary melanoma cases. These carriers have 2.8 times greater risk for melanoma. However, the patients have also the risk of pancreatic cancer. CDKN2A encodes two mechanism of genetic connection is not clear. proteins: First of them, P16INK4A is a cell-cycle regulator. P16INK4A binds and inhibits cyclin-dependent kinases, CDK4 and CDK6 thus Melanoma Treatment causes G1 cell cycle arrest. If p16 loses its function or is inactivated According to staging system developed by American Joint Committee by mutation, unrestrained CDK4 phosphorylates and inactivates on Cancer (AJCC), patients with MM are evaluated in three categories. retinoblastoma protein, and brings out transcription factor, E2- These are localized disease (stage I-II), regional disease (stage III) and F, and thus causes the cells to enter the S-phase. In the absence of metastatic disease (stage IV). Wide surgical excision is the primary check-point regulation, increased cellular proliferation leads to treatment for localized disease. The recommended surgical margins for melanoma formation. The second protein encoded by CDKN2A is melanomas measuring 1.00 mm or less, 1.01 to 2 mm and more than 2 P14ARF. This protein inhibits the cellular oncogen, HDM2 which mm in thickness are 1 cm, 1 to 2 cm and 2 cm, respectively. Wide surgical accelerates the degradation of p53, a tumor-suppressor gene. The excision of primary tumor and complete lymph node dissection should mutation of P14ARF causes melanomagenesis by dysfunction of be performed to patients with regional disease. After surgical treatment, p53. Thus germline mutations in CDKN2A lead to formation of adjuvant treatment options such as IFN-α, high dose ipilimumab, tumor
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