Melanoma

Melanoma Pathophysiology

Melanocytes are found in the basal layer of the epidermis and are responsible for producing melanin.1 The transformation of melanocytes into melanoma cells encompasses clonal successions and acquisition of deleterious genomic alterations.2 After the vertical phase, the tumor cell invades the dermis/hypodermis leading to the endothelium capillaries which allows access to the bloodstream.2 Key microenvironmental factors play crucial roles in modulating this transformation process, increasing the likelihood of melanomagenesis and progression.2 Metastatic melanoma has a history of being difficult to treat, with low cure and survival rates post-surgical resection and radiation treatment.1,2 Looking closely at the cellular level- cancer cells have the ability to evade apoptosis and grow exponentially without relying on growth factors, angiogenesis, and metastasis.1

Though oncogene-directed therapy proves promising for patients with melanoma, an estimated half of cases lack BRAF or KIT mutations, paving the way for further investigation into therapeutic strategies.2,3

Immunotherapies in Melanoma

Under normal circumstances, the interaction between PD-1 and PD-L1 (or PD-L2) results in inhibition of the immune response by reducing T-lymphocyte function signaling inhibiting T-cell activation, proliferation and cytokine production.4 Many tumor cells express PD-L1 in the attempt to induce negative regulation of T-cells via the PD-1 checkpoint.4  After prolonged activation, T-cells upregulate surface PD-1 expression, to which the tumor cells bind to, sending an inhibitory signal inhibiting apoptosis.4 By blocking this pathway using PD-L1 antibodies, T-cells can be activated and become more efficient in tumor surveillance.4 PD-1 antagonist monoclonal antibodies add to the possibilities of options to treat metastatic melanoma. Currently, there are monoclonal antibodies designed to prevent PD-1 interaction with its ligands (PD-L1 or PD-L2). Anti-PD-1 monotherapy may be preferable to anti-CTLA monotherapy in some cases, however combination of the two therapies may increase response and remission rates.5 Of note, this combination of immunotherapies may increase the risk of higher toxicity (GI, hepatic and cutaneous AE).5

Resources:

  1. Liu Y, Sheikh S. Melanoma Molecular Pathogenesis and Therapeutic Management. Molecular & Cellular Biology. 2014;6(3):228
  2. Paluncic J, Kovacevic Z et al. Roads to melanoma: Key pathways and emerging players in melanoma progression and oncogenic signaling. BBA Molecular Research. 2016; Vol 1863, Iss 4, pp 770-784
  3. Flaherty KT, Hodi FS, Bastian BC. Mutation-driven drug development in melanoma. Current Opin in Onc. 2010;22(3):178-183
  4. Jaziehi AR, Lim A, Dinh T. PD-1 inhibition and treatment of advanced melanoma- role of pembrolizumab. Am J Cancer Research. 2016;6(10):2117-2128
  5. Apalla Z, Nashan D, et al. Skin Cancer: Epidemiology, Disease Burden, Pathophysiology, Diagnosis and Therapeutic Approaches. Dermatol Ther. 2017 (suppl 1) S5-S19