Malignant melanoma: genetics and therapeutics in the genomic era

Abstract

Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

High expression of DNA repair pathways is associated with metastasis in melanoma patients

“…Nevertheless, tumors may take advantage of the overexpression of all these gene products to improve both their cellular response and survival following DNA damage as well as their capacity to invade internal organs. To become a primary melanoma, melanocytes should undergo some type of genetic instability leading to various gene amplifications, gene deletions and mutations (Chin et al, 2006). From our data, we can hypothesize that a primary melanoma cell that will metastasize, that is, be able to leave the tumor, enter the circulation, extravasate, survive and grow in a distant organ, needs to stabilize its genome in order to achieve this dangerous journey.…”

“…Genetic predisposition to melanoma is very well characterized but represents only 5-10% of all reported cases (Chin et al, 2006). Sunlight exposure represents a major environmental risk factor as exemplified by the increase of melanoma incidence in relation to latitude for fair-skinned people.…”

Dopamine- and tyramine-based derivatives of triazenes: Activation by tyrosinase and implications for prodrug design

“…Among all the chemotherapeutic agents tested against this malignancy, DTIC is the most active single agent and thus considered the reference drug [10,11]. Related 1-aryl-3,3-dimethyltriazenes, 3, (see Scheme 1) are also documented as anticancer drugs, but with reduced selectivity for tumour cells [12,13].…”

Therapeutic window for melanoma treatment provided by selective effects of the proteasome on Bcl-2 proteins

“…1 However, recent discoveries elucidating aspects of the underlying molecular biology of metastatic melanoma have led to optimism about the rational design of more effective treatments. 2,3 The proteasome may one such attractive new target for cancer therapeutics. In experimental models, melanoma cells are highly dependent on proteasomal function for survival.…”