Chemoprevention of Melanoma

Abstract

Despite advances in drug discovery programs and molecular approaches for identifying drug targets, incidence and mortality rates due to melanoma continue to rise at an alarming rate. Existing preventive strategies generally involve mole screening followed by surgical removal of the benign nevi and abnormal moles. However, due to lack of effective programs for screening and disease recurrence after surgical resection, there is a need for better chemopreventive agents. Although sunscreens have been used extensively for protecting from UV-induced melanomas, results of correlative population–based studies are controversial, with certain studies suggest increased skin cancer risk in sunscreen users. Therefore, these studies require further authentication to conclusively confirm the chemoprotective efficacy of sunscreens. This chapter reviews the current understanding regarding melanoma chemoprevention and the various strategies used to accomplish this objective.

Introduction

Chemoprevention is a strategy that was first proposed by Sporn et al., (1976). It was referred to the use of natural or synthetic agents to reverse, suppress, or prevent molecular or histologic premalignant lesions from progressing to invasive cancer (Sporn et al., 1976). The original definition also included treating patients who had undergone successful primary cancer treatment but were at increased risk of developing a second primary lesion (Sporn et al., 1976; Sporn et al., 1976). Cancer delay has been emphasized as yet another goal of chemoprevention (Lippman & Hong, 2002a,b). Chemopreventive agents that delay the onset of melanoma are extremely important as even small changes in the early melanocytic lesion size can significantly alter the 5-year survival rate (Balch et al., 2001; Lao et al., 2006). For example, a change in the Breslow's depth of 4 mm compared to 0.7 mm could decrease the 5-year survival rate by 40% (Balch et al., 2001; Lao et al., 2006). In breast and other cancers, chemoprevention has proven successful (Jordan, 2007). Tamoxifen, the first Food and Drug Administration (FDA)-approved chemopreventive agent, has been used effectively to reduce breast cancers (Freedman et al., 2003) (http://www.fda.gov/NewsEvents/Testimony/ucm115118.htm) (April 12, 2012). Similarly, the FDA-approved topical diclofenac and imiquimod were proven effective for actinic keratoses treatment (Weinberg, 2006).

Chemoprevention of melanoma is based on the principle that melanoma is a progressive disease, and various molecular events and pathways associated with different stages of the disease can be targeted using synthetic or naturally occurring chemical compounds (Demierre & Nathanson, 2003). However, chemoprevention of melanoma remains an underdeveloped area. One of the reasons for this under-exploration is the logistical and procedural difficulties associated with testing of chemopreventive agents in clinical trials. Even though ∼30% melanomas are linked to exposure to UV radiation, risk factors responsible for about 60% melanomas are unknown (Husain et al., 1991; Madhunapantula & Robertson, 2011; Pathak, 1991; Robertson, 2005). Furthermore, the molecular basis for UV-mediated transformation of melanocytes to melanomas is also not fully understood (Abdel-Malek et al., 2010; Lund & Timmins; 2007; Quinn, 1997). Moreover, results of recent trials evaluating whether limiting or blocking sun exposure to reduce melanoma incidence and mortality rates are confusing and not encouraging (Barton, 2011; Goldenhersh & Koslowsky, 2011; Loden et al., 2011; Planta, 2011). Therefore, chemoprevention of melanoma remains a challenge to the scientific community. Recent studies have focused on identifying the molecular pathways triggering the transformation of melanocytes to melanomas when exposed to UV light, as well as genetic and nongenetic risk factors that could be targeted for chemoprevention (Afaq et al., 2005; Bennett, 2008a,b; Demierre & Nathanson, 2003; Walker, 2008; Wang et al., 2010). For example, Ras-signaling can be used as a chemoprevention target in UV-induced melanomas (Demierre & Merlino, 2004; Lluria-Prevatt et al., 2002). In addition, analysis of mutational data from the reported literature demonstrated high abundance of UVB signature mutations in CDKN2A, TP53, and PTEN loci in cutaneous melanomas compared to nonskin cancers (Hocker & Tsao, 2007).

Broadly, three categories of melanoma chemopreventive agents exist (Lao et al., 2006; Manoharan & Balakrishnan, 2009) (Fig. 12.1). The first category prevents the occurrence of melanoma in healthy individuals, whereas, the second and third categories prevent the development in melanoma patients (Lao et al., 2006; Manoharan & Balakrishnan, 2009) (Fig. 12.1). Secondary chemopreventive agents would prevent premalignant lesions from developing into malignant melanomas (Lao et al., 2006; Manoharan & Balakrishnan, 2009) (Fig. 12.1). Tertiary chemopreventive agents would prevent melanoma recurrence after getting treated for melanomas (Lao et al., 2006; Manoharan & Balakrishnan, 2009) (Fig. 12.1).

An ideal chemopreventive agent should inhibit (a) oncogenic kinases inducing the transformation of melanocytes and (b) trigger apoptosis in damaged melanocytes (Demierre & Nathanson, 2003; Gupta & Mukhtar, 2001). In addition, chemopreventive agents should also induce DNA repair pathways so that UV-induced damage could be alleviated thereby preventing transformation (Nambiar et al., 2011; Nichols & Katiyar, 2010; Rajendran et al., 2011). Therefore, chemoprevention strategies should consider the following key aspects while developing a particular compound for preventing melanomas: (a) molecular basis of melanoma genesis and tumor progression; (b) reasons for the failure of existing agents; (c) selection of appropriate in vitro and in vivo models representing different stages of tumor progression for testing the identified agents; and (d) better methods of drug delivery to reduce toxicity and release of the preventive agent at the site of action (Demierre & Sondak, 2005a,b).