Taking stock of translational research in melanoma at the 2010 Society for Melanoma Research Congress

The 2010 Society for Melanoma Research Congress in Sydney, Australia represented a crossroads for the melanoma field in several respects. For the first time, a molecularly targeted therapeutic approach has been clinically validated with two highly selective v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors (Flaherty et al., 2010). Groundbreaking clinical trial results were presented for the phase II trial of PLX 4032 and mature follow-up of the phase I trial of GSK2118436 (Kefford et al., 2010). With oncogenic BRAF having been a major topic of discussion at each of the SMR congresses since the meeting’s inception in 2003, a milestone has been achieved with the successful translation of numerous groups work regarding the significance of BRAF as a potential therapeutic target. In the intervening years, a distinct subset of melanomas was found to harbor activating KIT mutations, and preliminary clinical investigations presented within the past year have demonstrated that clinically available KIT inhibitors produce tumor regression in a subset of patients whose tumors harbor these mutations (Carvajal et al., 2009; Curtin et al., 2006). Perhaps the most striking theme of this year’s Congress was the presentation of so much ongoing research regarding potential resistance mechanisms to BRAF inhibitors. In addition to work regarding the downstream consequences of BRAF inhibition and potential compensatory mechanisms that might serve as complementary therapeutic targets, one could see an intersection between oncogene-targeted therapy and altogether novel therapeutic targets and many of the investigations into melanoma’s fundamental biologic principles. It is increasingly clear that we must now turn our attention back to the laboratory if we hope to achieve the next quantum leap in outcome for patients with advanced melanoma. Having been discovered as an oncogene in melanoma in 2002, the therapeutic promise of targeting BRAF was first demonstrated with mRNA depletion of mutated BRAF in vitro (Davies et al., 2002; Wellbrock et al., 2004). At the time and for several years to follow, selective pharmacologic inhibitors were not available to further explore the mechanistic underpinnings of BRAF inhibition. However, the role of BRAF in inducing proliferation and senescence was established by several groups (Goodall et al., 2004; Michaloglou et al., 2005). And the complementary function of additional genetic alterations needed to facilitate full transformation and invasiveness was elegantly worked out in transgenic models (Dankort et al., 2009; Dhomen et al., 2009; Patton et al., 2005). Despite the presence of a vast array of concomitant genetic alterations, it is now clear that treatment of patients with metastatic melanoma tumors harboring a BRAF mutation results in profound tumor regression and symptom improvement in the majority of patients (Flaherty et al., 2010). This realization of the ‘Gleevec moment’ in melanoma has clearly revitalized the field and validated the work of many translational researchers. But clinical limitations of this approach have also been established and highlight the need for additional research to understand the compensatory mechanisms by which melanoma can ultimately resist such an initially highly effective therapy. For many years, the publications generated by melanoma researchers who were interested in understanding oncogenic and aberrant signal conduction incorporated pharmacological reagents that were far from relevant in the clinical setting. Conversely, the standard treatments used to treat advanced melanoma in years past hardly perturbed melanoma biology in a way that was sufficient to make research into melanomas adaptive response and potential vulnerabilities tractable. In some instances, suitably selective pharmacologic inhibitors existed, such as allosteric MEK inhibitors, but did not produce clinical responses to match what was observed in preclinical testing (Solit et al., 2006). With the results of the GSK1120212 phase I trial being presented within the past year, that gap between preclinical and clinical observations has been narrowed (Infante et al., 2010). But largely, highly selective pharmacologic inhibitors against other key signal transduction molecules have been lacking in years past and have left the field uncertain regarding the significance of the preclinical observations made within these three reagents. The use of LY294002 as a PI3 kinase inhibitor and sorafenib as a RAF inhibitor serve as two illustrative examples (Aziz et al., 2009; Wilhelm et al., 2004). Only recently have both privately and publicly funded pharmacologic development evolved