Melanoma — The pieces of the puzzle finally start coming together!

Since the report in 2008 of a near complete response to imatinib in a patient with metastatic melanoma harboring KIT mutation, hope that some disseminated melanomas might also be cured by targeted treatments rose among the community (Hodi et al., 2008). After several years of failures and frustration, the treatment of metastatic cutaneous melanoma is eventually advancing. Ipilimumab, a human monoclonal antibody that binds to CTLA-4, has opened the way in demonstrating for the first time ever an improved overall survival in patients with stage IV melanoma (Hodi et al., 2010), and the targeted anti-BRAF therapy with PLX4032 given in patients with stage IV Braf mutated melanoma has showed extremely encouraging and durable responses in a phase 2 trial (Flaherty et al., 2010). However, resistance to BRAF inhibitors is a significant clinical challenge (Nazarian et al., 2010; Paraiso et al., 2010; Poulikakos and Rosen, 2011; Solit and Rosen, 2011; Villanueva et al., 2010). Several mechanisms of secondary resistance typically emerge making melanoma cells cross-resistant to PLX4032 and other BRAF-selective inhibitors. Resistance involves switching among RAF isoforms (Villanueva et al., 2010). IGF-1R/PI3 K signaling is enhanced in resistant melanomas, and combination of IGF-1R/PI3 K and MEK inhibitors can kill BRAF inhibitor-resistant melanoma cells (Villanueva et al., 2010). In this special issue of Molecular Oncology, Puzanov et al. describe the biological challenges of BRAF inhibitor therapy and potential combination regimens that can overcome these resistance mechanisms. Several prediction nomograms have integrated somatic genetic characteristics of the tumor and histopathological characteristics. (Bauer et al., 2011) For instance, the degree of elastolysis and of intra-epidermal spreading of melanocytes can be strongly and significantly associated with presence or absence of KIT or BRAF mutations. This leads to an important discussion on what should be the next classifications systems of cutaneous melanoma. This topic is reviewed and discussed by Scolyer et al. who put this issue in the perspective of a multidisciplinary melanoma clinic. On the contrary to other solid tumors, the impact of anti-angiogenic therapy in cutaneous melanoma remains uncertain. Data on the role of tumor-induced neoangiogenesis for disease progression in vivo are conflicting but the vascular phenotype in the primary tumor and metastasis emerges as an important factor (Helfrich and Schadendorf, 2011; Velazquez and Herlyn, 2003). Also, the role of the pericyte needs to be elucidated as several studies have clearly showed that melanoma cells can move in contact with the pericyte environment (Lugassy et al., 2004). Helfrich et al. review this broad topic and bring more clarity in this field. This is important to understand why trials with anti-endothelial targeted agents in monotherapy did not show very encouraging results so far, and to better drive the development of a rational basis for future combination treatments. Ghanem et al. review the role of TYRP1/gp75 in cutaneous melanoma. Several ongoing early clinical trials evaluate vaccines with TYRP1 protein or cDNA (Patel et al., 2007). The FoxP3 (forkhead box P3) gene is an X-linked gene that is an essential transcription factor in CD4+CD25+FoxP3+ regulatory T cells (TReg). FoxP3 expression is also required to maintain suppressive properties of TReg cells. Therefore understanding the structure and function of FoxP3 gene is crucial to gaining insight into the biology of melanoma and, consequently, of new biologics. Redpath et al. review these aspects of the FoxP3 gene. Interestingly, FoxP3 is an important tumor suppressor gene in carcinomas and has putative cancer suppressor gene function in cutaneous melanoma as well. Different spliced variants have been identified, including in melanomas, but the biological significance of these variants is largely unknown. Specific anti-ctla-4 therapy and the FoxP3 gene bridge cancer and autoimmunity. Although the report on ipilumimab suddenly shed light on the importance of Tregs in melanoma progression, it is important to realize that it is mainly the search for tumor-associated antigens (TAA) capable to induce a tumor-directed immune response and the development of cancer vaccines targeting these TAA that have been a major effort for the tumor immunology community in the past two decades since the discovery of MAGE-1. In a thorough review of the biology of the cancer testis antigens (CTAs) and their therapeutic potential, Fratta et al., unveil several very specific characteristics of these genes families. However, it must be acknowledged that the precise role of the CTAs and the reason of the localization of half of them on the X-chromosome are still mysterious. As Bouwhuis et al. state in their review of immunologic functions and melanoma prognosis, a major challenge to address is providing ways to uncouple tumor immunity from autoimmunity. In other words, can we break tumor tolerance without inducing autoimmunity? This question implies that autoimmunity will indeed be a limiting toxicity of the effective immunologic treatments of melanoma, and there are specific pathways of tumor immunity and autoimmunity. The authors point out that tumor immunity and autoimmunity could be separated by modulating the STAT4/STAT6 signaling axis and that tumor immunity is dependent upon STAT6 signaling. In their review, they also stress the importance of correcting the prognostic significance of immunologic factors for guarantee-time bias. This issue of lead-time bias is probably one of the most important methodological challenge we face in the biomarkers area, especially for circulating biomarkers (Huo et al., 2007; Mahnken et al., 2008; Mittra, 1993; Tanner et al., 2010). An interesting retrospective analysis of autoimmunity during interferon therapy in melanoma made by the same authors clearly demonstrated that uncorrected data for lead-time bias can be seriously flawed and lead to false conclusions (Bouwhuis et al., 2010). The published guidelines for publication in the biomarker field, i.e., the REMARK guidelines, should be updated to include resolution of lead-time biases. Another important methodological challenge is how to address the multidimensionality of high-throughput experiments. This subject is reviewed by Michiels et al., who also propose and adapted sequence of biomarker development and evaluation. Finally, Field and Newton-Bishop review the fascinating issue of vitamin D and melanoma. Vitamin D supplementation to keep adequate vitamin D levels is becoming an essential aspect of preventive care of melanoma. Many other promising biologics are under advanced evaluation in monotherapy or in combination. The development of these active molecules gratifies years of fruitful interactions across different disciplines and excellent communication between basic researchers and clinicians in the melanoma field. Contributing to this two-way feeding process between fundamental and clinical research is exactly under the scope of the Molecular Oncology journal. We are therefore pleased to propose you this special issue on cutaneous melanoma with articles from worldwide leaders coming from different fields.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.