11th SMR International Congress

av Stefano Caramuta, 13–16 november 2014

The 11th SMR International Congress 2014 highlighted the best science in the field melanoma from institutions all over the world. Focusing on basic and translational research, SMR can be considered one of the most important and relevant meetings on melanoma worldwide.

Melanoma has a really complex nature so it requires an interdisciplinary approach to research and accomplish further progresses in this field. Since my postdoctoral project is focused on the role of small-non coding RNAs in the development and drug resistance in melanoma, I had a particular interest in this conference where I was given the opportunity to improve my knowledge, interacting with well-known and established investigators in the melanoma field. Attending this conference with other scientists and professionals from around the globe opened up a world of opportunities to network, to attend sessions outside of my own area of expertise,  enhance my professionalism, share experiences with others, have access to the best ideas, and learn how to apply exiting new concepts, tools and techniques to my own research.

Malignant melanoma is a highly aggressive tumor responsible for the majority of skin cancer-related deaths and its incidence is increasing every year. Despite our improved knowledge of molecular pathways involved in tumorigenesis of malignant melanoma, treatment options for this disease are limited and the survival rate for patients in advanced stage is still really poor.

In this respect, during the conference, outstanding speakers gave an overview of the latest data related to the treatment of melanoma, and presented their implications and guidance on how best to integrate into clinical practice.

Recent advances in understanding of the molecular background of malignant melanoma allowed an evolution of melanoma management; predominantly, the identification of specific mutations (e.g. BRAFV600E) has led to the development of targeted agents, such as BRAF inhibitors (e.g. Vemurafenib and Dabrafenib). Despite the encouraging results, acquired resistance to these drugs after an initial response, remains the major limiting factor; this makes the treatment of malignant melanoma one of the most challenging issues in oncology. Thus, the scientific community is facing new challenges in order to better understand the mechanisms of acquired resistance in melanoma and identify novel targets (and therapeutic approaches) to defeat this terrible disease.

The protein kinase BRAF is mutated in over 60% of human melanomas and is a component of the RAS/RAF/MEK/ERK pathway. It’s well established that acquired resistance to BRAF inhibitors is mainly due to reactivation of MAPK pathway; thus the scientific community is really much working in understanding the molecular mechanisms behind this scenario.

Most of the speakers seemed to agree with the idea that the solution would be to “hit the same pathway and hit it harder”: this brings to the concept of combined therapies to overcome the resistance to BRAF inhibitors. Interestingly, Dr. Richard Marais showed the results from his lab regarding the use of pan-RAF inhibitor which targets mutant BRAF and wild-type CRAF proteins. The efficacy of this compound was tested both in vitro and in vivo. They showed that this novel compound inhibited the growth of melanoma cells that were resistant to BRAF-selective inhibitors due to pathway reactivation mediated by different mechanisms. The drug was active against patient derived xenografts (PDXs) from patients with acquired or intrinsic resistance to BRAF-selective inhibitors and in whose tumors resistance was associated with ERK pathway reactivation.   Further, the compound seems to be active in a PDX from a patient whose tumor developed acquired resistance to a combination of a BRAF-selective plus a MEK inhibitor and associated with acquisition of an NRAS mutation. Potentially the pan-RAF inhibitor can provide a first-line treatment for naïve patients and a second-line treatment for a range of relapsed patients.

Another important focus of melanoma research over the last years has been immunotherapy; complementary to the discovery of BRAF as an oncogenic driver in melanoma, the improved understanding of the immune system has resulted in novel immune-therapies for metastatic melanoma. Thus, among others, Dr. Georgina Long presented new insights on the importance of immunotherapy in melanoma. Compared to target therapies, the immune-checkpoints inhibitors can achieve long-term remission and cure of patients with metastatic melanoma: however these compounds seem to be effective in a smaller proportion of patients and biomarkers to predict which patients may benefits of this treatments are not yet available. The first immune-checkpoint inhibitor to enter the clinic was Ipilimumab, an anti-CTLA-4 monoclonal antibody which shows significant benefits in terms of overall survival. At the moment, a number of clinical trial are ongoing to test the efficacy of Ipilimumab alone or in combination with all the treatment options, including radiotherapy, targeted therapies and conventional therapies. Indeed, over the last five years, despite the achievement of remarkable advances in the development of both targeted and immune-therapies, not all the patients respond and not all the patients achieve durable responses: so, combination therapies are being tested to reach a more effective response in these patients. To date, preliminary results show an improvement in overall survival for Ipilimumab in combination with BRAF-inhibitors: however, an important issue to keep in consideration with combined therapies is how to sequence the drugs; these compounds are quite different: targeted therapies block the biochemical pathways or mutant proteins that stimulate tumor cell growth and survival, while immunotherapies boost the ability of the immune system to recognize cancer cells. Moreover, the response to targeted therapies occurs within weeks while responses to immune therapies are generally slower and can take up to 6 months. However, from preliminary results, it seems that initial treatment with BRAF-inhibitors followed shortly after by Ipilimumab might give a better response (instead of treating patients with both drugs at the same time or starting treatment with Ipilimumab). Monoclonal antibodies targeting PD-1 (programmed death-receptor) and PD-L1 (programmed death-ligand) have been also produced (e.g. Nivolumab and MDX-1105). Preliminary reports show that these antibodies are well tolerated and gave encouraging results in terms of patient response.

Looking into novel mechanisms of resistance in melanoma, particularly interesting was the talk by Dr. Mitchell Stark regarding the involvement of miRNAs in acquired resistance to BRAF inhibitors. A number of recent studies reported that miRNA aberrant expression is implicated in anticancer drug resistance in various tumor types. However, at present virtually nothing is known about the involvement of miRNA in drug resistance in malignant melanoma. In their work, they observed miR-514a to be highly up-regulated in melanoma cell lines as compared to other solid cancers. In addition, among others, they identified NF1, a well known melanoma tumor suppressor gene, as a direct target of miR-514a. Interestingly, they showed that modulation of miR-514a expression could affect sensitivity of melanoma cells treated with the BRAF-inhibitor PLX4032. These data provide and additional mechanism to explain the profound resistance to current RAF-targeted therapies.

Another remarkable talk was the one about comprehensive genomic characterization of cutaneous melanoma introduced by Dr. Ian R. Watson. The Cancer Genome Atlas Project (TCGA) analyzed exome sequence, DNA structural variations (copy number and translocations), promoter methylation, mRNA, miRNA, and protein expression in 336 primary or metastatic melanoma samples.

Interestingly, through RNA-seq data, they identified 3 different subgroups of melanomas, categorized by elevated lymphocytic, keratin, and melanocyte differentiation markers. Mutation analysis from exome sequencing identified 13 significantly mutated genes which included known melanoma oncogenes and tumor suppressors (BRAF, NRAS, CDKN2A, TP53, and PTEN); genes previously implicated in melanoma, but found in this study for the first time to be significantly mutated (e.g.  RAS-GAP NF1, IDH1 and RB1) and recently implicated melanoma genes possessing either characteristic hotspot or loss of function mutations (RAC1, MAP2K1, PPP6C, and ARID2).

Over 80% of samples included in the study showed at least one mutation in the significantly mutated genes BRAF, NRAS, or NF1 involved in the MAPK pathway. Given these findings, they proposed that melanoma could be categorized into four genetic subgroups distinguished by MAPK driver mutations in BRAF, NRAS or NF1, and a fourth group named as triple-wild type (no mutations observed in any of the three mentioned genes). Integrative analysis revealed enrichment of copy number gains in KIT, PDGFRA, KDR (VEGFR2), CCND1,CDK4, MDM2, and TERT in the triple wild-type melanomas. In summary, these data provide novel and important insights on the different genetic mechanisms leading to cutaneous melanoma.

Finally, I found really interesting and fruitful the interaction and discussions rose during the poster session with scientist from all over the world. I had the opportunity to get connected to other researchers working in the same field with the possibility to start new collaborations; I received comments, constructive criticisms and new stimuli and ideas to continue my research.