Melanoma is a cancer that exhibits one of the most aggressive and heterogeneous features. Despite the great progress of therapeutic strategies, long-term survival of 5 years and more was only achieved in 5-10% of patients with metastatic melanoma regardless of the specific therapeutic strategy used.
Based on the Reflectance confocal microscopy (RCM), which gives the opportunity to analyze architectural and cytological features in horizontal sections in vivo, is possible to identify four distinct melanoma subtypes: 1) Dendritic-cell melanomas; 2) Round cell melanomas; 3) Dermal-nest melanomas; 4) Combined-type melanomas.
Two-Pore Channel 2 (TPC2), an ionic channel present on the membrane of melanosomes and other acidic intracellular Ca2+ stores, is basic for the metastatic behaviour of other cancer cells and recently we demonstrated that Naringenin (Nar), a flavanone present in citrus fruit and other vegetables, is a newly discovered inhibitor of TPC2; in melanoma cell lines the TPC2 activating second messenger NAADP controls growth and invasion, in vitro and in vivo.
Our hypothesis is that melanoma subtypes are endowed with different genetic signatures and signaling pathways, that in turn account for diverse biologic behaviors and response to therapy. In addition, we demonstrated that melanosomal TPC2/NAADP signaling is crucial for melanoma progression, and that targeting TPC2 can prevent growth and metastatic behaviour of melanoma cells. In particular it is expected that preventing the release of melanosomes/extracellular vesicles from early stage melanoma, the formation of the tumor niche would be impaired and metastatic invasion consequently blocked.
Our aim is to assess the involvement of the melanosome and of autophagy in the control of melanoma growth and invasion and to test the impact of pharmacologic/genetic inhibition of TPC2 in RCM melanoma subtypes with different aggressiveness and susceptibility to therapy.
Epidemiologic data from Europe indicate a continuous and dramatic increase in melanoma incidence during the last decades (13.2 and 13.1 new cases per year, per 100,000 for men and women, respectively). In Italy, approximately 3.150 new cases for men and 2.850 for women were diagnosed every year (Italian Agency of tumor records). Despite the great progress of therapeutic strategies like kinase inhibitors for BRAF-mutant melanoma and immune checkpoint blockers within the past few years, long-term survival of 5 years and more was only achieved in 5-10% of patients with metastatic melanoma regardless of the specific therapeutic strategy used (Ugorel et al, 2015). Encouraging results were obtained in patients with stage III melanoma receiving both neoadjuvant and adjuvant treatments (Ascierto and Eggermont, 2018). Adjuvant and neoadjuvant therapy have several potential advantages, including a possibility of decreased surgical morbidity, prevention of micrometastases, personalization of adjuvant therapy based on the response to neoadjuvant therapy.
The great scientific potential of this project is first based on the unique opportunity of a collaboration between Prof Pellacani, one of the most prominent international experts in melanoma imaging, and Sapienza's group (Prof. A. Filippini). The molecular characterization of the melanoma subtypes, as detected by dermoscopy and confocal microscopy will possibly lead to identifying novel and more targeted therapies.
The chance to collect bio-specimens derived from different melanoma subtypes would be fundamental for the identification of the morphologic-biomolecular profile and for the evaluation of the different response to TPC2 inhibition target therapy. We expect to identify a set of clinical, dermoscopic (very high magnification) and RCM features that significantly correlate with a novel signature encompassing genetic mutation and biologic alteration in NAADP/TPC2 signaling pathway.
A better knowledge of NAADP/TPC2 signaling pathway and their involvement in melanoma metastasis could be relevant to define tumor aggressiveness among different melanoma subtypes. In this respect, blocking their signaling, as novel targets of therapy in RCM selected melanoma subtypes, is of special importance. In particular, this approach would be an alternative to immunotherapy which fails to take into account patients characteristics or selective biomarkers.
The tumor differentiation based on cyto-morphology (as seen by in vivo confocal microscopy) and molecular profile will help to define the different therapeutic strategies to be applied in different melanoma types according to their predominant pathway and the need of combination or sequential therapy in order to fight tumour drug resistance and escape. Given the heterogeneity of melanoma cells, this will ultimately lead to a personalized therapy for melanoma.