Patterns of disease presentation, treatment choices and survival in real world for patients diagnosed with advanced melanoma: A prospective observational study by Spanish Melanoma Group (GEM-1801).

e22022 Background: In the past decade, melanoma treatment has improved due to the advances in targeted therapy and immunotherapy. There are few data, however, about the treatment elections and the outcomes of the patients in the real world setting, specifically in a prospective manner. Methods: GEM1801 is a prospective cohort study that analyses the clinical and pathological disease presentation patterns, the different lines of treatment choices and the health outcomes derived from these treatments in 400 patients (pts) diagnosed with resected stage III (N = 47) and irresectable III/IV melanoma (N = 353). Here we focus on the pts diagnosed with advanced melanoma and the first line (1L) treatments. Results: Pts diagnosed after Jan 2018 were included from 35 hospitals in 15 different Spanish regions (recruitment Aug 2018 to Aug 2019). A survival cutoff was made by January 2020. 55.2% pts were male; median age was 65.1 (23.3- 95.2). 66% were cutaneous, 5.4% acral, 2.8% uveal, 17.3% non-disclosed and 4.2% were classified as “other” subtypes. According to AJCC 8th edition, 9.3% were unresectable IIIB/C/D and 90.7% IV (27.5% A, 16.6% B, 37.5% C and 18.4% D). ECOG was 0-1 in 85%; LDH levels were available in 282 pts (79.9%), being normal in 61.7%, > 1x to 2x ULN in 29.8% and > 2x ULN in 8.5%. BRAF was evaluated in 344 pts (97.5%), being 52.9% mutated. Median survival follow up was 9.7 months (0.2-24) with 73.9% patients alive at time of analysis (over 345 pts with data available). Median overall survival was not reached, with a median follow up of 9.7 months (0.2-24.0). 72.2% of pts were alive at the time of analysis. Table summarize the 1L options according to BRAF status in the 326 pts with data available (17 received no systemic treatment and in 10 was unknown). Conclusions: this study reflects real world data in a representative cohort of pts with melanoma in Spain. Survival results, pending on more follow up, could be considered consistent with the results of modern clinical trials. TT is the most frequent 1L choice for patients with BRAF+ melanoma (almost 2/3 of cases). In terms of IT, monotherapy based in anti PD-1 is the most frequent 1L choice, with a rank between 75-90% of cases. [Table: see text]

Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis

The incidence of melanoma is increasing over the years with a still poor prognosis and the lack of a cure able to guarantee an adequate survival of patients. Although the new immuno-based coupled to target therapeutic strategy is encouraging, the appearance of targeted/cross-resistance and/or side effects such as autoimmune disorders could limit its clinical use. Alternative therapeutic strategies are therefore urgently needed to efficiently kill melanoma cells. Ferroptosis induction and execution were evaluated in metastasis-derived wild-type and oncogenic BRAF melanoma cells, and the process responsible for the resistance has been dissected at molecular level. Although efficiently induced in all cells, in an oncogenic BRAF- and ER stress-independent way, most cells were resistant to ferroptosis execution. At molecular level we found that: resistant cells efficiently activate NRF2 which in turn upregulates the early ferroptotic marker CHAC1, in an ER stress-independent manner, and the aldo-keto reductases AKR1C1 ÷ 3 which degrades the 12/15-LOX-generated lipid peroxides thus resulting in ferroptotic cell death resistance. However, inhibiting AKRs activity/expression completely resensitizes resistant melanoma cells to ferroptosis execution. Finally, we found that the ferroptotic susceptibility associated with the differentiation of melanoma cells cannot be applied to metastatic-derived cells, due to the EMT-associated gene expression reprogramming process. However, we identified SCL7A11 as a valuable marker to predict the susceptibility of metastatic melanoma cells to ferroptosis. Our results identify the use of pro-ferroptotic drugs coupled to AKRs inhibitors as a new valuable strategy to efficiently kill human skin melanoma cells.

Oleuropein, the Main Polyphenol of Olea europaea Leaf Extract, Has an Anti-Cancer Effect on Human BRAF Melanoma Cells and Potentiates the Cytotoxicity of Current Chemotherapies

Oleuropein (Ole), a secoiridoid glucoside present in Olea europaea leaves, gained scientific interest thanks to its several biological properties, including the anticancer one. We verified whether Ole might potentiate the cytotoxicity of conventional drugs used to treat melanoma, disclosing a potentially new therapeutic strategy. We tested the cytotoxic action of Ole alone or in combination with chemotherapeutics on A375 human melanoma cells. We found that Ole was able, at a dose of 500 µM, to stimulate apoptosis, while at a non-toxic dose of 250 µM, it affected cell proliferation and induced the downregulation of the pAKT/pS6 pathway. A dose of 250 µM Ole did not potentiate the effect of Vemurafenib (PLX4032), but it succeeded in increasing the cytotoxic effect of Dacarbazine (DTIC). The major effect was found in the association between Ole and Everolimus (RAD001), also on PLX4032-resistant BRAF melanoma cells, which possibly cooperate in the inhibition of the pAKT/pS6 pathway. Of interest, an olive leaf extract enriched in equimolar Ole was more effective and able to further improve DTIC and RAD001 efficacy on BRAF melanoma cells with respect to Ole alone. Therefore, Ole represents a natural product able to potentiate a wide array of chemotherapeutics against BRAF melanoma cells affecting the pAKT/pS6 pathway.

Oleuropein, the Main Polyphenol of Olea europaea Leaf Extract, Has an Anti Cancer Effect on Human BRAF Melanoma Cells and Potentiates the Cytotoxicity of Current Chemotherapies

Oleuropein (Ole), a secoiridoid glucoside present in Olea europaea leaves, gained the interest of many scientists thanks to its several biological properties, including the anticancer one. We verified whether Ole might potentiate cytotoxicity of conventional drugs used to treat melanoma, disclosing new potential therapeutic strategy. We tested the cytotoxic action of Ole alone or in combination with chemotherapeutics on A375 human melanoma cells. We found that Ole was able, at a dose of 500 μM, to stimulate apoptosis in melanoma cells, while at a non-toxic dose of 250 μM, it affected cell proliferation and induced the downregulation of pAKT/pS6 pathway. 250 μM Ole did not potentiate the effect of Vemurafenib (PLX4032), but it succeeded in increase the cytotoxic effect of Dacarbazine (DTIC). The mayor effect was found in the association between Ole and Everolimus (RAD001), also on PLX4032-resistant BRAF melanoma cells, possibly cooperating in the inhibition of pAKT/pS6 pathway. Of interest, an olive leaf extract enriched in equimolar Ole was more effective and able to further improve DTIC and, particularly, RAD001 efficacy on BRAF melanoma cells than Ole alone. Therefore, Ole represents a natural product able to potentiate a wide array of chemotherapeutics against BRAF melanoma cells affecting pAKT/pS6 pathway.