Explore the vast range of titles available.

Non-melanoma skin cancers (NMSCs) include basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and Merkel cell carcinoma (MCC). These neoplasms are highly diverse in their clinical presentation, as well as in their biological evolution. While the deregulation of the Hedgehog pathway is commonly observed in BCC, SCC and MCC are characterized by a strikingly elevated mutational and neoantigen burden. As result of our improved understanding of the biology of non-melanoma skin cancers, innovative treatment options including inhibitors of the Hedgehog pathway and immunotherapeutic agents have been recently investigated against these malignancies, leading to their approval by regulatory authorities. Herein, we review the most relevant biological and clinical features of NMSC, focusing on innovative treatment approaches.

Purpose of ReviewSummarize the writings published in the last years on the management and novel therapies of mucosal melanoma (MM).Recent FindingsNew research has demonstrated a difference between MM and cutaneous melanoma (CM) in their genomic and molecular landscapes, explaining the response's heterogeneity. Immunotherapy and targeted therapy have limited benefit, but novel therapies are rapidly expanding.SummaryMM is aggressive cancer occurring in gastrointestinal, respiratory, or urogenital mucosa; whose incidence is greater in the Asian population. The etiology and pathogenesis remain unclear since UV exposure is not a proven risk factor as in cutaneous melanoma. In contrast to CM, lesions on the mucosal surface are less likely to be recognized early; therefore, the disease is diagnosed in an advanced stage. Clinical manifestations, such as bleeding or pain, can help to detect this tumor, although the prognosis remains unfavorable with an overall 5-year survival rate of less than 20%. The mutational landscape of MM includes mutations of BRAF and NRAS, as well as mutations in the c-KIT/CD117 gene (in 50% of patients), thus limiting therapeutic interventions to immunotherapy. However, clinical studies show less responsiveness to immunotherapy compared to CM, therefore novel therapeutic strategies targeting new molecules are needed to improve the survival of patients with MM.

In the last decade, the inhibition of the mechanistic target of Rapamycin (mTOR) in renal clear cell carcinoma (RCC) has disappointed the clinician's expectations. Many clinical trials highlighted the low efficacy and unmanageable safety profile of first-generation mTOR inhibitors (Rapalogs), thus limiting their use in the clinical practice only to those patients who already failed several therapy lines. In this review, we analyze the major resistance mechanisms that undermine the efficacy of this class of drugs. Moreover, we describe some of the possible strategies to overcome the mechanisms of resistance and their clinical experimentation, with particular focus on novel mTOR inhibitors and the combinations of mTOR inhibitors and other anti-cancer drugs. Keywords: everolimus, temsirolimus, Rapa-Link, anti-angiogenics, autophagy