**18. Conclusion**

The development of drugs in the treatment of melanoma has never been as intense as at present. Single-agent chemotherapy is considered to have rather palliative effect on patients with melanoma; it is usually well tolerated but is associated with lower response rate. Detailed knowledge of protein structures and the understanding of their role in key signaling pathways in melanoma development lead to the designation of new targets for treatment of melanoma. Targeted therapy for patients whose tumors harbor the BRAF mutation achieves high response rates and OS benefit with combination BRAF/MEK inhibition. No other therapy in melanoma has shown a better response rate in late-phase clinical trials than combined BRAF and MEK inhibitors. The rapid kinetics of response to BRAF plus MEK targeted therapies represents the ideal frontline treatment for symptomatic, BRAF-mutant advanced melanoma patients. Although the concept of a combination of immunotherapeutic and targeted agents appears to be crucial in the treatment of melanoma, the synergy between these two approaches in melanoma treatment remains controversial due to the potential increased toxicity. Recently enormous progress in cancer therapy has been achieved by the use of immune checkpoint inhibitors. Activating the body's own immune system has added a novel and powerful therapeutic option for the treatment of melanoma. The potential use of immunotherapy is being extensively explored also in other malignancies. In the future, it is necessary to conduct further clinical trials and collect more data about overall survival, response rates, appropriate timing and sequence of combination therapy to manage the complexity of melanoma treatment.

### **Author details**

**Figure 4.** Chemical structure of venetoclax.

**17. Future direction in targeted therapy**

124 Human Skin Cancers - Pathways, Mechanisms, Targets and Treatments

Despite extensive new approaches in the treatment of advanced stage melanoma, i.e. chemotherapy, targeted therapy and immunotherapy, response rate is rarely higher than 20%. Especially in the treatment with BRAF inhibitors the drug resistance is very common [79]. Due to this reason there is an urgent need to invent other alternatives and targeted therapies. Preclinical studies looking at least this main drug association strategies seems to be very promising: targeting of either MEK or phosphatidylinositol-3 kinase (PI3K)/mammalian target of rapamycin (mTOR); strategies aimed at blocking anti-apoptotic proteins belonging to B-cell lymphoma (BCL-2) or inhibitors of apoptosis (IAP) families associated with MEK/ BRAF/p38 inhibition; co-inhibition of other molecules important for survival (proteasome, histone deacetylase and signal transducers and activators of transcription) [80]. *PI3K-AKTmammalian target* of rapamycin signaling pathway is important for melanoma initiation and progression so the preclinical investigation of a novel and highly potent PI3K-mTOR dual inhibitor *VS-5584* was realized. VS-5584 induced caspase-dependent apoptotic death in melanoma cells, and its cytotoxicity was alleviated by the caspase inhibitors [81]. Whereas the main aim of inhibiting MAPK signaling pathway is to prevent cancer cell proliferation, apoptosis is controlled by the availability of anti-apoptotic *BCL-2 proteins* (e.g. BCL-2), which reside at the outer mitochondrial membrane. BCL-2 supports neoplastic growth by blocking cell death and this target may be future direction in the treatment of various types of cancers [82]. Development of small molecule inhibitors specific for antiapoptotic BCL-2 proteins is a novel approach not only for therapy of chronic lymphocytic leukemia [83] but is very promising in therapy of advanced melanoma [84]. This new targeted approach could by more successful when the combination with retinoid derivative is used [85]. *Venetoclax (ABT-199)* (**Figure 4**) is the first orally bioavailable selective inhibitor of BCL-2 protein often over-expressed in chronic lymphotic leukemia (CLL) and other types of B-cell related cancers developed by AbbVie in partnership with Roche. It is currently being evaluated in Phase II and Phase III studies for CLL and in Phase I and II studies for several other blood cancers and can be one of

the next molecules used in the treatment of melanoma in the near future [86].

Marcela Valko-Rokytovská\*, Jana Šimková, Mária Milkovičová and Zuzana Kostecká

\*Address all correspondence to: marcela.valko.rokytovska@gmail.com

Department of Chemistry, Biochemistry and Biophysics, University of Veterinary Medicine and Pharmacy in Košice, Košice, Slovak Republic
