**Acknowledgments**

MiRNA replacement therapy is more limited regarding the current attempts and results, although it seems to emerge as a more efficient form of treatment considering that the majority of pathological expressed miRNAs consist in downregulated or inhibited tumor suppressor sequences [140]. Even if the success of this therapeutic strategy could be greater than miRNA inhibition workflows, the requirements for the structure and composition of the replacement fragment are much more stringent considering the necessity of RISC uptake. Furthermore, the impediments regarding the delivery system for these oligonucleotides are the same as in the

Lung cancer remains the most deadly disease from the oncological field, being an aggressive form of cancer that is usually diagnosed in late stages with minimal therapeutic alternatives. Even in the case of early discovery, the classical treatments have failed numerous times due to compensatory mechanisms developed within the tumor environment leading to the same negative outcome. Therefore, we face a crisis situation where we need to develop new therapeutic tools for lung cancer management able to target key elements/pathways, but avoid in the same time the possibility of alternative carcinogenic pathways activation. One of the hallmarks of cancer is represented by angiogenesis, process that is in the sight of researchers for some time, but the classical inhibition of central molecules like VEGF has failed to deliver long‐lasting results. Therefore, ncRNAs have emerged as potential lifesaving agents due to the capacity of extensive modulation, where the same ncRNA is able to target multiple genes and regulate their function. Also the same microRNA, or more recently discovered, the lncRNA can be encounter in different consecutive processes in pulmonary carcinogenesis, as in the case of hypoxia and angiogenesis. Development of novel therapeutic tools able to transform the pathological expression of ncRNAs, mainly through silencing of upregulated patterns, will enable a more extensive, and in the same time, specific approach that will probably excludes the installation of compensatory mechanism and significantly contribute to a better outcome in lung cancer patients. The concept of noncoding RNAs as therapeutic targets in the clinical context is now more feasible than ever, being supported by numerous preclinical studies. One of the main approaches should involve manipulation of miRNAs that are actively implicated in the regulation of VEGF genes expression, genes that hold a key role in the vascular development process. Even more, a heterogeneous approach that implies the administration of different miRNA sequences able to target multiple genes and naturally multiple pathological pathways within the angiogenic process will represent a more extended form of therapy that could modify extensive regulatory networks. This type of targeting will also minimize the compensatory mechanisms that are usually encountered after the implementation of classical therapeutic strategies due to concomitant regulation of multiple signaling pathways. Additionally, some other approaches may be used for the inhibition of angiogenesis. For example, semaphorins are now emerging as important regulators of vascular density in malignancies, with possible roles as prognostic tools or even therapeutic targets. Inhibition of procarcinogenic semaphorins would represent a novel course of action regarding cancer treatment considering their central role in vascular density. Moreover, the

case of inhibitory antisense attempts.

**7. Conclusions and future perspectives**

278 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

This work was supported by the POC‐P\_37\_796 grant, entitled "Clinical and economical impact of personalized targeted anti‐microRNA therapies in reconverting lung cancer chemoresistance"*-*CANTEMIR.
