# Involvement of the Orexinergic System in Cancer: Antitumor Strategies and Future Perspectives
## 4 Therapeutic Strategies and Future Directions
### OXR Agonists and OXR Antagonists  
Signaling mediated through OXRs promoted a dual effect: orexins, through OXRs, induced apoptosis in some tumor cells, but in others promoted a proliferative activity. This means that OXR antagonists or agonists are potential antitumor agents against tumors expressing OXRs, since OXR antagonists block the proliferative action mediated by orexins and, in addition, promote the apoptosis of tumor cells. In some tumors, OXR agonists favor the apoptosis of cancer cells. Thus, the use of these compounds is a promising antitumor research line that must be fully developed.  
Selective OXR2 agonists such as TAK-925, TAK-994, and YNT-185 have been developed, but not selective OXR1 agonists [1; 130; 131; 132]. OXR antagonists are classified into dual OXR antagonists (DORAs (e.g., almorexant, suroxant, daridoxerant, emborexant)), which similarly interact with OXR1 and OXR2, and single orexin receptor antagonists (SORAs) which are in turn classified into SORA1s (selective OXR1 antagonists (e.g., SB-334,867)) and SORA2s (selective OXR2 antagonists (e.g., NJJ-42847922 (seltorexant)) [1; 133; 134; 135; 136; 137; 138]. Currently, suroxant, daridoxerant, and emborexant are approved by the U.S. Food & Drug Administration (FDA) for the treatment of insomnia [1]. Suroxant and almorexant induced apoptosis in AsPC-1 cells and blocked the release of calcium promoted by orexin A; almorexant also decreased tumor volume (AsPC-1 xenografted cells) [120]. It has been suggested that almorexant acts as a partial agonist and antagonist toward Gq proteins by activating src kinases, through \(\beta/\lambda\) subunits, and by inactivating \(\alpha\)q subunits [1]. Another important finding is that orexin A, via OXR1, promoted the proliferation of pancreatic cancer cells and protected them from apoptosis, but the blockade of OXR1 promoted apoptosis in these cancer cells [119]. This emerging antitumor strategy must be studied in depth and entirely developed. Previous data show the important role that OXR antagonists could play as antitumor agents; however, the antitumor effect exerted by more OXR agonists and antagonists must be tested in the future against more tumor types, since, for example, only a few OXR antagonists have been currently tested against some tumors. This is a research line that must be fully developed to establish new and promising antitumor strategies. But it is also crucial to develop basic research lines focused on the expression of the orexinergic system in many cancer types, because only in a few tumors has this system been studied and, in some of them, the reported data are very fragmentary. Thus, in vitro and in vivo systematic studies on the involvement of the orexinergic system in cancer must be developed in many tumors (e.g., orexin A and B expression, OXR1 and OXR2 expression, tumor progression, or blockade by orexins). Much basic research knowledge is lacking. Moreover, the molecular interactions between OXRs and OXR antagonists or agonists must be understood in depth; this knowledge will allow us to design and develop new and more potent and specific antitumor agents. In this sense, an allosteric potentiation of OXR has been reported, and that allosteric compounds bind to OXR, on a place different from that of natural ligands. This allosteric potentiation does not stimulate the function of OXR independently but increases the response of OXR to ligands [139]. It seems that these potentiators promote natural cycles of receptor activation but do not drive chronic receptor activation [140; 141].