mTOR as a Target of Everolimus in Refractory/Relapsed Hodgkin Lymphoma

A.      Guarini; C.      Minoia; M.      Giannoccaro; A.      Rana; A.      Iacobazzi; A.      Lapietra; A.      Raimondi; N.      Silvestris; C.      D. Gadaleta; G.      Ranieri

Abstract

Despite impressive treatment advances, few options for refractory or relapsed Hodgkin Lymphoma (HL) are available and there is a need for new compounds development. A number of promising agents with multiple mechanisms of action are under investigation. Microenvironment and neoangiogenesis are acquiring a rising relevance in the pathophysiology and progression of HL. Everolimus (RAD001) is an oral antineoplastic agent derived from rapamycin, a macrocyclic lactone antibiotic, targeting the mammalian target of rapamycin (mTOR). Although the importance of mTOR signaling in the deregulated cell growth of human neoplastic cells has been recognized, this pathway is also emerging as a key regulator of the tumor response to hypoxia, as well as endothelial and stromal cells function, thereby regulating neoangiogenesis. Furthermore, mTOR plays an important role in anticancer drug resistance. The actions of everolimus within the mTOR pathway in HL result in decreased protein synthesis and cell cycle arrest, as well as in decreased angiogenesis. Everolimus has shown preliminary evidence of efficacy as a single-agent in heavily pretreated relapsed/refractory HL, with an overall fair safety profile. The purpose of this review is to discuss the employment of everolimus as an antiproliferative and antiangiogenic agent in HL and to report the critical role of the mTOR pathway and angiogenesis in this malignancy.

Keywords: Everolimus, refractory Hodgkin Lymphoma, relapsed Hodgkin Lymphoma, mTOR inhibitors, mTORC1, microenvironment, angiogenesis, microvessel density, HIF-1a, VEGF, PI3K/Akt pathway, Hodgkin Lymphoma progression, Hodgkin Lymphoma pathogenesis, stromal cells