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

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.

Everolimus as a single agent in refractory or relapsed Hodgkin's lymphoma: the Brazilian Named Patient Program Experience

“…One example is mTOR inhibitors with their rationale use in HL being based on studies that demonstrate activation of the PI3K pathway in this type of tumor. 7 …”

“…mTOR is a serine/threonine kinase involved in cell growth, metabolism and cell survival, regulation of the different stages of the cell cycle, and controlling the checkpoints that are responsible for the cell's responses to DNA damage. 7 , 8 , 9 Furthermore, there is evidence that mTOR is an important component of angiogenesis, especially in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt/mTOR activation pathway. This axis is directly associated with the vascular endothelial growth factor (VEGF), as its activation leads to the transcription of the HIF-1a pathway, which consequently increases VEGF levels.…”

Clinical Options in Relapsed or Refractory Hodgkin Lymphoma: An Updated Review

“…Everolimus is an oral antineoplastic agent that targets this pathway, specifıcally the mTORcomplex1 (mTORC1) that has been shown to be activated in patients with HL. Everolimus not only may target the signaling pathways within the RSc but may also suppress signaling within the immune infıltrate and production of cytokines present in the tumor microenvironment [ 67 ]. Nineteen evaluable patients with relapsed HL were treated with daily doses of 10 mg everolimus, the ORR rate was 47%, and 8 patients achieved PR and 1 CR [ 68 ].…”

Biomodulatory Treatment Regimen, MEPED, Rescues Relapsed and Refractory Classic Hodgkin’s Disease

“…In the three newly treated patients, we show a continuous complete remission (cCR), achieved without any dose-intensive consolidation treatment in an elderly, severely comorbid patient, a patient with relapsed cHL after allogenic hematopoietic stem cell transplantation (allo-HSCT) and a third patient who received MEPED (metronomic chemotherapy, everolimus, pioglitazone, etoricoxib, dexamethasone) (Table 1) as a salvage therapy to become eligible for allo-HSCT. We applied a combination of low-dose metronomic chemotherapy, pioglitazone, everolimus, dexamethasone, and etoricoxib as previously published (Guarini et al, 2012;Ugocsai et al, 2016). We also provide a long-term follow-up for the three patients already published by some of the authors of this study (Ugocsai et al, 2016).…”