Deregulation of the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)- mammalian target of rapamycin(m TOR) signaling pathway is one of the most commonlyinvolved pathways in tumorigenesis. It has also been reporte...Deregulation of the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)- mammalian target of rapamycin(m TOR) signaling pathway is one of the most commonlyinvolved pathways in tumorigenesis. It has also been reported as altered in neuroendocrine tumors(NETs). m TOR inhibitors used in clinical practice are derived from rapamycin,an anti-cancer agent also used as an immunosuppressor after organ transplantation. Everolimus and temsirolimus are the two rapamycin-derived m TOR inhibitors used in NETs. Notably everolimus has been approved in advanced progressive well/moderatelydifferentiated pancreatic NETs(p NETs). It inhibits specifically the m TORC1 subunit of m TOR,not interacting with m TORC2. Although everolimus produced a significant prolongation of progression-free survival a number of patients with p NETs do not benefit from the drug due to early or late progression. Two supposed mechanisms of resistance to m TOR inhibitors are Akt and PI3 K activation,by means of m TORC2 and insulin growth factor(IGF)- IGF receptor signaling,respectively. BEZ235 is a multi-targeted inhibitor binding to PI3 K,m TORC1 and m TORC2,therefore potentially turning off all the supposed molecular targets of resistance to everolimus. The two clinical trials designed in p NETs were stopped early due to unmet statistical endpoint and the global clinical development of BEZ235 was also halted. Tolerability of this drug was challenging and conditioned the feasibility of therapy. The BEZ experience is an example of the huge difference between the preclinical and clinical setting and prompts us to pay more attention to the phase Ⅰ step of clinical development and the design of phase Ⅱ clinical trials.展开更多
文摘Deregulation of the phosphoinositide 3-kinase(PI3K)/protein kinase B(Akt)- mammalian target of rapamycin(m TOR) signaling pathway is one of the most commonlyinvolved pathways in tumorigenesis. It has also been reported as altered in neuroendocrine tumors(NETs). m TOR inhibitors used in clinical practice are derived from rapamycin,an anti-cancer agent also used as an immunosuppressor after organ transplantation. Everolimus and temsirolimus are the two rapamycin-derived m TOR inhibitors used in NETs. Notably everolimus has been approved in advanced progressive well/moderatelydifferentiated pancreatic NETs(p NETs). It inhibits specifically the m TORC1 subunit of m TOR,not interacting with m TORC2. Although everolimus produced a significant prolongation of progression-free survival a number of patients with p NETs do not benefit from the drug due to early or late progression. Two supposed mechanisms of resistance to m TOR inhibitors are Akt and PI3 K activation,by means of m TORC2 and insulin growth factor(IGF)- IGF receptor signaling,respectively. BEZ235 is a multi-targeted inhibitor binding to PI3 K,m TORC1 and m TORC2,therefore potentially turning off all the supposed molecular targets of resistance to everolimus. The two clinical trials designed in p NETs were stopped early due to unmet statistical endpoint and the global clinical development of BEZ235 was also halted. Tolerability of this drug was challenging and conditioned the feasibility of therapy. The BEZ experience is an example of the huge difference between the preclinical and clinical setting and prompts us to pay more attention to the phase Ⅰ step of clinical development and the design of phase Ⅱ clinical trials.
