Other activating events include PTEN loss and AKT amplification (59)-(61). Activation of this Calcitriol pathway was associated with poor prognosis

and contributed to chemoresistance in many cancers (62)-(66). Thus, the PI3k/Akt/mTOR pathway is an attractive pathway to target in pancreas cancer. mTOR inhibitors Everolimus 10mg daily was evaluated in 33 metastatic gemcitabine-refractory pancreas Inhibitors,research,lifescience,medical cancer patients (67). No objective responses (complete and partial) were reported and 21% had stable disease at the time of first surveillance CT scan. Median PFS and OS were 1.8 and 4.5 months respectively. In two smaller clinical trials, 4 gemcitabine-refractory patients received temsirolimus (CCI-779) and 16 received a combination of everolimus (30mg once weekly) and erlotinib (150 mg daily) (68). The former study with temsirolimus was halted due to toxicities and no objective response was observed, and the median PFS was 19 days and survival 44 days. The everolimus and erlotinib combination was better tolerated, but no response was observed and median PFS Inhibitors,research,lifescience,medical and survival Inhibitors,research,lifescience,medical was 49 days and 87 days respectively. These trials demonstrate that mTOR inhibition as a single agent is ineffective and combining inhibitors of multiple steps and the role for these inhibitors may lie in combination regimens. Akt inhibitors Akt inhibitors are another class

of agents that abrogate Akt/mTOR signaling. MK-2206, an allosteric Akt1-3 inhibitor, was evaluated in a phase I trial of 70 patients with advanced cancers (69). Interestingly, tumor shrinkage (23%) Inhibitors,research,lifescience,medical was observed in a patient with PTEN-negative pancreas cancer and was associated with a 60% decrease in CA19-9. MK-2206 is being evaluated as weekly (300mg) and every other day (75mg and 90mg) dosing schedules. MK-2206 is also being evaluated in combination with cytotoxic chemo-agents and inhibitors of c-Met and EGFR (70),(71). RX-0201 is an antisense oligonucleotide against Akt1 mRNA, thereby interrupting the pathway’s activation. Inhibitors,research,lifescience,medical The anti-sense oligonucleotide demonstrated activity against pancreas cancer cell lines in low nanomolar range, reducing the expression of Akt1

mRNA and protein. Dipeptidyl peptidase In in vivo studies, RX-0201 treatment led to complete response in 2 out of 3 pancreas tumor-bearing mice (72). As such, RX-0201 in combination with gemcitabine is currently being evaluated in a phase II trial for metastatic pancreas cancer patients (73). Given the short half-life typical of anti-sense agents, RX-0201 is being administered by continuous infusion for 14 days of a 21-day cycle and presents a potential obstacle to patient accural. Liposomal formulations are in development (74). PI3K inhibitors XL147 and BKM120 are oral class I PI3k inhibitors that are being evaluated in phase I trials, alone and in combination therapies (75)-(77). These trials have focused on lung, colorectal and breast cancers given the higher frequency of pathway aberrations in these tumor types.