Considerable evidence supports an important role for the PI3K/Akt/mTOR pathway in pancreatic cancer biology.13
Point mutations in K-RAS
are an early molecular event in the progression of normal pancreatic ducts to ductal adenocarcinoma.12,26
These mutations lead to constitutive activation of the K-RAS protein, and subsequently, the activation of several downstream intracellular pathways, including the RAF/MAPK, PI3K/Akt/mTOR, and Ral GDS pathways.13
In addition, excess energy balance, as noted with obesity and a sedentary lifestyle, increases pancreatic cancer risk27,28
and leads to activation of the PI3K/Akt/mTOR pathway upstream through the insulin and insulin-like growth factor receptors29
and at the level of mTOR by energy and nutrient availability.30
When activated by these mechanisms, the PI3K/Akt/mTOR pathway provides important downstream signaling that promotes cellular proliferation, survival, and neoangiogenesis.31
In preclinical studies, inhibitors of PI3K, Akt, and mTOR have demonstrated antitumor activity in pancreatic cancer cells, both alone and in combination with other agents, suggesting their possible utility in patients with pancreatic cancer.20-25
Therefore, there is a strong rationale to examine inhibitors of mTOR in patients with pancreatic cancer.
In this multi-institutional, single-arm phase II study, the oral mTOR inhibitor RAD001 was successfully administered to patients with gemcitabine-refractory, metastatic pancreatic cancer with modest toxicity. When necessary, treatment delays and dose reductions were due primarily to resultant grade 3 hyperglycemia and thrombocytopenia. Nonetheless, RAD001 as a single agent failed to demonstrate meaningful clinical activity in this patient population, with no objective treatment responses and relatively brief median PFS and overall survival times.
Traditional chemotherapeutic agents have limited efficacy in patients with metastatic pancreatic cancer.2,10
After these patients experience progressive disease on a gemcitabine-containing regimen, appropriate second-line therapy is poorly defined.11
Several second-line studies of cytotoxic agents have demonstrated median survival times of 3 to 7 months.32-38
Recently, we reported that the combination of capecitabine and erlotinib in patients with gemcitabine-refractory disease had an overall response rate of 10%, a median PFS of 3.4 months, and median survival time of 6.5 months.39
In contrast, in the current study of RAD001 conducted at the same institutions and for the same indication, we observed no objective responses, a median PFS of 1.8 months, and median overall survival of 4.5 months.
In phase I studies, 10 mg of daily RAD001 has demonstrated the ability to inhibit mTOR activity in peripheral mononuclear cells, skin cells, and tumors, as measured by abrogated phosphorylation of downstream target proteins.40-42
In addition, these studies have suggested that once-daily dosing may result in more profound and persistent inhibition of mTOR activity than other schedules of administration. In the current study, patient compliance with oral RAD001 was good, with only two of 33 patients reporting missing more than a single dose of the drug. Therefore, inconsistent administration of drug or lack of target inhibition seems to be less likely reasons for the ineffectiveness of RAD001 in this patient population.
In recent years, the complexity of the PI3K/Akt/mTOR pathway has become increasingly apparent, particularly in relation to its potential as a therapeutic target in cancer.43,44
Recent data suggest the presence of a negative feedback loop, whereby increased activation of mTOR leads to a physiologic brake on further stimulation of this pathway ().45-48
In some tumor types, mTOR inhibitors may interfere with this inhibitory feedback, resulting in a paradoxical increase in signaling by PI3K and increased activation of other Akt-target proteins that promote cell survival. Although the loss of this negative feedback from mTOR inhibition may limit the efficacy of single-agent mTOR inhibitors in these tumor types, it also supports the investigation of treatment regimens that combine mTOR inhibitors with other agents, such as inhibitors of PI3K and upstream receptor tyrosine kinases.
Fig 2. Schematic representation of the PI3K/Akt/mTOR pathway. Binding of insulin or IGF to transmembrane receptors leads to activation mTOR via PI3K and Akt. Activation of mTOR promotes protein synthesis, cell growth, and cytoskeletal modeling, important factors (more ...)
In conclusion, daily RAD001 administered as a single agent had minimal clinical activity in patients with gemcitabine-refractory, metastatic pancreatic cancer. Nonetheless, given substantial preclinical data implicating activation of the PI3K/Akt/mTOR pathway in pancreatic cancer, this pathway remains an interesting target in the treatment of patients with this disease. To realize the potential of this strategy, future studies of mTOR inhibitors will likely need to assess the combination of these agents with drugs that inhibit upstream components of the PI3K/Akt/mTOR pathway. Concurrent work will be necessary to verify target inhibition and investigate potential mechanisms of resistance in patients with this difficult to treat disease.