Targeting mTOR dependency in pancreatic cancer

Abstract

ObjectivePancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease.DesignActivating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of KrasG12D-driven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition.ResultsWe found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours.ConclusionsKRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future.

NEMA NU4-2008 Performance Evaluation of Albira: A Two-Ring Small-Animal PET System Using Continuous LYSO Crystals

“…Instead of a triangle-shape, one can observe two minor peaks corresponding to the centres of individual rings of the sub-system, which are in agreement with results reported for the 1-ring Bruker Albira PET. In practical terms, Morran et al [18] have recently shown that the sensitivity of the two ring system is sufficient to detect differences in 18 F-FLT uptake between pancreatic tumours from two different mouse models of pancreatic ductal adenocarcinoma following treatment with the mTOR inhibitor rapamycin.…”

“…(5) (described in more detail in the count-rate performance section). All three were filled with 18 F supplied by the West of Scotland PET Radiopharmaceutical Production Unit (Glasgow, UK). The coincidence timing window was 5 ns and the energy window was set to 50% (255-767 keV) for all tests except Image Quality and animal study, where the energy window was set to the manufacturer-suggested setting of 30% (358-664 keV).…”

“…A cylindrical hole of 3.2 mm in diameter was drilled along the central axis at 17.5 mm radial offset. Tubing of 2.5 mm external diameter was filled with 233 MBq of 18 F over 140 mm and threaded through the phantom, so the activity in the tubing was aligned with the central 140 mm of the phantom. After positioning the phantom in the centre of the FOV, a series of 20 minute acquisitions was taken until the activity decayed to 115.6 kBq.…”

“…The phantom was filled with 3.55 MBq of 18 F, positioned centrally within the FOV and imaged for 20 minutes. The image was then reconstructed using Albira built-in reconstruction software with a 0.5 mm voxel size (the smallest available) and MLEM algorithm using variable number of iterations: from 2 to 100.…”

The mTOR Signaling Pathway and Regulation of Pancreatic Function

“…Currently attention has focused on dual agent therapy as well as identifying patients with specific patterns of gene activation that may be more responsive. In this context, genetically modified mice with Ras mutation and PTEN deficiency show sensitivity to TORC1 inhibition in contrast to those with Ras and p53 mutations which are not sensitive (28). Another study using a mouse model of decreased TSC1 by haploid sufficiency showed enhanced mTOR signaling and tumorigenesis could be blocked with dual inhibition of mTOR and MEK (25).…”