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.

Isobutyl-deoxynyboquinone (IB-DNQ) is a selective substrate for NAD(P)H:quinone oxidoreductase (NQO1), an enzyme overexpressed in many solid tumors. Following activation by NQO1, IB-DNQ participates in a catalytic futile reduction/reoxidation cycle with consequent toxic reactive oxygen species generation within the tumor microenvironment. To elucidate the potential of IB-DNQ to serve as a novel anticancer agent, in vitro studies coupled with in vivo pharmacokinetic and toxicologic investigations in the domestic felid species were conducted to investigate the tractability of IB-DNQ as a translationally applicable anticancer agent. First, using feline oral squamous cell carcinoma (OSCC) as a comparative cancer model, expressions of NQO1 were characterized in not only human, but also feline OSCC tissue microarrays. Second, IB-DNQ mediated cytotoxicity in three immortalized feline OSCC cell lines were studied under dose-dependent and sequential exposure conditions. Third, the feasibility of administering IB-DNQ at doses predicted to achieve cytotoxic plasma concentrations and biologically relevant durations of exposure were investigated through pharmacokinetic and tolerability studies in healthy research felines. Intravenous administration of IB-DNQ at 1.0-2.0 mg/kg achieved peak plasma concentrations and durations of exposure reaching or exceeding predicted in vitro cytotoxic concentrations. Clinical adverse side effects including ptyalism and tachypnea exhibited during and post-IV infusion of IB-DNQ were transient and tolerable. Additionally, IB-DNQ administration did not produce acute or delayed-onset unacceptable hematologic, non-hematologic, or off-target oxidative toxicities. Collectively, the findings reported here within provide important safety and pharmacokinetic data to support the continued development of IB-DNQ as a novel anticancer strategy for NQO1 expressing cancers.

Abstract:Goals: This paper presents the performance review based on a dual-ring Positron Emission Tomography (PET) scanner being a part of Bruker Albira: a multi-modal small-animal imaging platform. Each ring of Albira PET contains eight detectors arranged as octagon, and each detector is built using a single continuous lutetium-yttrium oxyorthosilicate crystal and multi-anode photo multiplier tube. In two-ring configuration, the scanner covers 94.4 mm in axial-and 80´80 mm in trans-axial direction, which is sufficient to acquire images of small animals (e.g. mice) without the need of moving the animal bed during the scan. Methods:All measurements and majority of data processing were performed according to the NEMA NU4-2008 standard with one exception. Due to the scanner geometry, the spatial resolution test was reconstructed using iterative algorithm instead of the analytical one. The main performance characteristics were compared with those of the other PET sub-systems of tri-modal smallanimal scanners. Results:The measured spatial resolution at the centre of the axial field of view in radial, tangential and axial directions was 1.72, 1.70 and 2.45 mm, respectively. The scatter fraction for the mouse-like phantom was 9.8% and for the rat-like phantom, 21.8%. The maximum absolute sensitivity was 5.30%. Finally, the recovery co-efficients for 5, 4, 3, 2, 1 mm diameter rods in image quality phantom were: 0.90, 0.77, 0.66, 0.30 and 0.05, respectively. Conclusion:The Bruker Albira is a versatile small-animal multi-modal device that can be used for variety of studies. Overall the PET sub-system provides a good spatial resolution coupled with better-than average sensitivity and the ability to produce good quality animal images when administering low activities.