Citations

Key Points miR-155 levels are significantly and increasingly overexpressed as normal B cells progress to MBL and to CLL. Plasma levels of miR-155 before treatment were significantly lower in patients with CLL who experienced complete response than in all others.

Abstract The recent identification of activating fibroblast growth factor receptor 2 (FGFR2) mutations in endometrial cancer has generated an opportunity for a novel target-based therapy. Here, we explore the therapeutic potential of 2 FGFR inhibitors, the multikinase inhibitor dovitinib (TKI258) and the more selective FGFR inhibitor NVP-BGJ398 for the treatment of endometrial cancer. We examined the effects of both inhibitors on tumor cell growth, FGFR2 signaling, cell cycle, and apoptosis using a panel of 20 molecularly characterized human endometrial cancer cell lines. Anchorage-independent growth was studied using soft agar assays. In vivo studies were conducted using endometrial cancer xenograft models. Cell lines with activating FGFR2 mutations (S252W, N550K) were more sensitive to dovitinib or NVP-BGJ398 when compared with their FGFR2 wild-type counterparts (P = 0.073 and P = 0.021, respectively). Both agents inhibited FGFR2 signaling, induced cell-cycle arrest, and significantly increased apoptosis in FGFR2-mutant lines. In vitro, dovitinib and NVP-BGJ398 were both potent at inhibiting cell growth of FGFR2-mutant endometrial cancer cells, but the activity of dovitinib was less restricted to FGFR2-mutant lines when compared with NVP-BGJ398. In vivo, dovitinib and NVP-BGJ398 significantly inhibited the growth of FGFR2-mutated endometrial cancer xenograft models. In addition, dovitinib showed significant antitumor activity in FGFR2 wild-type endometrial cancer xenograft models including complete tumor regressions in a long-term in vivo study. Dovitinib and NVP-BGJ398 warrant further clinical evaluation in patients with FGFR2-mutated endometrial cancer. Dovitinib may have antitumor activity in endometrial cancer beyond FGFR2-mutated cases and may permit greater flexibility in patient selection. Mol Cancer Ther; 12(5); 632–42. ©2013 AACR.

Abstract Mesenchymal Stem Cells (MSCs) have the ability to migrate specifically to tumours in vivo, and coupled with their capacity to bypass immune surveillance, are potentially attractive vehicles for tumor-targeted delivery of therapeutic agents. The aim of this study was to determine the potential of MSC-mediated expression of the sodium iodide symporter (NIS) for in vivo imaging and therapy of breast tumours. Expression of NIS allows cells to concentrate radionuclides including technetium-99m (Tc-99m) and 131-Iodine (131-I). This could potentially support imaging of NIS-expressing MSCs following engraftment, and 131-I therapy of surrounding tumour tissue based on the bystander effect of the radionuclide. Methods: Tumor bearing animals (MDA-MB-231 flank) were given an intravenous or intratumoral injection of NIS expressing human MSCs (MSC-NIS), followed by imaging 3, 7, 10 or 14 days later. Imaging was performed using a Bazooka SPECT γ-camera, following intraperitoneal injection of 2mCi/74MBq Tc-99m. Following imaging, animals were sacrificed and organs harvested for analysis of hNIS expression by RQ-PCR. A second group of animals received an intraperitoneal injection of 1mCi/37MBq 131-I or saline (controls) 14 days following intratumoral or intravenous injection of MSC-NIS, and tumour volume was tracked for 8 weeks. Results: Bazooka SPECT imaging of animals revealed uptake of tracer (Tc-99m) in the mouse thyroid/salivary glands and stomach, representing native NIS expression. Following injection of MSC-NIS, an image of animal intestines was also observed at D3, with a weak image of the tumour also visible. By Day14, uptake of tracer was visible at the site of the tumour with no significant image of non-target tissue observed. Expression of hNIS in harvested organs supported the imaging data, with hNIS detected in the intestines, heart, lungs and tumour at early timepoints. While NIS expression depleted in non-target tissues by D7, gene expression persisted at the tumour site. Based on imaging/biodistribution data, animals were given a therapeutic dose of 131-I 14 days following MSC-NIS injection to avoid toxicity to non-target organs. No adverse effect of injection of MSC-NIS or radionuclide was observed. Tracking of tumour volume revealed a significant reduction in tumour growth in animals that had received an intravenous injection of 131-I 14days following MSC-NIS injection (Mean ± SEM, 236 ± 62mm3 versus 665 ± 204 mm3 in controls). Following intratumoral injection of MSC-NIS + 131-I, although tumour size was reduced compared to controls (472 ± 80 mm3), the difference in volume was not significant. Conclusion: The ability to non-invasively track MSC migration and transgene expression in real time prior to therapy is a major advantage to this strategy. This promising data supports the viability of this approach as a novel therapy for metastatic breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5392. doi:10.1158/1538-7445.AM2011-5392

AbstractWe tested the effects of overexpression of the endothelial nitric oxide synthase (eNOS) gene in the normal arterial wall by adenoviral-mediated gene transfer. Rabbit carotid arteries were surgically isolated and exposed to adenoviral vectors encoding eNOS (AdeNOS) or β-galactosidase (AdβGal) on the contralateral side. Vector solutions at a concentration of 1×1010plaque forming units/mL were instilled for 20 minutes before restoration of flow. Arteries were harvested 4 days later for immunostaining, measurement of cGMP, and vasomotor studies. Endothelium-specific gene transfer was confirmed by staining for β-galactosidase in the AdβGal arteries. Immunostaining of en face endothelial cell imprints from AdeNOS-transduced arteries with a monoclonal antibody to eNOS showed increased immunoreactivity. Basal cGMP levels were significantly greater in the AdeNOS-transduced arteries (18.4±4.6 versus 4.2±0.5 pmol/mg protein;P<.05). Contractions to phenylephrine were significantly reduced in the AdeNOS-transduced arteries (area under curve, 106±5 versus 119±7;P<.05), but in the presence of the eNOS inhibitor,NG-monomethyl-l-arginine (L-NMMA, 3×10−4mol/L), there was no difference between the two (area under curve, 148±5 versus 153±6;P=NS). Relaxations to acetylcholine obtained during submaximal contractions to phenylephrine were significantly enhanced in the AdeNOS-transduced arteries (EC50, 7.45±0.05 versus 7.23±0.03;P<.05). We conclude that overexpression of eNOS in the endothelium results in diminished contractile responses, as well as enhanced endothelium-dependent relaxations. These findings imply a possible role for vascular eNOS gene transfer in the treatment of vasospasm and endothelial dysfunction.