WntResearch (Sweden)

Abstract Most current anti-cancer therapeutic drugs are targeting the proliferation and/or survival of cancer cells while very few drugs are aimed at specifically targeting the dissemination process. Several reports have demonstrated that low-levels or lack of Wnt-5a protein expression in primary breast-, colon-, and prostate cancer tissues correlates with shortened patient recurrence-free survival and overall survival pointing to a biological role of Wnt5a signaling in the dissemination process of cancer cells. The Wnt5a ligand mediates its effects vid interaction with G-protein coupled Frizzled receptors and tyrosine-kinase coupled receptors such as ROR1 and ROR2. Therefore, we developed two peptides, one being a Wnt-5a agonist (Foxy-5) and one being a Wnt-5a antagonist (Box-5). The Foxy-5 is a formylated Wnt5a-derived hexapeptide that mimics the ability of the Wnt-5a molecule to impair cancer cell migration in vitro and significantly reduces the formation of distant metastases in vivo in mouse models of breast- and prostate cancer. In addition, a 4-week toxicology study in rats and dogs with a final dose well exceeding the dose previously used in the mouse models showed no drug-induced toxic reactions.Based on all these pre-clinical data we initiated a clinical phase 1 study with the primary objective to evaluate the safety and tolerability of Foxy-5. All eligible patients are pre-screened for Wnt-5a immunoreactivity in archival tumor tissue and from dose level 7 and onwards only patients with negative or low level Wnt5a expressing metastatic breast-, colon-, or prostate cancer are enrolled in the study. This study has currently recruited cohorts 1-7 without reaching MTD and the final recruitment for the last dose level (dose level 8) is ongoing. Clinical trial information: NCT02020291. This study will be finalized during early fall 2015 and followed by a phase 1b study which will continue dose escalation but with a specific focus on determining the Biological Active Dose (BAD) since Foxy-5 does not possess anti-proliferative activities and is therefore not expected to induce tumor regression. In contrast to breast, colon and prostate cancer, Wnt5a signaling promotes tumor progression in vitro in melanoma and gastric cancer. The antagonistic Wnt5a-derived peptide Box5 possesses the capacity to impair Wnt5a signaling and migration in melanoma cells. We are now performing additional pre-clinical experiments to enable us to test the in vivo effects of Box5 in a melanoma animal model. Future clinical development plans include a phase II study enrolling patients with stage III colorectal cancer and then add Foxy-5 to standard 5FU plus oxaliplatin adjuvant treatment. Citation Format: Tommy Andersson, Lena Axelsson, Purusottam Mohapatra, Chandra Prasad, Peter Grundtvig Soerensen, Morten Mau-Soerensen, Ulrik Lassen, Tine Molvadgaard, Ulla Buhl, Nils Brünner, Dorte Nielsen. Targeting the Wnt-5a signaling pathway as a novel anti-metastatic therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A116.

Im Zuge der Erfolgsmessung werden verstarkt auch nicht-monetare Indikatoren wie die Effizienz des Produktionsprozesses als wertmasiges Verhaltnis von Output zu Input herangezogen. Im Versicherungsunternehmen stehen der Einfachheit des Effizienzkonzeptes jedoch Schwierigkeiten bei der praktischen Bestimmung gegenuber, da aufgrund ihres immateriellen Charakters Outputs und Inputs meist nicht direkt messbar sind. In der vorliegenden Untersuchung wurden daher mittels der Data Envelopment Analysis (DEA), einem nichtparametrischen Benchmark-Verfahren und einer deskriptiven Methodik zur Effizienzmessung von Produktionseinheiten, 53 deutsche Kompositversicherer hinsichtlich ihrer Gesamteffizienz, technischen Effizienz und Skaleneffizienz sowie mittels des Malmquist-Modells deren zeitliche Entwicklung im Zeitraum von 1998 bis 2003 analysiert. Damit konnte fur die deutsche Kompositversicherung nachgewiesen werden, dass dort zwar so genannte Economies of Scale vorliegen. Die Skaleneffizienz der Versicherer ist jedoch branchenweit sehr hoch und beeinflusst daher die Gesamteffizienz weniger als die technische Effizienz. Bei der technischen Effizienz bestehen grosere Verbesserungspotenziale und grosere Unterschiede zwischen den Versicherern. Die durchschnittliche technische Effizienz ist bei kleinen und grosen Versicherern hoher als bei den mittelgrosen Unternehmen. Im Zeitvergleich zeigt sich, dass die von den meisten Kompositversicherern im Untersuchungszeitraum verbesserte Effizienz durch (negative) Veranderungen der Rahmenbedingungen nivelliert worden ist. Dieser Befund konnte uberdies eine Erklarung dafur bieten, warum es den meisten Versicherern trotz zahlreicher Effizienzsteigerungsprogramme nicht gelingt, ihre Kosten spurbar zu senken.

Kiwifruit are novel in that they contain high levels of quinic acid (1-2% w/w), which contributes to the flavour, sugar/acid balance and health-giving properties of the fruit. In a study of quinic acid storage and metabolism in three kiwifruit species (Actinidia chinensis Planch. var. chinensis, Actinidia deliciosa (A. Chev.) C.F. Liang et A.R. Ferguson var. deliciosa and Actinidia arguta (Sieb. et Zucc.) Planch. ex Miq. var. arguta) quinic acid accumulation occurred principally in the early stages (<60 days after anthesis; (DAA)) of fruit development. The present study established that there are separate quinate dehydrogenase (QDH) and shikimate dehydrogenase (SDH) activities in kiwifruit, probably representing different proteins. Quinate dehydrogenase activity was at a maximum around the time of greatest quinic acid accumulation and declined markedly in late fruit development, and was also higher in the species that accumulated the largest amounts of quinic acid (A. chinensis and A. deliciosa). In contrast, SDH activity was highest in the early stages of fruit development and only declined to 30-50% at later stages of fruit development in all three species. Dehydroquinate synthase gene expression levels measured by quantitative real-time PCR showed a high level in the early season, which was sustained through the mid-season. The quantitative real-time PCR results for a kiwifruit EST that had homology to chloroplastic isoforms of SDH showed an induction in the middle to late season; therefore, the high level of SDH activity in the early season (<30 DAA) may have resulted from the expression of a cytosolic isoform of the enzyme. The results are also consistent with the relative levels of the bifunctional dehydroquinate dehydratase/SDH enzyme and QDH enzyme controlling the accumulation and utilisation of quinic acid in kiwifruit.