Developing oncolytic viruses for clinical use: A consortium approach

The use of oncolytic viruses forms an appealing approach for cancer treatment. On the one hand the viruses replicate in, and kill, tumor cells, leading to their intra-tumoral amplification. On the other hand the viral infection will activate virus-directed immune responses, and may trigger immune responses directed against tumor cells and tumor antigens. To date, a wide variety of oncolytic viruses is being developed for use in cancer treatment. While the development of oncolytic viruses has often been initiated by researchers in academia and other public institutions, a large majority of the final product development and the testing of these products in clinical trials is industry led. As a consequence relatively few pre-clinical and clinical studies evaluated different oncolytic viruses i

An exploratory first-in-man study to investigate the pharmacokinetics and safety of liposomal dexamethasone at a 2- and 1-week interval in patients with metastatic castration resistant prostate cancer

Dexamethasone has antitumor activity in metastatic castration resistant prostate cancer (mCRPC). We aimed to investigate intravenous liposome-encapsulated dexamethasone disodium phosphate (liposomal dexamethasone) administration in mCRPC patients. In this exploratory first-in-man study, patients in part A received a starting dose of 10 mg followed by five doses of 20 mg liposomal dexamethasone at 2-week intervals. Upon review of part A safety, patients in part B received 10 weekly doses of 18.5 mg. Primary outcomes were safety and pharmacokinetic profile, secondary outcome was antitumor efficacy. Nine mCRPC patients (5 part A, 4 part B) were enrolled. All patients experienced grade 1-2 toxicity, one (part B) patient experienced grade 3 toxicity (permanent bladder catheter-related urosepsis). No infusion-related adverse events occurred. One patient had upsloping glucose levels 50% PSA biochemical response was observed. Bi- and once weekly administrations of IV liposomal dexamethasone were well-tolerated. Weekly dosing enabled trough concentrations of liposomal- and free dexamethasone >LLOQ. The data presented support further clinical investigation in well-powered studies. Clinical trial registration: ISRCTN 10011715.Prostatic carcinom

Molecular alterations that drive breast cancer metastasis to bone.

Epithelial cancers including breast and prostate commonly progress to form incurable bone metastases. For this to occur, cancer cells must adapt their phenotype and behaviour to enable detachment from the primary tumour, invasion into the vasculature, and homing to and subsequent colonisation of bone. It is widely accepted that the metastatic process is driven by the transformation of cancer cells from a sessile epithelial to a motile mesenchymal phenotype through epithelial-mesenchymal transition (EMT). Dissemination of these motile cells into the circulation provides the conduit for cells to metastasise to distant organs. However, accumulating evidence suggests that EMT is not sufficient for metastasis to occur and that specific tissue-homing factors are required for tumour cells to lodge and grow in bone. Once tumour cells are disseminated in the bone environment, they can revert into an epithelial phenotype through the reverse process of mesenchymal-epithelial transition (MET) and form secondary tumours. In this review, we describe the molecular alterations undertaken by breast cancer cells at each stage of the metastatic cascade and discuss how these changes facilitate bone metastasis

Fibulin-4 deficiency differentially affects cytoskeleton structure and dynamics as well as TGF beta signaling

Fibulin-4 is an extracellular matrix (ECM) protein essential for elastogenesis and mutations in this

Nuclear Eg5 (kinesin spindle protein) expression predicts docetaxel response and prostate cancer aggressiveness

Novel biomarkers predicting prostate cancer (PCa) aggressiveness and docetaxel therapy response of PCa patients are needed. In this study the correlation between nuclear Eg5-expression, PCa docetaxel response and PCa aggressiveness was assessed. Immunohistochemical staining for nuclear Eg5 was performed on 117 archival specimens from 110 PCa patients treated with docetaxel between 2004 and 2012. Samples were histologically categorized as positive/negative. Median follow-up time from diagnosis was 11.6 years. Nuclear Eg5-expression was significantly related to docetaxel response (p=0.036) in tissues acquired within three years before docetaxel initiation. Nuclear Eg5-expression was not related to Gleason-score (p=0.994). Survival of patients after docetaxel initiation did not differ based on nuclear Eg5-expression (p=0.540). Analyzing samples taken before hormonal therapy, overall survival and time to docetaxel use were significantly decreased in patients with nuclear Eg5-expressing tumors (p<0.01). Eg5-positive nuclei were found more frequently in T4-staged tumors (p=0.04), Gleason 8-10 tumors (p=0.08), and in metastasized tumors (p<0.01). Multivariate analyses indicated that nuclear Eg5-expression may be an independent parameter for tumor aggressiveness. Limitations of a retrospective analysis apply. In conclusion, nuclear Eg5-expression may be a predictive biomarker for docetaxel response in metastatic castrate-resistant PCa patients and a prognostic biomarker for hormone-naive PCa patients. Prospective validation studies are needed

The identification of small molecule inhibitors that reduce invasion and metastasis of aggressive cancers

Transformed epithelial cells can activate programs of epithelial plasticity and switch from a sessile, epithelial phenotype to a motile, mesenchymal phenotype. This process is linked to the acquisition of an invasive phenotype and the formation of distant metastases. The development of compounds that block the acquisition of an invasive phenotype or revert the invasive mesenchymal phenotype into a more differentiated epithelial phenotype represent a promising anticancer strategy. In a high-throughput assay based on E-cadherin (re)induction and the inhibition of tumor cell invasion, 44,475 low molecular weight (LMW) compounds were screened. The screening resulted in the identification of candidate compounds from the PROAM02 class. Selected LMW compounds activated E-cadherin promoter activity and inhibited cancer cell invasion in multiple metastatic human cancer cell lines. The intraperitoneal administration of selected LMW compounds reduced the tumor burden in human prostate and breast cancer in vivo mouse models. Moreover, selected LMW compounds decreased the intra-bone growth of xenografted human prostate cancer cells. This study describes the identification of the PROAM02 class of small molecules that can be exploited to reduce cancer cell invasion and metastases. Further clinical evaluation of selected candidate inhibitors is warranted to address their safety, bioavailability and antitumor efficacy in the management of patients with aggressive cancers.Prostatic carcinom

Note on analysis of quartz grain dimensions in foliated greywackes

Quarzkorn-Abmessungen aus Grauwacken wurden auf ein internes Referenzsystem (reference aspect ratio, RAR) bezogen und mit Hilfe der linearen Regressionsanalyse der reduzierten Hauptachse (reduced major axis, RMA) ausgewertet. Das verwendete statistische Verfahren unterscheidet im Gegensatz zur Methode der kleinsten Quadrate nicht zwischen abhängigen und unabhängigen Variablen. Die Anwendung der RMX-Methode in Verbindung mit den RAR-Meßwerten kann sehr hilfreich für Vergleiche innerhalb geschieferter Grauwacken sein, bei denen unterschiedliche Prozesse in Korngrößenbereich wirksam waren wie etwa Drucklösung und Festkörper-Rotation. Die RAR/RMA-Analyse erfaßt Kornregelungen und ist daher auch einsetzbar für die Klassifikation von Schieferungen. Darüber hinaus wird die Anwendung der RAR/RMA-Analyse für die Bestimmung der Deformation diskutiert. Robin strain-Werte werden mit arithmetischen und harmonischen Mittelwerten der RAR-Analyse verglichen. Es zeigt sich, daß das arithmetische Mittel des RAR ein vernünftiges Maß für die longitudinale Deformation darstellt. Quartz grain dimensions, measured parallel to an internal reference system (reference aspect ratio, RAR), were analyzed using the »reduced major axis« (RMA) linear regression analysis. In contrast to least-squares analysis, this statistical technique does not distinguish between dependent and independent variables. Application of the RMA analysis in conjunction with RAR values can be most useful for comparisons between foliated greywackes in which different grain scale processes, such as pressure solution and rigid-body rotation, were active. The RAR/RMA analysis reflects grain alignment and is therefore also useful for cleavage classification. In addition to the above, the application of RAR/RMA analysis for the determination of strain is discussed. Robin strains are compared with the arithmetic and harmonic means from RAR's and it is concluded that the arithmetic mean RAR produces a reasonable estimate of longitudinal strain in these rocks. Les dimensions des grains de quartz, mesurés parallèlement à un système de référence interne (»reference aspect ratio«: RAR) ont été traitées par la méthode de la régression linéaire (»reduced major axis«: RMA). Contrairement à la méthode des moindres carrés, cette technique statistique ne fait pas de distinction entre les variables dépendantes et indépendantes. L'application de ce type de méthode s'avère très utile à la comparaison de grauwackes schisteuses dans lesquelles les dimensions des grains peuvent être la conséquence de processus différents, tels que la dissolution (pressure solution) et la rotation. L'analyse RAR/RMA traduit l'alignement des grains et peut, de ce fait, être utilisée aussi à l'appréciation du type de schistosité. D'autre part, l'auteur discute l'application de l'analyse RAR/RMA à la détermination de la déformation finie. Si on compare les déformations »Robin« aux moyennes arithmétique et harmonique des RAR, on peut conclure que les moyennes RAR arithmétiques fournissent une estimation raisonnable de la déformation longitudinale. Помимо интернациона льной системы RAR, разме ры зерен кварца анализи ровали с помощью регр ессивного анализа «Изменение о сновных осей» — RMA. В отличие от анализа ме тодом наименьшего кв адратов, при названном статис тическом методе разл ичия между зависимыми и не зависимыми переменн ыми не учитываются. Компл ексное применение RAR иPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47848/1/531_2005_Article_BF01821068.pd

The direct oral anticoagulants rivaroxaban and dabigatran do not inhibit orthotopic growth and metastasis of human breast cancer in mice

Factor Xa‐targeting DOACs were recently found to reduce recurrentVTE efficiently in cancer patients when compared to the standard treatment withlow‐molecular‐weight heparins (LMWHs). While the anticancer effects of LMWHshave been extensively studied in preclinical cancer models, the effects of FXa‐targetingDOACs on cancer progression remain to be studied.We investigated whether the FXa‐targeting DOAC rivaroxaban and thethrombin‐targeting DOAC dabigatran etexilate (DE) affected human breast cancergrowth and metastasis in orthotopic xenograft models.Mice that were put on a custom‐made chow diet supplementedwith rivaroxaban (0.4 or 1.0 mg/g diet) or dabigatran etexilate (DE) (10 mg/g diet)showed prolonged ex vivo coagulation times (prothrombin time [PT] and activatedpartial thromboplastin time [aPTT] assay, respectively). However, rivaroxabanand DE did not inhibit MDA‐MB‐231 tumor growth and metastasis formationin lungs or livers of 7‐week‐old fully immunodeficient NOD/SCID/ƴC−/− (NSG) mice.Comparable data were obtained for rivaroxaban‐treated mice when using NOD‐SCIDmice. Rivaroxaban and DE treatment also did not significantly inhibit tumor growthand metastasis formation when using another human triple negative breast cancer(TNBC) cell line (HCC1806) in NOD‐SCID mice. The FXa and thrombin‐induced geneexpression of the downstream target CXCL8 in both cell lines, but FXa and thrombin,did not significantly stimulate migration, proliferation, or stemness in vitro.Although effectively inhibiting coagulation, the DOACs rivaroxaban andDE did not inhibit orthotopic growth and metastasis of human TNBC. It remains to beinvestigated whether DOACs exert antitumorigenic effects in other types of cancer.Toxicolog