First Report on Alternative Evaluation Methodology PROMISE Deliverable 4.1

The first report on alternative evaluation methodology summarizes work done within the PROMISE environment and especially within Work package 4 - Evaluation Metrics and Methodologies. The report outlines efforts to develop and support alternative, automated evaluation methodologies, with a special focus on generating ground truth from existing data sources like Log files or annotations. Events like LogCLEF 2011, PatOlympics 2011 or the CHiC2011 workshop are presented and reviewed on their impact on the three main uses case domains

M402, a Novel Heparan Sulfate Mimetic, Targets Multiple Pathways Implicated in Tumor Progression and Metastasis

Heparan sulfate proteoglycans (HSPGs) play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS) mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1α, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis

M402 targets primary tumors.

<p>Fluo-M402 biodistribution in 4T1 tumor bearing mice. Female Balb/c mice were implanted orthotopically into the first mammary fat pad at a concentration of 1×10⁵ 4T1 cells on Day 0. Mice were injected on Day 3 with a single subcutaneous dose of either 10 mg/kg fluorescently-labeled M402 or free dye of approximately the same intensity in saline. (A) Mice were imaged in the ventral view at various time points after injection with Fluo-M402 (upper panels) or free dye (lower panels). White circles indicate primary tumors, and yellow boxes highlight signals from the liver regions. (B) Quantification of fluorescent signals (Mean±SEM) at the primary tumor site at different times after Fluo-M402 or free dye injection. (C) CD31 immunohistology. Groups of female BALB/c mice (n = 16) were inoculated orthotopically with 8×10⁴ 4T1 cells in the 4th mammary fat pad on day 0. Saline or M402 (20 mg/kg/day) treatment delivered by s.c. implanted osmotic pumps started on day 5. Primary tumors were removed on day 9 by surgery and the tumor weights were recorded. There was no significant difference in primary tumor weight between the groups 4 days after the start of the treatments. Primary tumors were fixed in buffered-formalin, embedded in paraffin and stained for CD31 by immunohistochemistry. Representative CD31-staining is presented in the left panel where the brownish staining (arrows) indicate CD31⁺ vessels. Quantification of microvessel density as numbers of CD31⁺ vessels/40× field (Mean±SEM) is displayed on the right. *, P<0.05 (t-test) when compared with saline control group.</p

Physiochemical characteristics of M402, M-ONC 202 and Dalteparin.

<p>Physiochemical characteristics of M402, M-ONC 202 and Dalteparin.</p