Showing papers by "Joseph Negri published in 2013"

The role of tumour-stromal interactions in modifying drug response: challenges and opportunities.

Abstract: The role of stromal cells and the tumour microenvironment in general in modulating tumour sensitivity is increasingly becoming a key consideration for the development of active anticancer therapeutics. Here, we discuss how these tumour-stromal interactions affect tumour cell signalling, survival, proliferation and drug sensitivity. Particular emphasis is placed on the ability of stromal cells to confer - to tumour cells - resistance or sensitization to different classes of therapeutics, depending on the specific microenvironmental context. The mechanistic understanding of these microenvironmental interactions can influence the evaluation and selection of candidate agents for various cancers, in both the primary site as well as the metastatic setting. Progress in in vitro screening platforms as well as orthotopic and 'orthometastatic' xenograft mouse models has enabled comprehensive characterization of the impact of the tumour microenvironment on therapeutic efficacy. These recent advances can hopefully bridge the gap between preclinical studies and clinical trials of anticancer agents.

Niche-based screening identifies small-molecule inhibitors of leukemia stem cells

Abstract: Efforts to develop more effective therapies for acute leukemia may benefit from high-throughput screening systems that reflect the complex physiology of the disease, including leukemia stem cells (LSCs) and supportive interactions with the bone marrow microenvironment. The therapeutic targeting of LSCs is challenging because LSCs are highly similar to normal hematopoietic stem and progenitor cells (HSPCs) and are protected by stromal cells in vivo. We screened 14,718 compounds in a leukemia-stroma co-culture system for inhibition of cobblestone formation, a cellular behavior associated with stem-cell function. Among those compounds that inhibited malignant cells but spared HSPCs was the cholesterol-lowering drug lovastatin. Lovastatin showed anti-LSC activity in vitro and in an in vivo bone marrow transplantation model. Mechanistic studies demonstrated that the effect was on target, via inhibition of HMG-CoA reductase. These results illustrate the power of merging physiologically relevant models with high-throughput screening.

Automated quantification of Zebrafish tail deformation for high-throughput drug screening

Abstract: Zebrafish (Danio rerio) is an important vertebrate model organism in biomedical research thanks to its ease of handling and translucent body, enabling in vivo imaging. Zebrafish embryos undergo spinal deformation upon exposure to chemical agents that inhibit DNA repair. Automated image-based quantification of spine deformation is therefore attractive for whole-organism based assays for use in early-phase drug discovery. We propose an automated method for accurate high-throughput measurement of tail deformations in multi-fish micro-plate wells. The method generates refined medial representations of partial tail-segments. Subsequently, these disjoint segments are analyzed and fused to generate complete tails. Based on estimated tail curvatures we reach a classification accuracy of 91% on individual animals as compared to known control treatment. This accuracy is increased to 95% when combining scores for fish in the same well.