Abstract IA2: Developing therapeutics using the zebrafish

Abstract

Abstract The zebrafish is a wonderful disease model, and it is now possible to develop new therapies to treat human disease. A screen for blood stem cells in the developing aorta led to the discovery of PGE2 as a regulator of stem cell engraftment. After studies with mouse and human hematopoietic cells, a clinical trial proceeded to test PGE2 in cord blood transplantation. In 12 leukemic patients receiving 2 cord blood units, one treated with dmPGE2, 10 patients engrafted with the treated cord blood. The neutrophils and platelets recovered more quickly than the untreated cord blood. Another chemical, leflunomide, was found in zebrafish to block neural crest development. Leflunomide also suppressed neural crest gene transcription in human melanomas, and reduced the rate of human tumor formation in mouse xenografts. The effect was stronger in combination with a BRAF inhibitor known to block cell proliferation. This has led to a clinical trial in which 43 patients will be treated for metastaic melanoma. To date, three patients have been treated. In another example, a chemical suppressor screen was done on the rps29 mutant that resembles Diamond Blackfan anemia. Calmodulin antagonists rescue the defect in hematopoiesis. These antagonists also rescue the hematopoietic block found in human CD34 cells treated with an shRNA to rps19. This suggests that calmodulin antagonists could be used to treat patient with Diamond Blackfan anemia. The zebrafish offers an excellent opportunity to find new therapeutics. Citation Format: Leonard I. Zon. Developing therapeutics using the zebrafish. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA2.