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Zebrafish Functional Genetics Approach to the Pathogenesis of Well-Differentiated Liposarcoma

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Technical Report,15 Sep 2013,14 Sep 2015

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Children's Hospital Corporation Boston United States

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Well-differentiated liposarcoma is the most common human sarcoma, and exposure to Agent Orange or radiation are keypredisposing factors. However, the pathobiology of this disease is very poorly understood, and there are no effective therapies for patientswith unresectable disease. Almost all tumors have amplifications of multiple genes located on chromosome 12q, but the lack of animalmodels previously made it impossible to define the key driver oncogenes within these amplicons. Our overarching hypothesis is thatdefining the oncogenes driving selection for 12q amplifications in well-differentiated liposarcoma will reveal highly productive moleculartargets for therapeutic intervention. During this award, we performed all work proposed under Aim 1 of our original proposal to test thehypothesis that FRS2 is a 12q oncogene that activates oncogenic signal transduction, using FRS2 overexpression in geneticallyengineered zebrafish models and in normal human preadipocytes. Aim 2 was also completed, and demonstrates that MDM2, CDK4 andHMGA2 are bona fide liposarcoma oncogenes and licensed therapeutic targets. This work provides a compelling rationale for testing smallmolecule inhibitors of these oncogenes in patients with well-differentiated liposarcoma, for whom there are currently no effective medicaltherapies.

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