It is our working hypothesis that mutations and altered expression of RB, p53, and PTEN, or those affectingregulatory genes involved in these pathways, produce a selective advantage for tumor growth andaggressive behavior in patients with soft tissue sarcomas (STS). This hypothesis will be tested by anintegrated approach, analyzing human tumor samples and conducting genetic studies that includegeneration of in vitro and in vivo models.
Aim 1. To define the clinical and biological implications of RBinactivation for proliferation and genomic stability in STS. We will characterize RB mutations, altered patternsof pRB and E2F1 expression, as well as upstream regulators (cyclin D, Cdk4). We will also assess Mad2expression, an E2F1 transcriptional target that when deregulated causes chromosome instability andaneuploidy. We will assess the consequences of RB inactivation, identifying up- and down-regulated targetsby high throughput studies.
Aim 2. To characterize molecular alterations affecting the p53 pro-apoptoticresponse and define their clinical significance in STS. We will conduct a systematic characterization of TP53mutations and p53 expression using a combination of methods. We will analyze regulatory events of the p53pathway, focusing on Hdm2 and p14/Arf expression. We will study p53 apoptotic signaling, centering on Baxand Bcl-2, PUMA and NOXA, defining their impact on tumor progression and lack of response to particulartreatments. The mechanistic consequences of p53 inactivation will be evaluated using functional assays.
Aim 3. To determine the molecular mechanisms of tumor suppression by the Pten pathway in STS. We willestablish the clinical relevance of detecting PTEN mutations and altered Pten expression. We will investigatethe impact of downstream events, such as activation of Akt, mTOR and elF4E, as they participate insarcomagenesis and STS progression. In addition, we are generating murine models to determine whetherinactivation of Rb, p53 and Pten are required and cooperate for sarcoma development and progression. Ourmain objectives include: i) to assess the basis of the functional crosstalk between RB, p53, and PTENpathways in tumor suppression; and ii) to translate basic and medical research findings into clinically appliedstudies. Our final translational goal is to produce a paradigm shift in clinical practice by incorporatingbiomarkers as robust decision tools to better guide the management of STS patients.
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