Molecular Analysis of Proliferative and Apoptotic Pathways in Soft Tissue Sarcoma

Sloan-Kettering Inst Can Research, New York NY

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Abstract

It is our working hypothesis that mutations and altered expression of RB, p53, and PTEN, or those affecting[unreadable] regulatory genes involved in these pathways, produce a selective advantage for tumor growth and[unreadable] aggressive behavior in patients with soft tissue sarcomas (STS). This hypothesis will be tested by an[unreadable] integrated approach, analyzing human tumor samples and conducting genetic studies that include[unreadable] generation of in vitro and in vivo models. Aim 1. To define the clinical and biological implications of RB[unreadable] inactivation for proliferation and genomic stability in STS. We will characterize RB mutations, altered patterns[unreadable] of pRB and E2F1 expression, as well as upstream regulators (cyclin D, Cdk4). We will also assess Mad2[unreadable] expression, an E2F1 transcriptional target that when deregulated causes chromosome instability and[unreadable] aneuploidy. We will assess the consequences of RB inactivation, identifying up- and down-regulated targets[unreadable] by high throughput studies. Aim 2. To characterize molecular alterations affecting the p53 pro-apoptotic[unreadable] response and define their clinical significance in STS. We will conduct a systematic characterization of TP53[unreadable] mutations and p53 expression using a combination of methods. We will analyze regulatory events of the p53[unreadable] pathway, focusing on Hdm2 and p14/Arf expression. We will study p53 apoptotic signaling, centering on Bax[unreadable] and Bcl-2, PUMA and NOXA, defining their impact on tumor progression and lack of response to particular[unreadable] treatments. The mechanistic consequences of p53 inactivation will be evaluated using functional assays.[unreadable] Aim 3. To determine the molecular mechanisms of tumor suppression by the Pten pathway in STS. We will[unreadable] establish the clinical relevance of detecting PTEN mutations and altered Pten expression. We will investigate[unreadable] the impact of downstream events, such as activation of Akt, mTOR and elF4E, as they participate in[unreadable] sarcomagenesis and STS progression. In addition, we are generating murine models to determine whether[unreadable] inactivation of Rb, p53 and Pten are required and cooperate for sarcoma development and progression. Our[unreadable] main objectives include: i) to assess the basis of the functional crosstalk between RB, p53, and PTEN[unreadable] pathways in tumor suppression; and ii) to translate basic and medical research findings into clinically applied[unreadable] studies. Our final translational goal is to produce a paradigm shift in clinical practice by incorporating[unreadable] biomarkers as robust decision tools to better guide the management of STS patients.