The objective of the proposed studies is the continued characterization of mutations and aberrant patterns of expression of cell cycle regulators as they rate to tumorigenesis and tumor progression in adult soft tissue sarcomas (STS). Our working hypothesis has been that mutations and altered expression of the TP53 and RB genes produce a selective advantage for tumor growth and aggressive behavior in STS patients. Their critical role requires stringent multi-level regulation by other factors such as cyclins, cyclin-dependent kinases (Cdk), and cyclin-dependent kinase inhibitors (Cki). Studies of these regulators are a logical extension of our previous work. The main goal of our project is to translate basic and clinical research findings into clinical studies.
The Specific Aims are outlined as follows:
Aim #1. Prognostic Significance of TP53 and RB in Adult Soft Tissue Sarcomas: Molecular and Functional Analyses.
This aim i s divided into two studies. In Study A we plan to: 1) prospectively validate the prognostic value of TP53 and RB; 2) determine the functional significance of different TP53 mutations; 3) determine the molecular basis of altered pRB expression and relating E2F levels with response to chemotherapy. In Study B we will determine if particular STS subtypes have specific molecular """"""""signatures"""""""" with respect to p53 and pRB.
Aim #2. Molecular Characterization of the p53-Pathway: Impact on Cell Cycle Arrest and Apoptosis. We will determine: 1) the clinical relevance of altered patterns of p21 expression; 2) the proportion of STS that over- express mdm2 by lack MDM2 amplification; 3) the proportion of STS cases that over-express mdm2 but do not express p19/ARF; and 4) the potential clinical impact of joint p53 and mdm2 alterations.
Aim #3. Molecular Characterization of the RB-Pathway: Impact on S- Phase Entry and Proliferation. We will determine: 1) the frequency, clinical significance, and nature of pRB over-expression; 2) the mutation frequency of INK4A in STS, and if these mutations involve p16, p19/ARF, or both; 3) the proportion of cases that over-express cyclin D1 and Cdk4, and what proportion is due to gene amplifications; 4) the frequency of co-amplification of CDK4 and MDM2; and 5 ) the frequency and potential clinical relevance of detecting altered expression patterns of E2F proteins (mainly E2F1, E2F4, and E2F5).
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