Research component 3 will focus on molecular imaging directed diagnosis and interrogation of human soft tissue sarcomas (STS) in the clinic and in new murine model. STS are a heterogeneous group of connective tissue tumors that comprise about 1 percent of aduit and 15 percent of pediatric malignancies. Non-invasive molecular imaging has become an effective modality to monitor therapeutic responses in human malignancies. Our recent studies have demonstrated this approach to be important in the management of certain histologic subtypes of STS. Our long-term goal is to apply existing imaging modalities and investigate novel molecular/metabolic imaging tools to direct and monitor targeted therapies in the context of cleariy defined pathway lesions in patients with STS. Our original finding that PTEN loss and increased FDG uptake correlate with the malignant transformation of benign neurofibromas (NF) to malignant peripheral nerve sheath tumors (MPNST) in both our mouse model and in human patients makes a compelling case for (i) the essential role of the PTEN/P13K/AKT pathway in controlling the benign to malignant transformation of NFs and (ii) the use of FDG-PET imaging to non-invasively infer the status of this pathway.
In Aim 1 we will use FDG-PET imaging to assess the PTEN/PI3K/AKT oncogenic pathways status and monitor the response to targeted combination treatments in our genetically engineered mouse model, in a direct-to-host xenograft model and in patients with MPNST.
In Aim 2 we will focus our investigation on those malignant STS, such as liposarcoma, which have low FDG uptake (low glycolytic activity) despite being clinically high grade. We reason that malignant tumors with these low glycolytic phenotypes may rely on carbon sources other than glucose for their continuous proliferation. We will conduct a comprehensive analysis of these tumors by interrogating our liposarcoma FDG-PET, SNP and mRNA array data sets. Our objective is to identify those signatures of malignancy that are independent of FDG signatures. We will then investigate other upregulated metabolic pathways associated with these FDG-independent malignant signatures. Understanding these pathways will enable us to design new strategies for their molecular imaging and targeted therapy.
The prognosis of patients with locally advanced and metastatic soft tissue sarcoma remains poor, with a 5 year survival of less than 10%. Surgical resection remains the only potentially curative treatment option and new therapeutic strategies are urgently needed. Non-invasive molecular/metabolic imaging provides an opportunity to direct, monitor and develop novel targeted therapies for patients with this lethal malignancy.
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