Mechanisms of Resistance in Sarcoma

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Adult soft tissue sarcomas are frequently described as unusual, heterogeneous and difficult to treat malignancies. Many patients initially respond to pre-operative neo-adjuvant chemotherapy and experience better long-term survival, but response assessment is difficult, and delayed until tumor resection. Sarcoma neoadjuvant chemotherapy is based on the use of anthracyclines in combination with other active drugs such as ifosphamide and cis-platin. Our objective in this new project is to define early response patterns in pre-operative chemotherapy using PET imaging methods with specific tracers designed to assess important processes in sarcoma treatment resistance: tumor proliferation, hypoxic volume, and activity of the p-glycoprotein (P-gp) pump as factors in drug resistance. Imaging data from these studies will also be analyzed for ability to predict patient outcome. Sarcomas are notoriously hypoxic, which confers significant treatment resistance to chemo- and radiotherapy regimens. They also have variable levels of P-gp pump activity which is a mechanism that can increase drug effiux from tumor and reduce therapeutic effectiveness. We will use [11C]thymidine as a specific agent to quantitate tumor cell proliferation as a sensitive and specific measure of response prior to initiation of neoadjuvant chemotherapy, after one cycle of treatment (the first of four cycles given pre-operatively), and again prior to resection. Specifically, we will identify early changes in tumor proliferation as evidence of response. Building on our previous experience imaging sarcomas with [18F]fluoromisonidazole, we will quantitate the tumor hypoxic volume prior to treatment and correlate image derived data will tissue based laboratory assays of specific markers that relate to hypoxia, such as HIF-1alpha and VEGF expression. A new imaging agent for the P-gp pump drug efflux, [11C]verapamil, will also be used in this study. Patients will be imaged with [11C]verapamil at the same imaging times as proposed for [11C]thymidine, to quantitate levels of P-gp pump activity. Surgical samples from patient tumors in this project will be analyzed by gene microarray analysis for gene clustering patterns relevant to the processes of cell proliferation control, tissue hypoxia response, and P-gp pump activity. In this series of proposed studies, we will make critical quantitative PET derived imaging observations on specific aspects of sarcoma biology to identify early response of the tumor to treatment, mechanisms of treatment resistance, and the ability to predict patient outcome.