IMAGING MDR CHEMOTHERAPY EFFECT IN SMALL CELL LUNG CANCER

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer related death in the United States. Approximately 20% of patients with newly diagnosed lung cancer have the small cell histological type (SCLC). Even though it is more responsive to chemotherapy, nearly all patients with extensive stage small cell lung cancer succumb to recurrent disease. Overexpression of the multidrug resistance gene (MDR1) and its protein product P-glycoprotein (Pgp) as well as the multidrug resistance-associated protein-1 (MRP1) have been shown to result in poor response to therapy and shorter survival in SCLC when compared to those whose tumors do not overexpress these MDR determinants. Because many of the drugs in current use are impacted by Pgp and MRP1 (i.e., etoposide, paclitaxel, anthracyclines, vincristine), it is conceivable that administration of these chemotherapeutic agents may contribute to the emergence of drug resistance clones, ultimately contributing to poor outcomes. Thus, functional identification of Pgp, and perhaps MRP1, at the time of presentation could provide important information which could direct the choice of chemotherapeutic options. We have discovered that Tc-99m-Sestamibi, a commercially available radiopharmaceutical, is recognized as a transport substrate by the human MDR1 P-glycoprotein in vitro and in vivo and may be recognized by MRP1. Thus, Tc-99m-Sestamibi may serve as a molecular imaging agent enabling functional identification of transporter-mediated resistance by scintigraphy. However, single photon agents such as Tc-99m-Sestamibi, while yielding high quality images for analysis of superficial tissues such as breast tumors, are prone to attenuate artifacts when applied to lesions deep in the thorax such as lung tumors. At Washington University, the cyclotron Research Resource can produce a variety of non-standard isotopes, including Tc-94m, a novel isotope suitable for positron emission tomography (PET). Thus, the WU ICMIC has an unique opportunity to directly translate our extensive biochemical and clinical experience with Tc-99m-Sestamibi imaging of MDR into novel PET studies with Tc-94m-Sestamibi. Exploiting the quantitative advantages of PET in this project, we propose to use Tc-94m-Sestamibi PET to image patients with extensive stage SCLC. We propose to test the hypothesis that dynamic imaging of lung tumors with Tc-94m-Sestamibi will predict treatment failure in patients with extensive stage small cell lung cancer and determine whether Pgp and MRP1 together or independently impact Tc-94m-Sestamibi pharmacokinetics in lung tumors in vivo. Molecular imaging of the MDR phenotype with radiopharmaceuticals may provide a novel tool to rapidly characterize clinically relevant MDR in human tumors in vivo, target MDR modulators in vivo, and ultimately provide a means to direct patients to molecular-specific cancer therapies.