title: FLT-PET may not be a reliable indicator of therapeutic response in p53-null malignancy.
abstract: FDG (18F-deoxy-glucose) is the current gold standard for PET imaging. FLT (3'-deoxy-3'-(18F-fluorothymidine), a PET imaging marker of proliferation, has been proposed as an alternative to FDG for the assessment of therapeutic response. We examined the therapeutic predictive value of FLT-PET and FDG-PET using CALU-6, a human, p53-null, non-small cell lung cancer cell line with comparison of combined targeted therapy, TRAIL and sorafenib, versus combined conventional chemotherapy, docetaxel and cisplatin. CALU-6 tumor-bearing nu/nu mice (n=46) were evaluated in 3 therapeutic trials measuring FLT and FDG prediction of tumor response at 72 h following initiation of daily combination therapy with targeted agents, TRAIL (200 µg i.v.) and sorafenib (30 mg/kg i.p.) and compared to conventional chemotherapeutics cisplatin (3 mg/kg i.p.) and docetaxel (7.5 mg/kg i.p.). PET imaging response was compared to morphological and histological indicators of therapeutic response, including decreased vascularity (in vivo AngioSense imaging and anti-CD31 staining), slowed tumor growth (caliper measurements), decreased cellular proliferation (Ki-67 staining) and increased apoptosis (TUNEL staining). Decreases in tumor accumulation of FLT (FLTMAX -30%, p=0.03) at 72 h post treatment were observed in response to TRAIL and sorafenib combination therapy resulting in smaller, less vascular, more apoptotic tumors. No similar reduction in tumor accumulation of FLT (FLTMAX -2%, p=0.67) was observed 72 h following initiation of cisplatin and docetaxel combination therapy, despite histological and morphological evidence of drug response. In contrast, tumor imaging with FDG did demonstrate a decrease in accumulation in both treatment groups, -21% (p=0.30) in response to cisplatin/docetaxel and -8% (p=0.59) in response to TRAIL/sorafenib, but did not reach statistical significance. FLT, but not FDG, is predictive of therapeutic response to the targeted regimen TRAIL/sorafenib. However, FLT-PET may not predict therapeutic response to DNA damaging agents in p53-null tumors, likely due to loss of cell cycle control of thymidine kinase 1 (TK1). Thus, tumor imaging response by FLT may be limited in human tumors without functional p53.
authors.affiliation: Department of Radiology, University of Pennsylvania School of Medicine, 1 Silverstein Building, 3400 Spruce Street, Philadelphia, PA 19104, USA. sharyn.katz@uphs.upenn.edu
authors.forename: Sharyn I
authors.initials: SI
authors.lastname: Katz
authors.forename: Lanlan
authors.initials: L
authors.lastname: Zhou
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Ferrara
authors.forename: Wenge
authors.initials: W
authors.lastname: Wang
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Mayes
authors.forename: Charles D
authors.initials: CD
authors.lastname: Smith
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001557:Benzenesulfonates / Q000494:pharmacology / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004195:Disease Models, Animal; D005462:Fluorine Radioisotopes / Q000378:metabolism / Q000592:standards; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D049268:Positron-Emission Tomography / Q000592:standards; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D000077157:Sorafenib; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D005462:Fluorine Radioisotopes; D010671:Phenylurea Compounds; D011725:Pyridines; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; D019788:Fluorodeoxyglucose F18; D009536:Niacinamide; D000077157:Sorafenib; D002945:Cisplatin