Phase I Clinical Trial of Systemically Administered TUSC2(FUS1)-Nanoparticles Mediating Functional Gene Transfer in Humans

作者：Charles Lu, David J. Stewart, J. Jack Lee, Lin Ji, Rajagopal Ramesh, Gitanjali Jayachandran, Maria Ines Nunez, Ignacio Ivan Wistuba, Jeremy J. Erasmus, Marshall E. Hicks, Elizabeth Ann Grimm, James M. Reuben, Veerabhadran Baladandayuthapani, Nancy Smyth Templeton, John D. McMannis, Jack A. Roth · 发表于：PLoS ONE · 年份：2012 · DOI：10.1371/journal.pone.0034833 · 被引用次数：186 · 研究领域：Cell death mechanisms and regulation、Cancer Research and Treatments、Phagocytosis and Immune Regulation

BACKGROUND: Tumor suppressor gene TUSC2/FUS1 (TUSC2) is frequently inactivated early in lung cancer development. TUSC2 mediates apoptosis in cancer cells but not normal cells by upregulation of the intrinsic apoptotic pathway. No drug strategies currently exist targeting loss-of-function genetic abnormalities. We report the first in-human systemic gene therapy clinical trial of tumor suppressor gene TUSC2. METHODS: Patients with recurrent and/or metastatic lung cancer previously treated with platinum-based chemotherapy were treated with escalating doses of intravenous N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP):cholesterol nanoparticles encapsulating a TUSC2 expression plasmid (DOTAP:chol-TUSC2) every 3 weeks. RESULTS: Thirty-one patients were treated at 6 dose levels (range 0.01 to 0.09 milligrams per kilogram). The MTD was determined to be 0.06 mg/kg. Five patients achieved stable disease (2.6-10.8 months, including 2 minor responses). One patient had a metabolic response on positron emission tomography (PET) imaging. RT-PCR analysis detected TUSC2 plasmid expression in 7 of 8 post-treatment tumor specimens but not in pretreatment specimens and peripheral blood lymphocyte controls. Proximity ligation assay, performed on paired biopsies from 3 patients, demonstrated low background TUSC2 protein staining in pretreatment tissues compared with intense (10-25 fold increase) TUSC2 protein staining in post-treatment tissues. RT-PCR gene expression profil...