Phase I Clinical Trial of Systemically Administered TUSC2(FUS1)-Nanoparticles Mediating Functional Gene Transfer in Humans
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{"title"=>"Phase I Clinical Trial of Systemically Administered TUSC2(FUS1)-Nanoparticles Mediating Functional Gene Transfer in Humans", "type"=>"journal", "authors"=>[{"first_name"=>"Charles", "last_name"=>"Lu"}, {"first_name"=>"David J.", "last_name"=>"Stewart"}, {"first_name"=>"J. Jack", "last_name"=>"Lee"}, {"first_name"=>"Lin", "last_name"=>"Ji"}, {"first_name"=>"Rajagopal", "last_name"=>"Ramesh"}, {"first_name"=>"Gitanjali", "last_name"=>"Jayachandran"}, {"first_name"=>"Maria I.", "last_name"=>"Nunez"}, {"first_name"=>"Ignacio I.", "last_name"=>"Wistuba"}, {"first_name"=>"Jeremy J.", "last_name"=>"Erasmus"}, {"first_name"=>"Marshall E.", "last_name"=>"Hicks"}, {"first_name"=>"Elizabeth A.", "last_name"=>"Grimm"}, {"first_name"=>"James M.", "last_name"=>"Reuben"}, {"first_name"=>"Veerabhadran", "last_name"=>"Baladandayuthapani"}, {"first_name"=>"Nancy S.", "last_name"=>"Templeton"}, {"first_name"=>"John D.", "last_name"=>"McMannis"}, {"first_name"=>"Jack A.", "last_name"=>"Roth"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"1932-6203", "scopus"=>"2-s2.0-84865850008", "pui"=>"365585967", "doi"=>"10.1371/journal.pone.0034833", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "sgr"=>"84865850008", "pmid"=>"22558101"}, "id"=>"a6c18331-6e5c-3904-a54f-0c32a5bc5c2f", "abstract"=>"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 profiling analysis of apoptotic pathway genes in two patients with high post-treatment levels of TUSC2 mRNA and protein showed significant post-treatment changes in the intrinsic apoptotic pathway. Twenty-nine genes of the 82 tested in the apoptosis array were identified by Igenuity Pathway Analysis to be significantly altered post-treatment in both patients (Pearson correlation coefficient 0.519; p<0.01). CONCLUSIONS: DOTAP:chol-TUSC2 can be safely administered intravenously in lung cancer patients and results in uptake of the gene by human primary and metastatic tumors, transgene and gene product expression, specific alterations in TUSC2-regulated pathways, and anti-tumor effects (to our knowledge for the first time for systemic DOTAP:cholesterol nanoparticle gene therapy). TRIAL REGISTRATION: ClinicalTrials.gov NCT00059605.", "link"=>"http://www.mendeley.com/research/phase-i-clinical-trial-systemically-administered-tusc2fus1nanoparticles-mediating-functional-gene-tr", "reader_count"=>46, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>3, "Researcher"=>9, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>19, "Student > Postgraduate"=>1, "Other"=>3, "Student > Master"=>2, "Student > Bachelor"=>6}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>3, "Researcher"=>9, "Student > Doctoral Student"=>3, "Student > Ph. D. Student"=>19, "Student > Postgraduate"=>1, "Other"=>3, "Student > Master"=>2, "Student > Bachelor"=>6}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>3, "Environmental Science"=>1, "Biochemistry, Genetics and Molecular Biology"=>3, "Materials Science"=>2, "Agricultural and Biological Sciences"=>16, "Medicine and Dentistry"=>8, "Pharmacology, Toxicology and Pharmaceutical Science"=>7, "Chemistry"=>2, "Social Sciences"=>1, "Computer Science"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Materials Science"=>{"Materials Science"=>2}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>8}, "Chemistry"=>{"Chemistry"=>2}, "Social Sciences"=>{"Social Sciences"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>16}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Unspecified"=>{"Unspecified"=>3}, "Environmental Science"=>{"Environmental Science"=>1}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>7}}, "reader_count_by_country"=>{"United States"=>2, "Japan"=>1, "India"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/647035"], "description"=>"<p>The patient is a 54 year old female with a large cell neuroendocrine carcinoma. She had received six prior chemotherapy regimens. Prior to entry in the protocol, two hepatic metastases were progressing on gemcitabine. The patient also had a metastasis in the head of the pancreas and a peripancreatic lymph node (arrows). A. Pretreatment PET scan. The dose of Fluorodeoxyglucose(18F) was 8.8mCi B. Post-treatment PET scan performed 20 days following the fourth dose of DC-<i>TUSC2</i>. The dose of Fluorodeoxyglucose(18F) was 9.0mCi. All scans were performed within a 60 to 90 minute window after injection.</p>", "links"=>[], "tags"=>["metabolic", "metastatic", "cancer"], "article_id"=>317510, "categories"=>["Cancer"], "users"=>["Charles Lu", "David J. Stewart", "J. Jack Lee", "Lin Ji", "Rajagopal Ramesh", "Gitanjali Jayachandran", "Maria I. Nunez", "Ignacio I. Wistuba", "Jeremy J. Erasmus", "Marshall E. Hicks", "Elizabeth A. Grimm", "James M. Reuben", "Veerabhadran Baladandayuthapani", "Nancy S. Templeton", "John D. McMannis", "Jack A. Roth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034833.g002", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DC_TUSC2_metabolic_tumor_response_in_a_metastatic_lung_cancer_patient_/317510", "title"=>"DC-<i>TUSC2</i> metabolic tumor response in a metastatic lung cancer patient.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-25 02:05:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/647417"], "description"=>"<p>Abbreviations: ECOG, Eastern Cooperative Oncology Group; NOS, not otherwise specified.</p>", "links"=>[], "tags"=>["characteristics"], "article_id"=>317891, "categories"=>["Cancer"], "users"=>["Charles Lu", "David J. Stewart", "J. Jack Lee", "Lin Ji", "Rajagopal Ramesh", "Gitanjali Jayachandran", "Maria I. Nunez", "Ignacio I. Wistuba", "Jeremy J. Erasmus", "Marshall E. Hicks", "Elizabeth A. Grimm", "James M. Reuben", "Veerabhadran Baladandayuthapani", "Nancy S. Templeton", "John D. McMannis", "Jack A. Roth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034833.t001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Baseline_Characteristics_of_Patients_/317891", "title"=>"Baseline Characteristics of Patients.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-04-25 02:11:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/334585", "https://ndownloader.figshare.com/files/334807", "https://ndownloader.figshare.com/files/335049", "https://ndownloader.figshare.com/files/335121", "https://ndownloader.figshare.com/files/335183", "https://ndownloader.figshare.com/files/335285", "https://ndownloader.figshare.com/files/335351", "https://ndownloader.figshare.com/files/335417"], "description"=>"<div><h3>Background</h3><p>Tumor suppressor gene <em>TUSC2/FUS1 (TUSC2)</em> is frequently inactivated early in lung cancer development. <em>TUSC2</em> 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 <em>TUSC2</em>.</p> <h3>Methods</h3><p>Patients with recurrent and/or metastatic lung cancer previously treated with platinum-based chemotherapy were treated with escalating doses of intravenous <em>N</em>-[1-(2,3-dioleoyloxy)propyl]-<em>N</em>,<em>N</em>,<em>N</em>-trimethylammonium chloride (DOTAP):cholesterol nanoparticles encapsulating a <em>TUSC2</em> expression plasmid (DOTAP:chol-<em>TUSC2</em>) every 3 weeks.</p> <h3>Results</h3><p>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 <em>TUSC2</em> 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 profiling analysis of apoptotic pathway genes in two patients with high post-treatment levels of TUSC2 mRNA and protein showed significant post-treatment changes in the intrinsic apoptotic pathway. Twenty-nine genes of the 82 tested in the apoptosis array were identified by Igenuity Pathway Analysis to be significantly altered post-treatment in both patients (Pearson correlation coefficient 0.519; p<0.01).</p> <h3>Conclusions</h3><p>DOTAP:chol-<em>TUSC2</em> can be safely administered intravenously in lung cancer patients and results in uptake of the gene by human primary and metastatic tumors, transgene and gene product expression, specific alterations in <em>TUSC2</em>-regulated pathways, and anti-tumor effects (to our knowledge for the first time for systemic DOTAP:cholesterol nanoparticle gene therapy).</p> <h3>Trial Registration</h3><p>ClinicalTrials.gov <a href=\"http://www.clinicaltrials.gov/ct2/show/NCT00059605\">NCT00059605</a></p> </div>", "links"=>[], "tags"=>["systemically", "administered", "mediating", "humans"], "article_id"=>126096, "categories"=>["Cancer"], "users"=>["Charles Lu", "David J. Stewart", "J. Jack Lee", "Lin Ji", "Rajagopal Ramesh", "Gitanjali Jayachandran", "Maria I. Nunez", "Ignacio I. Wistuba", "Jeremy J. Erasmus", "Marshall E. Hicks", "Elizabeth A. Grimm", "James M. Reuben", "Veerabhadran Baladandayuthapani", "Nancy S. Templeton", "John D. McMannis", "Jack A. Roth"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0034833.s001", "https://dx.doi.org/10.1371/journal.pone.0034833.s002", "https://dx.doi.org/10.1371/journal.pone.0034833.s003", "https://dx.doi.org/10.1371/journal.pone.0034833.s004", "https://dx.doi.org/10.1371/journal.pone.0034833.s005", "https://dx.doi.org/10.1371/journal.pone.0034833.s006", "https://dx.doi.org/10.1371/journal.pone.0034833.s007", "https://dx.doi.org/10.1371/journal.pone.0034833.s008"], "stats"=>{"downloads"=>35, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Phase_I_Clinical_Trial_of_Systemically_Administered_TUSC2_FUS1_Nanoparticles_Mediating_Functional_Gene_Transfer_in_Humans/126096", "title"=>"Phase I Clinical Trial of Systemically Administered <em>TUSC2(FUS1)-</em>Nanoparticles Mediating Functional Gene Transfer in Humans", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-04-25 01:41:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/646929"], "description"=>"<p>Consort style flowchart of participants through the study.</p>", "links"=>[], "tags"=>["flowchart"], "article_id"=>317405, "categories"=>["Cancer"], "users"=>["Charles Lu", "David J. Stewart", "J. Jack Lee", "Lin Ji", "Rajagopal Ramesh", "Gitanjali Jayachandran", "Maria I. Nunez", "Ignacio I. Wistuba", "Jeremy J. Erasmus", "Marshall E. Hicks", "Elizabeth A. Grimm", "James M. Reuben", "Veerabhadran Baladandayuthapani", "Nancy S. Templeton", "John D. McMannis", "Jack A. Roth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034833.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Consort_style_flowchart_of_participants_through_the_study_/317405", "title"=>"Consort style flowchart of participants through the study.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-25 02:03:25"}
  • {"files"=>["https://ndownloader.figshare.com/files/647176"], "description"=>"<p>A synthetic oligopeptide (GASGSKARGLWPFASAA) derived from the N-terminal amino-acid sequence of the TUSC2 protein was used to develop the anti-TUSC2 polyclonal antibody in rabbits used in this study. Red denotes TUSC2 positivity. DAPI nuclear staining is blue. All panels represent overlays of TUSC2 antibody and DAPI staining. Detailed methods are provided in the <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0034833#pone.0034833.s001\" target=\"_blank\">Information S1</a>. Pre- and post-treatment biopsies from patients 13, 26, and 31 were tested. Magnification is X40. Panels: (1) anti-TUSC2 antibody; (2) anti-TUSC2 antibody pre-absorbed with non-specific control peptide (NSP); (3) anti-TUSC2 antibody pre-absorbed with TUSC2 peptide (FP); (4) non-specific control antibody; (5) hematoxylin and eosin. Quantitation of PLA signals for pre- and post-treatment samples from patients 13, 26, and 31 (<b>B</b>). The anti-TUSC2 antibody was tested under the conditions described in A). The upper panels show PLA signals from the respective patient biopsies as detected by the anti-TUSC2 antibody with 400× magnification. The lower panel presents quantitative comparisons of six independent fields from each biopsy treated under the specified conditions. TUSC2 expression was significantly increased in post-treatment samples compared to pretreatment samples. TUSC2 expression was not significantly altered by anti-TUSC2 antibody pre-absorption with non-specific control peptide (NSP), but was significantly decreased by pre-absorption with TUSC2 peptide (FP). * p<0.05 compared to corresponding pretreatment sample; ▪ p<0.05 compared to post-treatment samples unabsorbed or pre-absorbed with NSP. All comparisons are by two-tailed unpaired Student's t-test assuming equal variances as determined by F test.</p>", "links"=>[], "tags"=>["proximity", "ligation", "assay", "tusc2", "biopsies"], "article_id"=>317646, "categories"=>["Cancer"], "users"=>["Charles Lu", "David J. Stewart", "J. Jack Lee", "Lin Ji", "Rajagopal Ramesh", "Gitanjali Jayachandran", "Maria I. Nunez", "Ignacio I. Wistuba", "Jeremy J. Erasmus", "Marshall E. Hicks", "Elizabeth A. Grimm", "James M. Reuben", "Veerabhadran Baladandayuthapani", "Nancy S. Templeton", "John D. McMannis", "Jack A. Roth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034833.g003", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_situ_Proximity_Ligation_Assay_PLA_for_TUSC2_protein_in_tumor_biopsies_A_/317646", "title"=>"<i>In situ</i> Proximity Ligation Assay (PLA) for TUSC2 protein in tumor biopsies (A).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-25 02:07:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/647360"], "description"=>"<p>Abbreviations: G3, grade 3; ALT, alanine aminotransferase elevation; SD, stable disease.</p>1<p>This cohort did not receive dexamethasone or diphenhydramine premedications.</p>2<p>reduction in primary tumor size of 14%.</p>3<p>reduction in primary tumor size of 26%.</p>4<p>metabolic response (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0034833#pone-0034833-g003\" target=\"_blank\">Figure 3</a>).</p>*<p>Cohorts used to determine maximum tolerated dose (MTD).</p>", "links"=>[], "tags"=>["oncology"], "article_id"=>317835, "categories"=>["Cancer"], "users"=>["Charles Lu", "David J. Stewart", "J. Jack Lee", "Lin Ji", "Rajagopal Ramesh", "Gitanjali Jayachandran", "Maria I. Nunez", "Ignacio I. Wistuba", "Jeremy J. Erasmus", "Marshall E. Hicks", "Elizabeth A. Grimm", "James M. Reuben", "Veerabhadran Baladandayuthapani", "Nancy S. Templeton", "John D. McMannis", "Jack A. Roth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034833.t002", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Dose_Escalation_Scheme_Toxicities_and_Tumor_Response_/317835", "title"=>"Dose-Escalation Scheme, Toxicities, and Tumor Response.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-04-25 02:10:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/647316"], "description"=>"1<p>Specimens not available.</p>", "links"=>[], "tags"=>["detection", "patients", "receiving"], "article_id"=>317785, "categories"=>["Cancer"], "users"=>["Charles Lu", "David J. Stewart", "J. Jack Lee", "Lin Ji", "Rajagopal Ramesh", "Gitanjali Jayachandran", "Maria I. Nunez", "Ignacio I. Wistuba", "Jeremy J. Erasmus", "Marshall E. Hicks", "Elizabeth A. Grimm", "James M. Reuben", "Veerabhadran Baladandayuthapani", "Nancy S. Templeton", "John D. McMannis", "Jack A. Roth"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034833.t003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Real_Time_RT_PCR_detection_of_TUSC2_gene_expression_in_patients_receiving_DC_TUSC2_/317785", "title"=>"Real Time <i>RT-PCR</i> detection of <i>TUSC2</i> gene expression in patients receiving DC-<i>TUSC2</i>.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-04-25 02:09:45"}

PMC Usage Stats | Further Information

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Relative Metric

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