Abstract
BackgroundTumor 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.MethodsPatients 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.ResultsThirty-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).ConclusionsDOTAP: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 RegistrationClinicalTrials.gov NCT00059605
Highlights
The focus of cancer therapy has shifted from the tissue to the genetic level. [1] Mutations in two major classes of genes, oncogenes and tumor suppressor genes (TSGs), play central roles in the oncogenic process
[3] Intratumoral injection of retroviral or adenoviral vectors expressing the wildtype TSG p53 have been performed in patients with locally advanced nonsmall cell lung cancer (NSCLC) and head and neck cancer. [4,5,6] These studies showed that viral vectors expressing the TSG p53 can be safely injected into tumors repetitively and can mediate tumor regression
Homozygous deletions in the 3p21.3 region in lung cancer cell lines and primary lung tumors have led to the identification of multiple genes with tumor suppressor activity
Summary
The focus of cancer therapy has shifted from the tissue to the genetic level. [1] Mutations in two major classes of genes, oncogenes and tumor suppressor genes (TSGs), play central roles in the oncogenic process. [3] Intratumoral injection of retroviral or adenoviral vectors expressing the wildtype TSG p53 have been performed in patients with locally advanced nonsmall cell lung cancer (NSCLC) and head and neck cancer. Secondary objectives were to assess the expression of TUSC2 following intravenous delivery of DOTAP:chol-TUSC2 in tumor biopsies and assess any anti-cancer activity for DOTAP:chol-TUSC2. This is the first, to our knowledge, systemic gene therapy clinical trial that uses an intravenous nanoparticledelivery system for delivering a tumor suppressor gene expression plasmid We report the first in-human systemic gene therapy clinical trial of tumor suppressor gene TUSC2
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