Jack A. Roth, M.D.
Thoracic & Cardiovascular Surgery
University of Texas MD Anderson Cancer Center
1515 Holcombe Blvd, Unit 1489, FCT19.6025
Houston, TX 77030
United States of America
(713) 404-3154 pager
Gene therapy, molecular biology of lung cancer, targeted cancer therapy, nanotechnology, translational research and application. The major goals of our research effort are to identify critical genes and their products in the lung carcinogenesis pathway and their mechanism of action and to develop novel cancer treatment and prevention strategies targeted to specific genetic abnormalities, the biological hallmarks of cancer, and signaling pathways in lung cancer cells. Our current research activities are focused on understanding the molecular mechanisms of novel tumor suppressor genes recently identified in the human chromosome 3p21.3 region where the genomic and genetic abnormalities are frequently found in a wide spectrum of human cancers including lung and breast cancers and on exploring their therapeutic applications for lung cancers by nanoparticle-mediated gene transfer in vitro, in animal models, and in human clinical trials.We are also interested in using advanced genomics and proteomics approaches to identify signature genes and proteins that are involved in oncogenic and tumor suppressor pathways and associated with sensitivity phenotypes of lung cancer cells to novel experimental therapeutics. Our research activities emphasize an understanding the mechanisms of drug resistance by exploring combination treatment strategies for enhancing therapeutic efficacy and overcoming the drug resistance. Our current laboratory and translational research activities are summarized below.
Functional Characterization of 3p21.3 Tumor Suppressor Genes.
By collaborating with Dr. John Minna at The UT Southwestern Medical Center, Dallas through our Lung Cancer SPORE program, we have studied the effects of 3p21.3 genes on tumor cell proliferation and apoptosis in human lung cancer cells by recombinant adenovirus- and plasmid vector-mediated gene transfer in vitro and in vivo.We found that forced expression of several wild-type 3p21.3 genes include FUS1,101F6, RASSF1, and NPRL2 significantly inhibited tumor cell growth by induction of apoptosis and alteration of cell cycle processes in 3p-deficient NSCLC and SCLC cells and significantly suppressed tumor growth and progression in lung cancer mouse models. Our findings provided the first direct evidence for the tumor suppressing activities of 3p21.3 genes in vitro and in vivo and suggest that multiple contiguous genes in the critical 3p21.3 homozygous deletion region collectively function as a tumor suppressor region.
Development of Novel Vectors and Nanotechnology for Systemic and Targeted Delivery of Therapeutic Genes, siRNA, and Peptides and Molecular Imaging.
We developed Protamine-Adenoviral vector complexes (P-Ads) for efficiently delivering recombinant adenoviral vectors for treatment of human primary lung tumors and lung metastases by either systemic administration or by respiratory inhalation of the aerosolized P-Ad complexes.We developed numerous novel plasmid vectors and DOTAP:Cholesterol- and gold-nanoshell-based nanoparticle delivery systems for tumor-selective and high-efficient delivery of therapeutic genes, siRNAs, and peptides for clinical cancer therapy and for non-invasive molecular imaging and monitoring of gene expression, bio-distribution, and therapeutic efficacy.
Studies of therapeutic efficacy and molecular mechanisms of combination treatment with TUSC2 (FUS1)-nanoparticle and Molecular Targeted Therapeutic Drugs.
We investigated the therapeutic effects of combination treatments with multifunctional DOTAP:Cholesterol (DC)-FUS1 nanoparticles and small molecule tyrosine kinase inhibitors (TKIs), such as EGFR inhibitors gefitinib/erlotinib and ZD6474, Src inhibitor dasatinib and KX2-391, and MEK inhibitor AZD6244, AKT inhibitor MK2206, for enhancing the therapeutic potency of TKIs and overcoming drug resistance in lung cancer cells in vitro and in vivo, We found that that reactivation of wild-type FUS1 by FUS1 nanoparticle-mediated gene transfer into FUS1-deficient and TKI-sensitive or resistant lung cancer cells significantly sensitized their response to TKIs treatment by synergistic induction of apoptosis and inhibition of activities of multiple oncogenic kinases such EGFR, MEK, AKT, PDGFR, c-Kit, Src, and Met in EKFR/ERK/AKT in vitro and in lung cancer mouse models. Our findings suggest a combination treatment with DC-FUS1-nanoparticles and TKIs may be a useful strategy for more effectively treating lung cancer and overcoming drug resistance by simultaneously activating apoptosis and blocking oncogenic kinase signaling pathways.
Translational Application of Intravenous Gene Therapy with Tumor Suppressor TUSC2(FUS1)-Nanoparticles for Advanced Lung Cancer.
We conducted the first in-human systemic gene therapy clinical trial that involves intravenous nanoparticle-delivery of the tumor suppressor gene TUSC2 (FUS1). We showed evidence of uptake of the gene by human primary and metastatic tumors, vector-specific transgene RNA expression, expression of the gene product, specific alterations in TUSC2-regulated pathways, and clinical efficacy. Thirty-one patients with recurrent lung cancer were treated with escalating doses of intravenous DOTAP:cholesterol (DC) nanoparticles encapsulating the TUSC2 expression plasmid. RT-PCR analysis detected high TUSC2 plasmid expression in 6 of 7 post-treatment tumor specimens but not in pretreatment specimens. TUSC2 protein staining in pretreatment tissues was low or absent compared with intense TUSC2 protein staining in post-treatment tissues. RT-PCR gene expression profiling analysis of apoptotic pathway genes showed significant post-treatment changes. Five patients achieved stable disease (2.6-10.8 months, including 2 minor responses). One patient with stable disease had a metabolic response on positron emission tomography (PET) imaging. We have shown for the first time that a functioning TSG can be delivered intravenously to human cancer cells using a nanoparticle vector, express high levels of mRNA and protein in cancer cells in the primary tumor and distant metastatic sites, alter relevant pathways in the cancer cell, and mediate clinically beneficial anti-tumor activity.