Our research is aimed at developing a better understanding of cancer biology and creating an improved gene-based therapy by exploiting special properties of the adenovirus. We have utilized the efficient gene transfer property of adenovirus to create improved, tissuetargeted therapeutic strategies for cancer. By applying this targeted gene-expression approach to molecular imaging, metastatic lesions were detected in living tumor-bearing mice. Transcriptional targeted approaches are being developed to express the different therapeutic genes and imaging genes in prostate and breast cancer models. In a second strategy, we are exploiting the distributive property of the adenovirus and use it to investigate tumor vasculatures and cancer metastasis. As a third strategy, the viral replication property is usurped to create cancer-specific lysis. Molecular imaging techniques such as optical CCD imaging and positron emission tomography (PET) are fundamental tools of our investigation. Our ultimate goal is to create a potent and effective cancer-targeted gene therapy to diagnose and treat advanced stage and metastatic cancer.
Cancer-targeted Gene Therapy and Imaging
Cancer-targeted Gene Therapy and Imaging Our laboratory is focused on development of effective gene therapy protocol from the basic molecular and virology research at the bench level to ultimately apply to treat cancer patients. Current ongoing research topics are: 1. Improving tissue- and cancer-specific gene expression at the transcriptional level. We have developed several strategies to augment the activity of tissue-specific promoters, using the prostate-specific PSA promoter as our initial model system. One of the most potent approach termed two-step transcriptional activation (TSTA) displays 1000-fold higher activity than native PSA promoter while retaining androgen regulation and cell-specificity. Besides prostate-specific promoters, cancer-specific promoters, breast-specific promoters and vascular growth factor promoters are being investigated. 2. Transcriptionally-targeted gene therapy. The approaches developed in topic 1 will be utilized in therapeutic strategies. Current cancer-directed therapeutic strategies under investigation include expression of cytotoxic genes (HSV-tk and TRAIL), anti-angiogenic genes (TSP-1 and METH-1), cell-cycle control gene (p27) and oncolytic viruses. 3. Cancer-targeted molecular imaging. Non-invasive imaging techniques such as optical charge coupled device (CCD) imaging, micro-Positron Emission Tomography (PET) and microCT are applied to monitor vector-based gene expression in vivo. These molecular imaging approaches will be coupled to gene therapy developed in topic 2. 4. Cancer metastasis and tumor vasculature. Non-invasive imaging is being applied to facilitate the monitoring of the metastatic process in living animal. Active investigation is underway to delineate the contribution tumor blood and lymphatic vessels to cancer metastasis. The goal is to develop better therapy to manage this advanced stage of cancer through a better understanding of tumor and vascular biology.
- Jiang Z.K., Sato M., Wei L.H., Kao C., Wu L., “Androgen-independent molecular imaging vectors to detect castration-resistant and metastatic prostate cancer,” Cancer Res. 2011 Oct 1;71(19):6250-60. Epub 2011 Sep 20.
- Pouliot F., Karankikolas B.D., Johnson M., Sato M., Priceman S.J., Stout D., Sohn J., Satyamurthy N., deKernion J.B., Wu L., “In vivo imaging of intraprostatic-specific gene transcription by PET,” J Nucl Med. 2011 May;52(5):784-91. Epub 2011 Apr 15.
- Chen K.J., Wolahan S.M., Wang H., Hsu C.H., Chang H.W., Durazo A., Hwang L.P., Garcia M.A., Jiang Z.K., Wu L., Lin Y.Y. Tseng H.R., “A small MRI contrast agent library of gadolinium(III)-encapsulated supramolecular nanoparticles for improved relaxivity and sensitivity,” Biomaterials. 2011 Mar;32(8):2160-5. Epub 2010 Dec 16.
- Liu H., Wu L., Zhou Z.H., “Model of the trimeric fiber and its interactions with the pentameric penton base of human adenovirus by cryo-electron microscopy,” J Mol Biol. 2011 Mar 11;406(5):764-74. Epub 2010 Dec 10.
- Sloan E.K., Priceman S.J., Cox B.F., Yu S., Pimentel M.A., Tangkanangukul V., Arevalo J.M., Morizono K., Karanikolas B.D., Wu L., Sood A.K., Cole S.W., “The sympathetic nervous system induces a metastatic switch in primary breast cancer,” Cancer Res. 2010 Sep 15.70(18):7042-52. Epub 2010 Sep 7.
- Liu H., Jin L., Koh S.B., Atansasov I., Schein S., Wu L., Zhou Z.H., “Atomic structure of human adenovirus by cryo-EM reveals interactions among protein networks,” Science. 2010 Aug 27;329(5995):1038-43.
- Imaizumi S., Grijalva V., Priceman S., Wu L., Su F., Farias-Eisner R., Hama S., Navab M., Fogelman A.M., Reddy S.T., “Mitogen-activated protein kinase phosphatase-1 deficiency decreases atherosclerosis in apolipoprotein E null mice by reducing monocyte chemoattractant protein-1 levels,” Mol Genet Metab. 2010 Sep;101(1):66-75. Epub 2010 Jun 9.
- Karanikolas B.D., Figueiredo M.L., Wu L., “Comprehensive evaluation of the role of EZH2 in the growth, invasion, and aggression of a panel of prostate cancer cell lines,” Protate. 2010 May 1;70(6):75-88.
- Priceman S.J., Sung J.L., Shaposhnik Z., Burton J.B., Torres-Collado A.X., Moughon D.L., Johnson M., Lusis A.J., Cohen D.A., Iruela-Arispe M.L., Wu L., “Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy,” Blood. 2010 Feb 18.115(7):1461-71. Epub 2009 Dec 11.
- Yan M., Du J., Gu Z., Liang M., Hu Y., Zhang W., Priceman S., Wu L., Zhou Z.H., Liu Z., Segura T., Tang Y., Lu Y., “A novel intracellular protein delivery platform based on single-protein nanocapsules,” Nat Nanotechnol. 2010 Jan;5(1):48-53. Epub 2009 Nov 22.