Molecular Diagnostics & Therapeutics
Translational Research Laboratory
Project 1. Previously our laboratory clearly demonstrated that Bcl-2 over expression in prostatic tumors were associated with radiation resistance. Down regulation of Bcl-2 by viral gene therapy or small molecule inhibitors sensitized these tumors (in vitro and in vivo) to the effects of radiation. In these same experiments our laboratory discovered that tumoral Bcl-2 expression was associated with increased vascular endothelial growth factor (VEGF) expression and angiogenesis. In vitro studies confirmed that VEGF can not only increase proliferation of endothelial cells, but can increase expression of Bcl-2 in endothelial cells and stabilize Bcl-2 mRNA. Furthermore, Bcl-2 expression is regulated by several pathways (e.g., mTOR, PI3K, PKC, ERK).
Endothelial cells subjected to the environment of a Bcl-2 expressing tumor possess a unique molecular profile. Currently we are studying the effect of VEGF on the Bcl-2 promoter and we are further exploring the molecular profile of endothelial cells from Bcl-2 expressing tumors.
In addition we are close to opening a neoadjuvant clinical trial combining a small molecule inhibitor of Bcl-2 with bevazicumab in subjects with localized high-risk prostate cancer.
Project 2. Much attention has turned to the association of infection and carcinogenesis. My laboratory has demonstrated a strain of Mycoplasma to be associated with prostate cancer.
In addition a novel protein (p37) to this Mycoplasmal strain can: generate a unique molecular profile, increase the invasive nature, produce significant changes in proliferation and morphology in in vitro assays that are indicative of a more aggressive phenotype. Currently we are investigating the incidence of this infectious organism in normal subjects and subjects with prostate cancer and exploring the mechanism by which Mycoplasma inducing carcinogenesis/progression.
Project 3. Bladder cancer continues to be a major care to our healthcare system. Specifically individuals with non-invasive bladder cancer are routinely managed conservatively and will be monitored by routine visual bladder inspection.
We hope to identify a panel of genes indicative of bladder cancer that may be used to screen or surveil for bladder cancer in a non-invasive manner. We have preliminary results of a unique molecular profile identified in the urine of subjects with bladder cancer. Currently we are prospectively validating our panel of tumor-associated genes in a large cohort of diverse individuals.
Rosser CJ, Reyes AO, Vakar-Lopez F, Levy LB, Kuban DA, Hoover DC, Lee AK, Pisters LL.Bcl-2 is significantly overexpressed in localized radio-recurrent prostate carcinoma compared to localized radio-naive prostate carcinoma. Int J Radiat Oncol Biol Phys 56(1): 1-6, 2003.
Anai S, Goodison S, Shiverick K, Iczkowski K, Tanaka M, Rosser CJ. Combination of PTEN gene therapy and radiation inhibits the growth of human prostate cancer xenografts. Hum Gene Ther 2006 Oct;17(10):975-84.
Anai S, Goodison S, Shiverick K, Hirao Y, Brown BD, Rosser CJ. Knock-down of Bcl-2 by antisense oligodeoxynucleotides induces radiosensitization and inhibition of angiogenesis in human PC-3 prostate tumor xenografts. Mol Cancer Ther 2007 6: 101-111.
Ketcham CM, Anai S, Reutzel R, Sheng S, Schuster SM, Brenes RB, Agbandje-McKenna M, McKenna R, Rosser CJ, Boehlein SK.P37 induces tumor invasiveness. Mol Cancer Ther 2005 Jul;4(7):1031-8.
Kreunin P, Zhao J, Rosser CJ, Urquidi V, Lubman DM, Goodison S. Bladder Cancer Associated Glycoprotein Signatures revealed by Urinary Proteomic Profiling. J Proteome Res 2007 Jul;6(7):2631-9.