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Raymond Rackley, M.D.
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Area of general research interest:
Translational research (Interstitial Cystitis, Urinary Tract Infections and Bladder Cancer) of the role of normal and aberrant signal transduction pathways in the elucidation of pathophysiological changes of the bladder urothelium and smooth muscle.
Current programs:
- Defining the NF- k B pathway in normal and abnormal urothelial conditions of the bladder as it may relate to the immuno/inflammatory regulation and dysfunction in Interstitial Cystitis
- Defining the JAK-STAT pathway in normal and abnormal urothelial conditions of the bladder as it may relate to the genesis and therapeutic interventions for the treatment of bladder cancer
- Developing telomerase immortalized somatic genitourinary cell lines for molecular research studies of the genitourinary tract
- Cancer Biology: Genetic expression, mutational studies, and cytokine research of urologic diseases
Investigators:
- Mei Kuang, M.S., Senior Research Technologist
Collaborators:
- Joseph DiDonato, PhD, Department of Cancer Biology, The Cleveland Clinic Foundation, Cleveland, OH
- Ratan Maitra, PhD, Director of the Viral Core Facility, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH
Brief Description:
Translating Basic Science into Clinical Therapies for Interstitial Cystitis Patients
Information transfer from the cellular membrane to the nucleus involves several well-characterized molecular signaling pathways that lead to transcriptional activation. One of these, the NF-kB (nuclear factor-kB) signaling pathway, regulates host inflammatory/immune responses and cellular growth properties by increasing the expression of specific cellular genes. Found in essentially all cell types, NF-kB is a collective name for inducible nuclear transcription factors that are involved in the activation of an exceptionally large number of genes in a cellular response to inflammation, infection, and other stressful cellular situations requiring rapid reprogramming of gene expression. The exact etiologies of Interstitial Cystitis (IC), a chronic debilitating inflammatory condition of the bladder compounded by acute flares, remain elusive and thus limit the development of successful treatment options. While several etiologies of IC have been proposed that are similar to the known activators of NF-kB, urine markers of Interstitial Cystitis disease have been recently found that may be under NF-kB regulation. We hypothesize that the NF-kB signaling pathway is the essential inflammatory/immunoregulatory mechanism for the pathogenesis of the inflammatory response of the bladder in Interstitial Cystitis and that regardless of the etiology(s), therapeutic manipulations of this signaling pathway represent a viable treatment option for patients with this condition.
Interferon-ing with Bladder Cancer
Interferons (IFNs) are known to have a variety of biological activities including antitumor, antiviral, and immunomodulatory effects. IFN- a therapy has in general proven to be beneficial for many superficial bladder cancers but some tumors do not respond well to this form of therapy. Interferons were initially discovered as antiviral compounds and many viruses have evolved strategies to inhibit the action of IFNs. Like many viruses, some malignant cells may have the capabilities of inhibiting the action of interferon either by altered expression of essential components of IFN-alpha signaling molecules or by expressing proteins which interfere with IFN- alpha signaling molecule(s).
In clinical trials, intravesical IFN-alpha therapy has proven beneficial for treating bladder cancer but unfortunately therapy has failed for a significant percentage of patients. The reason for the IFN-alpha therapy resistance is unknown. To test the hypothesis that the resistance of superficial bladder cancer to interferon immunotherapy may be due to altered expression of essential components of the interferon pathways, we have investigated inducible interferon gene expressions, as well as, cell proliferation and apoptosis in established transitional carcinoma cells, primary tumor cells, and normal primary urothelial cells in response to IFN-alpha and IFN-g treatment. So far, studies have revealed specific defects in the interferon signaling necessary for the normal response to IFN-alpha. Interestingly, a normal IFN-alpha biological response may be restored in these specific cell lines by pretreating the cells with IFN-g. This mechanism is due to complementation of the IFN-alpha pathway by inducing the overlapping IFN-g pathway. Additionally, the same complementation can render normally responsive malignant cells increasingly sensitive to IFN-alpha treatment.
These results represent novel characterization of the interferon pathway in urothelial cells and provide original insights into the different mechanisms of bladder cancer resistance to immunotherapy with interferons. These efforts have provided a molecular explanation for understanding the observed synergistic response in clinical trials of combination immunotherapy such as BCG / IFN-alpha and IFN-alpha / IFN-g.
Grant Support:
NIH-NIDDK-R21-DK 066135. Rackley R (PI), Vasavada S, Sadhukhan, Didonato J (Co-Investigators)The Role of NF-kB Signaling in the Pathogenesis of Interstitial Cystitis. 2003-2005
Fishbein / ICA Grant: Diagnostic markers for Interstitial Cystitis: Rackley, RR (PI), Vasavada, SP, Sadhukhan, P, Abdelmalak, J. 2002-2003.
Interferon Signaling Mechanisms in Transitional Cell Carcinoma. National Kidney Foundation Young Investigators Award. 1999-2001
Defective Interferon Signaling Mechanisms in Transitional Cell Carcinoma. American Cancer Society, Institutional Research Grant: July, 1998
Immunomodulatory Regulation of Signal Transduction Pathways in Urothelial Malignancy: CCF RPC #5963: July 1, 1997
Immunomodulatory Regulation of Signal Transduction Pathways in Bladder Cancer: Kidney Foundation of Ohio, April 1, 1997
The Molecular Characterization of Renal Compensatory Growth: CCF RPC 1993-1994
Key References:
Raymond Rackley, T. Lewis, E. Preston, C. Delmoro, E. Bradley, M. Resnick, T. G. Pretlow, and T. Pretlow. 5' Nucleotidase Activity in Prostatic Carcinoma and Benign Prostatic Hyperplasia. Cancer Research. 49:3702-3707, 1989.
Raymond Rackley, T. Lewis, E. Bradley, H. Levin, M. Resnick, T. Pretlow, and T. Pretlow. Enzymatic Activities in Extracts of Needle Biopsy-sized Samples of Prostatic Carcinoma. Analytical Biochemistry, 184:128-134, 1990.
Raymond Rackley, B. Yang, T. Pretlow, F. Abdul-Kareem, T. Lewis, N. McNamara, C. Delmoro, E. Bradley, E. Kursh, M. Resnick,T.G. Pretlow. Differences in the Leucine Aminopeptidase Activity in Extracts from Human Prostatic Carcinoma and Benign Prostatic Hyperplasia. Cancer. 68(3):587-593, 1991.
Max Coppes, Ying Ye, Raymond Rackley, Xiao-lan Zhao, Gerrit Liefers, Graham Casey, and Bryan Williams. Analysis of WT1 in Granulosa Cell and Other Sex Cord-Stromal Tumors. Cancer Research. 53: 2712-2714, 1993.
Raymond Rackley, Ann Flenniken, Nishi Kuriyan, Patricia Kessler, Mark Stoler, and Bryan Williams. Expression of the Wilms Tumor Suppressor Gene,WT1, During Mouse Embryogenesis. Cell Growth and Differentiation. 4: 1023-1031, 1993.
Patricia Kessler, Sandip Vasavada, Raymond Rackley, Thomas Stackhouse, Fuh-Mei Duh, Farida Latif, Michael Lerman, Berton Zbar, and Bryan R.G. Williams. Expression of the von Hippel-Lindau Gene, VHL, in Human Fetal Kidney and Murine Embryogenesis. Molecular Medicine 1 (4): 445-466, 1995.
Raymond Rackley, Pat Kessler, and Bryan Williams. In Situ Expression of the Wilms Tumor Suppressor Gene, WT1, and Early Growth Response Gene, EGR-1, During Murine Nephrogenesis. Journal of Urology 154 (2): 700-705, 1995.
Raymond Rackley, Graham Casey, Xiao-lan Zhao, David Miller, Bryan Williams, Max Coppes. Analysis of the Wilms Tumor Gene, WT1, in Endometrial Carcinoma. Genes, Chromosomes Cancer. 14(4): 313-315, 1995.
Campbell CE, Kuriyan NP, Rackley RR, Caulfield MJ, Tubbs R, Finke J, Williams BRG. Constitutive Expression of the Wilms Tumor Suppressor Gene (WT1) in Renal Cell Carcinoma. International Journal of Cancer. 78:182-188, 1998.
Rackley R.R., Bandyopadhyay S.K., Fazeli-Matin S., Shin M.S., and Appell R.A. Immunoregulatory Potential of Urothelium: Characterization of NF-kB Signal Transduction. Journal of Urology. 162(5): 1812-1816, 1999.
Matin SF. Rackley RR. Sadhukhan PC. Kim MS. Novick AC. Bandyopadhyay SK. Impaired alpha-interferon signaling in transitional cell carcinoma: lack of p48 expression in 5637 cells. Cancer Research. 61(5):2261-6, 2001.
Sadhukhan, PC, Tchtgen, MB, Rackley, RR, Vasavada, SP, Liou, L, Bandyopadhyay, SK. Sodium Pentosan Polysulfate Reduces Urothelial Responses to Inflammatory Stimuli via an Indirect Mechanism. Journal of Urology 168(1): 289-292, 2002.
Liou LS. Sadhukhan PC. Bandyopadhyay SK. Rackley RR. Bacillus of Calmette and Guerin modulates nuclear factor kappa beta in two urothelial carcinoma cell lines. Advances in Experimental Medicine & Biology. 539:599-621, 2003.
Bandyopadhyay SK. Rackley RR. Matin SF. Sadhukhan PC. Interferon-alpha response and signal transduction pathway in transitional carcinoma cell lines. Advances in Experimental Medicine & Biology. 539:15-32, 2004.
Jones JS, et al. Sling may hasten return of continence after radical prostatectomy. Urology 2005;65:1163-7.
Jones JS, et al. Porcine small intestinal submucosa as a percutaneous mid-urethral sling: 2-year results. BJU Int 2005;96:103-6.
Moore C, Rackley R, Goldman H. Urologic applications of botox. Curr Urol Rep 2005;6:419-23.
Wein AJ, Rackley RR. Overactive bladder: a better understanding of pathophysiology, diagnosis and management. J Urol 2006;175(3 Pt 2):S5-10.
Woo LL, et al. Over expression of stem cell homing cytokines in urogenital organs following vaginal distention. J Urol 2007;177:1568-72.