Dr. Robert A. Sikes

Associate Professor

Contact

Sikes

Office: 330 Wolf Hall
Lab: 340 Wolf Hall

Mailing address:
Dept. of Biological Sciences
Wolf Hall
University of Delaware
Newark, DE 19716

Phone: (302) 831-6050
Fax: (302) 831-2281
E-mail: rasikes@udel.edu

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Education

B.A.: University of Colorado
Ph.D.: University of Texas
Postdoctoral: University of Texas, Health Science Center
Postdoctoral: University of Texas, M.D. Anderson Cancer Center

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Research Interests

The number of men affected by prostate cancer is staggering. In North America, there are approximately 219,000 cases of prostate cancer every year and around 27,000 deaths. This translates into a 1 in 6 lifetime chance of acquiring prostate cancer if you are an American male. Initially, prostate cancer is sensitive to the levels of male steroid hormones or androgens. Removal of the androgens, by surgical or chemical castration, is still a gold standard for prostate cancer therapy. For a time, the cancer responds by regressing under the conditions of androgen deprivation, however, the cancer eventually adapts and continues growing in the absence or reduced levels of androgens. The tumor has now shifted from being androgen dependent or sensitive to androgen independent. The development of metastases, tumor deposits away from the initial prostate cancer, along with the shift from androgen dependent to androgen independent is termed progression.

Research in my laboratory is concerned with the mechanism(s) that contribute to the development of prostate cancer, or cancer ontogeny. As the cancer becomes more aggressive this includes the mechanisms and adaptations that lead to the development of bone metastases and androgen independence. In working towards an understanding of prostate cancer development and progression, my lab has two areas of emphasis 1) stromal-epithelial cell interaction and 2) oncofetal translational genomics. Stromal-epithelial interactions include interactions between prostate epithelial and stromal cells as well as between prostate epithelial cells and the bone microenvironment. These interactions are mediated by growth factors, like IGF-I and EGF, as well as steroid hormones, like androgens and estrogens. These factors can dramatically affect the ability of a cell to live or die in response to chemotherapy or other genotoxic stress. Oncofetal translational genomics is a phrase that can be distilled to mean that a cancer cell may inappropriately express genes or gene products that were responsible for regulating the growth or development of the fetal prostate. As these genes/gene products are misexpressed in prostate cancer, the prostate cancer cell may lose the ability to regulate its growth or state of differentiation. My lab is in the process of identifying fetal prostate genes that are candidates for temporal or spatial miss-expression and we have begun by separating the epithelial from mesenchymal genes in the fetal UGS.

Another focus of the lab is the development and testing of novel therapeutics for cancer treatment. There is no long term, curative therapy for advanced prostate cancer, which is why my lab has an active program in therapeutic drug discovery/validation. Current preclinical research is evaluating a novel class of sodium channel inhibitors and anti-angiogenic compounds. In collaboration with a medicinal chemist, Dr. Milton Brown, Georgetown University, Lombardi Cancer Center, we have identified several lead compounds that dramatically impact prostate cancer cell growth in both two-dimensional and three-dimensional growth assays. Selected lead compounds are now in preclinical animal modeling. The mechanism by which sodium channels contribute to aggressive prostate cancer growth has become a focus for the laboratory. Additional areas of potential research include the mechanism of VSSC control of cell migration.

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Current Projects

• Tracking urogenital sinus cell progeny - this project involves a genomics approach to determine the segregation of fetal prostate genes into each of the four different lobes of the mouse prostate. The ultimate goal is to determine which genes are expressed in a lobe specific manner and how these patterns change with hormonally induced prostate cancer. Currently, we are constructing a gene expression map for E16.5 UGS that will provide abundant data for the dissection of genitourinary development.
• Ion channel therapeutics in prostate cancer - lead compounds that have been screened are being further evaluated to determine the mechanism of cell growth inhibition and for their anti-tumor effects. Combined treatment modalities, VSSC blockers plus chemotherapy are being investigated for favorable drug interactions.
• Role of IGF/IGFBPs and androgen in prostate cancer progression - Prostate cell responsiveness to these compounds changes as prostate cells lose their androgen sensitivity. The signal transduction associated with these molecules is being examined.

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Teaching

• BISC 401* - Molecular Biology of the Cell
• BISC 667* - Cancer Biology

*Course web site available through MyCourses

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Research Group

• Qian (Cynthia) Chen, M.S. - Graduate Student (M.S., University of Delaware).
• Fayth Miles, M.S. - Graduate Student (M.S., Johns Hopkins University).
• Adam Aguiar, B.A. - Graduate Student (B.A., Fairleigh Dickinson University).
• David DeGraff, B.S. - Graduate Student (B.S., Metropolitan State College of Denver). Doctoral candidate.
• Keith Jansson, B.S. - Graduate Student (B.S., University of Massachusetts - Amherst).
• Jill Lynch, B.S. - Graduate Student (B.S., University of Delaware).
• Mehrnoosh Soori, B.S. - Graduate Student (B.S., University of Tehran, Iran).
• Jennifer Ambrose - Undergraduate.
• Nina Blackhurst - Undergraduate.
• Sander Frank - Undergraduate.
• Vince Hill - Undergraduate.
• Christine Maguire - Undergraduate.
• Lauretta Ovadje - Undergraduate.

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Selected Publications

Degraff D.J., Malik M., Chen Q., Miyako K., Rejto L., Cohen P., Bancroft D.R.E., Aguiar A.A., and Sikes R.A. Hormonal regulation of IGFBP-2 proteolysis is attenuated with progression to androgen insensitivity in the LNCaP progression model. J Cell Physiol (in press).

Deeble P.D., Cox M.E., Frierson, Jr H.F., Sikes R.A., Palmer J.B., Davidson R.J., Amorino G.P., and Parsons S.J. Androgen-independent growth and tumorigenesis of prostate cancer cells is enhanced by the presence of cAMP-dependent protein kinase (PKA)-differentiated neuroendocrine cells. Cancer Research, 67(8): 3663-3672, 2007.

Fiske J., Fomin V., Duncan R.L., Brown M.L., and *Sikes R.A. Voltage-sensitive ion channels and cancer. Cancer and Metastasis Reviews, 25(3): 493-500, 2006.

Chen Q., Watson J.T., Marengo S.R., Decker K.S., Coleman I., Nelson P.S., and *Sikes R.A. Gene expression in the LNCaP human prostate cancer progression model: progression associated expression in vitro corresponds to expression changes associated with prostate cancer progression in vivo. Cancer Letters, 244: 274-288, 2006.

Tate A., Isotani S., Bradley M.J., Sikes R.A., Davis R., Chung L.W.K., and Edlund M. Met-independent hepatocyte growth factor-mediated regulation of cell adhesion in human prostate cancer cells. BMC Cancer, 6: 197, 2006.

*Sikes R.A., Cooper C.R., Beck G.L., Pruitt F., Brown M.L., and Balian G. Bone stromal cells as therapeutics targets in osseous metastasis. Chapter 21, pp. 369-386, In: Cancer Growth and Progression, Volume 15, "Integration/Interaction of Oncologic Growth." Ed. Gary Meadows, Series Ed. Kaiser H., Kluwer Academic Publishers, Boston, MA, 2005.

Krueckl S.L., Sikes R.A., Edlund N.M., Bell R., Hurtado-Coll A., Fazli L., Gleave M.E., and Cox M.E. Increased insulin-like growth factor 1 receptor expression and signaling is a component of androgen-independent progression in a lineage-derived prostate cancer progression model. Cancer Res, 64: 8620-8629, 2004.

Brennen W.N., Cooper C.R., Capitosti S., Brown M.L., and *Sikes R.A. Thalidomide and Analogs: Current Proposed Mechanisms and Therapeutic Usage. Clin Prostate Cancer, 3(1): 54-61, 2004.

*Sikes R.A., Nicholson B.E., Koeneman K.S., Edlund N.M., Bissonnette E.A., Bradley M..J., Thalmann G.N., Cecchini M.G., Pienta K.J., .and Chung L.W.K. Cellular interactions in the tropism of prostate cancer to bone. Int J Cancer, 110(4): 497-503, 2004.

Stewart D.A., Cooper C.R., and *Sikes R.A. Changes in extracellular matrix (ECM) and ECM-associated proteins in the metastatic progression of prostate cancer. Reproductive Biology and Endocrinology, 2(1), paper 2, 2004 Mini-review.

Cooper C.R., Sikes R.A., Nicholson B.E., Sun Y.-X., Pienta K.J., and Taichman R.S. Cancer cells homing to bone: the significance of chemotaxis and cell adhesion. Chapter 12, pp. 291-310, In: The Biology of Skeletal Metastasis. Eds. Chung L.W.K. and Keller E., Kluwer Academic Publishers, Boston, MA 2004.

Sikes R.A., Walls A.M., Brennen W.N., Anderson J.D., Choudhury I.M., and Brown M.L. Therapeutic approaches targeting prostate cancer progression using novel voltage-gated ion channel blockers. Clin Prostate Cancer, 2(3): 181-187, 2003.

Abbott D.E., Pritchard C., Clegg N.J., Ferguson C., Dumpit R., Sikes R.A. and Nelson P.S. Expressed sequence tag profiling identifies developmental and anatomic partitioning of gene expression in the mouse prostate. Genome Biology 4, R79, 2003.

Anderson J.D., Hansen T.P., Lenkowski P.W., Walls A.M., Choudhury I.M., Schenck H.A., Friehling M., Höll G.M., Patel M.K., Sikes R.A. and Brown M.L. Voltage Gated Sodium Channel Blockers as Cytostatic Inhibitors of Androgen Independent Prostate Cancer Cells. Mol Cancer Ther. 2: 1149-1154, 2003.

Bakin R.E., Gioelli D., Sikes R.A., Bissonette E.A., and Weber M.J. Constitutive activation of the ras/mitogen-activated protein kinase signaling pathway promotes androgen hypersensitivity in LNCaP prostate cancer cells. Cancer Res. 63: 1981-1989, 2003.

Tennant M.K., Vessella R.L., Sprenger C.C., Sikes R.A., Hwa V., Baker L.D., and Plymate S.R. Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1/mac 25) is reduced in human prostate cancer and is inversely related to tumor volume and proliferation index in Lucap 23.12 xenografts. The Prostate 56(2): 115-122, 2003.

Guo N., Ye J.-J., Liang S.-J., Mineo R., Li S.-L., Giannini S., Plymate S.R., Sikes R.A., and Fujita-Yamaguchi Y. The role of insulin-like growth factor-II in cancer growth and progression evidenced by the use of ribozymes and prostate cancer progression models. Growth Horm IGF Res. 13(1): 44-53, 2003.

Gregory C.W., Degeorges A., and Sikes R.A. The role of the IGF axis in the development and progression of prostate cancer. In Recent Research Developments in Cancer Volume 3, Part II, 3: 437-462, 2001, (Eds) Pandalai.S.G., Mukhtar H and Labrie F, Transworld Research Network, Kerala, India.

Edlund M., Miyamoto T., Sikes R.A., Ogle R., Laurie G.W., Farach-Carson M.C., Otey C.A., Zhau H.E., and Chung L.W.K. Integrin expression and usage by prostate cancer cell lines on laminin substrata., Cell Growth Differentiation 12(2): 99-107, 2001.

Thalmann G.N., Sikes R.A., Wu T.T., Degeorges A., Chang S.-M., Ozen M., Pathak S., and Chung L.W.K. The LNCaP progression model of human prostate cancer: androgen-independence and osseous metastasis. Prostate, 44: 91-103, 2000.

Thalmann G.N., Sikes R.A., Devoll R., Kiefer J.A., Markwalder R., Klima I., Farach-Carson M.C., Studer U.E. and Chung L.W.K. Osteopontin: Possible role in prostate cancer progression. Clin Cancer Res. 5: 2271-2277, 1999.

Degeorges A., Wang F., Frierson Jr. H.F., Seth A., Chung L.W.K., and Sikes R.A. Human prostate cancer expresses the low affinity insulin-like binding protein, IGFBP-rP1. Cancer Res. 59, 2787-2790, 1999.

Theodorescu, D.T., Frierson H.F. and Sikes R.A. Molecular determination of surgical margins following radical prostatectomy. J. Urology 161: 1442-1448, 1999.

Vafa A., Zhang Y., Sikes R.A., and Marengo S.R. Overexpression of p185-erbB2/neu in the NbE prostatic epithelial cell line increases cellular spreading and the expression of integrin a6b1. Int. J. Oncology, 13: 1191-1197, 1998.

Wu T.T., Sikes R.A., Cui Q., Thalmann G.N., Kao C., Murphy C.F., Yang H., Zhau H.Y.E., Balian G. and Chung L.W.K. Establishing human prostate cancer cell xenografts in bone: Induction of osteoblastic reaction by PSA-producing tumors in athymic and SCID/bg mice using LNCaP and lineage-derived metastatic sublines. Int. J. Cancer 77(6): 887-894, 1998.

*Corresponding author

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