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Integrative Physiology & Pharmacology Ph.D. Program at Wake Forest University


Wake Forest University Graduate School » Integrative Physiology & Pharmacology Ph.D. Program

William Gmeiner, Ph.D.

William Gmeiner, Ph.D.
Education & Training
  BA University of Chicago 1982
  PhD University of Utah 1989
  MBA Wake Forest University 2007
Fellowship   University Alberta Medical School-Canada 1991
Memberships
American Association of Cancer Research
American Chemical Society
American Society of Pharmacology & Experimental Therapeutics

 


Wu SY, Chen TM, Gmeiner WH, Chu E, Schmitz JC. Development of modified siRNA molecules incorporating 5-fluoro-2'-deoxyuridine residues to enhance cytotoxicity. Nucleic Acids Res. 2013;41(8):4650-4659.

Boyacioglu O, Stuart CH, Kulik G, Gmeiner WH. Dimeric DNA aptamer complexes for high-capacity-targeted drug delivery using pH-sensitive covalent linkages. Mol Ther Nucleic Acids. 2013;2():e107.

Pardee TS, Gomes E, Jennings-Gee J, Caudell D, Gmeiner WH. Unique dual targeting of thymidylate synthase and topoisomerase1 by FdUMP[10] results in high efficacy against AML and low toxicity. Blood. 2012;119(15):3561-3570.

Gmeiner WH. Carbon nanotubes for cancer therapy In: Kumar CSSR, ed. Carbon nanomaterials. Weinheim (Germany): Wiley-VCH;2011: 309-332.

Ghosh S, Salsbury FR Jr, Horita DA, Gmeiner WH. Zn2+ selectively stabilizes FdU-substituted DNA through a unique major groove binding motif. Nucleic Acids Res. 2011;39(10):4490-4498.

Gmeiner WH, Salsbury F Jr, Olsen CM, Marky LA. The stability of a model substrate for topoisomerase 1-mediated DNA religation depends on the presence of mismatched base pairs. J Nucleic Acids. 2011;2011():631372.

Pardee T, Gomes E, Jennings-Gee J, Caudell DL, Gmeiner W. Unique dual targeting of thymidylate synthase and topoisomerase1 by FdUMP10 results in high efficacy against AML and low toxicity [abstract]. Blood. 2011;118(21):1109-1110.


Pardee T, Gomes E, Jennings-Gee J, Caudell DL, Gmeiner W. The novel fluoropyrimidine FdUMP[10] is highly active against acute myeloid leukemia [abstract]. Blood. 2010;116(21):1353.

Ghosh S, Dutta S, Gomes E, Carroll D, D'Agostino R Jr, Olson J, Guthold M, Gmeiner WH. Increased heating efficiency and selective thermal ablation of malignant tissue with DNA-encased multiwalled carbon nanotubes. ACS Nano. 2009;3(9):2667-2673.

Gmeiner WH, Hellmann GM, Shen P. Tissue-dependent and -independent gene expression changes in metastatic colon cancer. Oncol Rep. 2008;19(1):245-251.

Gmeiner WH, Garg S, Hatcher HC, Smith TL, Bourland JD, Garg PK. MicroPET imaging to monitor tumor response to single agent and combined ionizing radiation therapy and FdUMP treatment [abstract]. J Nucl Med. 2007;48(6 Suppl 2):83P.

Bijnsdorp IV, Comijn EM, Padron JM, Gmeiner WH, Peters GJ. Mechanisms of action of FdUMP[10]: metabolite activation and thymidylate synthase inhibition. Oncol Rep. 2007;18(1):287-291.

Gmeiner WH. Genetic determinants for activated fluoropyrimidine chemotherapy. Drug Dev Res. 2006;67(2):119-129.

 

My laboratory is interested in understanding how efficacious anti-cancer drugs cause cancer cell death and in designing new drugs and novel drug delivery strategies.  Fluoropyrimidines (FPs) are an example of a class of drugs that is widely used for cancer chemotherapy, yet the cytotoxic mechanisms of FPs are not completely understood and clinical response to these drugs is limited.  I invented a novel polymeric form of FdUMP, the TS-inhibitory metabolite of 5FU, and have demonstrated the safety and efficacy of the FdUMP[10] polymer in tissue culture and animal models of human cancer.  The results indicate that FdUMP[N] polymers are likely to be highly efficacious for the treatment of human cancer.  Further, FdUMP[N] polymers are highly cytotoxic towards cancer cells that are not sensitive to 5FU, such as prostate cancer cells, but are not cytotoxic to normal prostatic epithelial cells.   

The increased activity of FdUMP[N] polymers relative to monomeric FPs results from the increased misincorporation of FdUTP into DNA and greater DNA damage.  In collaboration with Dr. Yves Pommier (NCI), we showed that exposure of cancer cells to FdUMP[10] results in trapping of topoisomerase I (Top1) cleavage complexes at the site of FdUTP misincoporation.  Thus, FdUMP[10] mechanistically resembles the camptothecin class of anticancer drugs. [ATP-levels in drug-treated cells are assessed using a luminescence assay].  In collaboration with Dr. Frits Peters (Free University, Amsterdam) we recently showed that FdUMP[10] retained activity towards TK-null cells while FdU does not implicating cellular degradation to FdU is not essential for FdUMP[10] cytotoxicity.  Current efforts in my laboratory are focused on elucidating the cell death pathways that are activated in human prostate cancer cells following exposure to FdUMP[10].  My laboratory has also demonstrated that FdUMP[10] is a potent radiosensitizer of prostate cancer xenografts in vivo. 

A major new initiative in my laboratory in recent years is the development of highly structured DNA molecules that are selectively cytotoxic to cancer cells.  The selective killing of malignant cells remains an important challenge that has not been fully met by the development of monoclonal antibodies and other targeted therapeutics.  The “CytotoxamersTM” being developed in my laboratory represent a novel approach to the selective killing of cancer cells.  These structured molecules are less prone to extracellular degradation than linear homopolymers and have the potential to be highly selective anticancer drugs ushering the antimetabolite class of anticancer drugs into the era of targeted therapeutics.