Students and faculty in the Molecular Pharmacology have three global aims:

1. Identify the molecular "targets" that distinguish cancer cells from normal cells;
2. Identify compounds that interact selectively with these molecular "targets"; and
3. Test these molecular "targets" and candidate drugs in a human clinical setting.

Most contemporary anti-cancer agents have two defects:

1. Poor selectivity toward cancer cells versus normal cells and
2. Poor efficacy against slow-growing tumors. These agents were identified empirically, using assays that measured inhibition of cell proliferation. Anti-cancer drugs discovered this way affect processes central to cell replication (e.g.DNA polymerase, ribonucleotide reductase, DHFR etc). Predictably, these drugs discriminate poorly between cancer and normal cells and thus have significant adverse. In favorable situations, the differences in growth rate between cancer and normal cells are sufficient to provide selectivity. However, most solid tumors associated with lung, colon, prostate, ovarian and breast cancer occur as indolent, slow-growing tumors, and there is no selectivity based on differential growth rates.

Students and faculty in Molecular Pharmacology seek molecular "targets" that are expressed preferentially in a tissue-restricted and diseased-restricted manner. Public and proprietary genomic databases enable discovery of relevant targets and thesis projects can emerge from such discoveries. Second, students and faculty seek drugs that propagate "apoptosis", or programmed cell death.. Activation of cell death is the most likely solution to management of slow growing tumors. Our research utilizes many contemporary methodologies such as gene expression microarray analysis and fluorescent scanning cytometry. The faculty complement these technologies with seminars, journal clubs and course work that imparts a rigorous foundation in principles of pharmacology and quantitative methods. This is a challenging program that demands a strong commitment to understand and integrate chemistry, biology and physiology. Second, certain faculty have had extensive experience in the pharmaceutical industry and can provide informed opinions about this career track.

Participating Faculty:

Cynthia J. Burrows - The Burrows lab studies DNA damage resulting from exposure to oxidizing and alkylating agents. Unrepaired DNA damage is linked to carcinogenesis because of misincorporations opposite damaged bases, particularly 8-oxoguanine and its further oxidation products. We investigate the chemistry of 8-oxoguanine and related lesions including sequence and structural effects on in vitro reactivity, misincorporation of bases by DNA polymerases, and formation of DNA-protein cross-links.

Frank Fitzpatrick - Students and post-doctoral fellows investigate the role of inflammation and inflammatory mediators as a risk factor and as host-defense responses against cancer. Scientists working in this laboratory must have a strong commitment to quantitative methodology and a desire to characterize biological processes according to laws of chemistry. Investigations focus on pharmacological mechanisms of modulating tumor suppressor and oncogenic processes, and techniques include chemical and instrumental analysis; cytometric analysis; gene expression analysis.

Charles B. Grissom - The Grissom laboratory is developing vitamin B-12 as a "Trojan Horse" delivery vehicle to deliver cytotoxic drugs, diagnostic reagents, oligonucleotides, and peptides to cancer cells. We are focusing on leukemia, as well as breast cancer and other solid tumors as early indications, as we see excellent selectivity for cancer cells and little or no uptake by normal cells. Students can design, synthesize, and test molecules with epifluorescence microscopy and cell-based assays.

Douglas Grossman - My laboratory is interested in how apoptosis influences the development and progression of melanoma and nonmelanoma skin cancer. Our initial studies have focused on survivin, a newly recognized inhibitor of apoptosis, that is expressed in basal and squamous cell carcinomas and melanomas, but not in normal keratinocytes or melanocytes. Current experimental approaches include adenoviral-mediated gene transfer, and transgenic and xenograft mouse models.

David Jones - Our lab studies the relationships between the control of gene expression and tumor cell responsiveness to chemotherapeutics. Our work aims to define new molecular targets for the development of novel cancer therapies. To accomplish our goals we rely on genomic technologies combined with molecular and cell biology techniques.

Linda Kelley - The lab is interested in how the Rb and p53 pathways are disrupted in erythroleukemic transformation resulting from overexpression of the PU.1 oncogene. PU.1 is a member of the ets family of transcriptions factors, which is required for normal development of B cells and monocytes, but causes leukemia when inappropriately regulated in erythrocytes. We use a murine model of virally-induced leukemia to perform genetic and biochemical studies to elucidate oncogenic events associated with leukemic transformation.

Jindrich Kopecek - Design, synthesis, and mechanism of action of macromolecular therapeutics. Attachment of anticancer drugs to polymeric carriers results in an increased accumulation in the tumor tissue, decreased non-specific toxicity, and a different mechanism of action when compared to free drugs. The toxicity, gene expression, and signaling pathways in human ovarian carcinoma models exposed to polymeric drugs are being evaluated in vitro and in vivo. Several conjugates are in clinical trials.

Steve Prescott - My laboratory is interested in the regulation of cellular events by lipid messengers. This is an area of signal transduction that affects multiple processes in cell growth, differentiation, and motility - all of which are normal processes that have been corrupted in cancer. Our experiments typically utilized cultured cell systems in which the cells have been genetically engineered to express different genes, and the analysis of responses includes techniques in biochemistry, molecular biology, and cell biology.

Glenn D. Prestwich - My lab studies the role of small molecules, including phosphoinositides, prenylated proteins, and hyaluronic acid -- in cell signaling. We synthesize and develop cellular uses of new biochemical reagents for target identification and active site mapping. The research in our laboratories includes organic synthesis, enzymology, protein isolation and characterization, receptor-ligand binding, radiochemical methods, molecular cloning and protein expression, cell biology, biomaterials preparation and analysis, protein NMR, and fluorescence and plasmon resonance analysis of ligand binding.

Wolfram E. Samlowski - My laboratory performs translational research in cancer immunotherapy. We are interested in evaluating mechanisms of cytokine antitumor activity, especially the induction of nitric oxide as a second messenger. Our current studies are evaluating the mechanism of apoptosis induced by nitric oxide, as well as transcriptional regulation of gene expression by this agent. This laboratory uses cell and molecular biology studies, including DNA microarray analysis to evaluate in vitro mechanisms of transcriptional regulation of genes and apoptosis. These observations are then tested in murine cancer models and in human clinical trials.

Janet Shaw - The Shaw lab studies the molecular basis of mitochondrial dynamics in eukaryotic cells. Changes in mitochondrial morphology and metabolic activity are associated with some cancers and could contribute to the uncontrolled growth of tumorigenic cells, or could be an indirect (and possibly diagnostic) consequence of cellular transformation. Using yeast as a model organism and a combination of genetic, molecular and cell biological techniques, we have identified proteins that control mitochondrial fission and fusion, mitochondrial transport during division, and mtDNA maintenance.

Gerald Spangrude - The Spangrude laboratory is interested in defining the cellular events that lead to blood development (hematopoiesis) in mammals. Hematopoiesis is a developmental program that persists after birth and continues throughout the life of mammals, and is regulated by cytokines, cell-cell interactions, and apoptotic mechanisms. We use flow cytometry, cell culture, and transplant models in the mouse to define cell populations that are critical to hematopoiesis and bone marrow transplantation.

Carl Thummel - Our lab studies the molecular mechanisms by which the steroid hormone ecdysone triggers programmed cell death during Drosophila metamorphosis. To date, we have defined an ecdysone-triggered genetic cascade that directs the rapid and massive destruction of obsolete larval tissues. These studies provide a framework for understanding how similar cell death pathways might function in other higher organisms.

Frederick G. West - Our lab is concerned with the challenges of chemical synthesis of complex molecules. In particular, we are focusing on the design and synthesis of molecules relevant to the treatment of cancer. This includes the total synthesis of natural and unnatural taxanes, and the construction of drug-bioconjugates derived from vitamin B-12.