Bernard W Futscher

Assistant Research Scientist, Cancer Center Division

Associate Professor, BIO5 Institute

Investigator, Center for Toxicology

Professor, Pharmacology and Toxicology

Professor, Cancer Biology - GIDP

Primary Department

Pharmacology and Toxicology

Department Affiliations

Pharmacology and Toxicology

Contact

(520) 626-4646

futscher@arizona.edu

Work Summary

Bernard Futscher's lab is studying the molecular origins of human cancer. Understanding epigenetic dysfunction in human cancer has been Dr. Futscher's primary research focus since establishing his own independent laboratory. This epigenetic research has moved into the area of noncoding RNAs and their potential role in cancer cell immortality.

Research Interest

Bernard Futscher, PhD, and his lab focus on the molecular origins of human cancer. More specifically, the lab group has 3 inter-related research objectives based on the underlying concept that developing an in-depth understanding of epigenetic mechanismsresponsible for governing cell fate will allow for the development of more effective strategies for the prevention, treatment, and cure of cancer. First, they wish to identify which epigenetic mechanisms participate in the transcriptional control of genes important to growth and differentiation. Second, they seek to determine how these epigenetic mechanisms, and therefore epigenetic homeostasis, become compromised during oncogenesis. Third, using a new and more complete understanding of epigenetic control of the genome, Dr. Futscher and his team are developing rational new therapeutic strategies that seek to repair these defects in the cancer cell and transcriptionally reprogram the malignant cancer cell to a benign state. To reach their objectives, a variety of in vitro models of cancer have been developed to address emerging hypotheses that are inferred from the literature in basic and clinical science as well as our own data. Results from these in vitro studies are then translated to the clinical situation to determine their meaning in the actual clinical face of the disease. Similarly, they attempt to take information obtained from the genome-wide assessment of clinical specimens in order to help guide our thinking and develop new hypotheses that can be tested experimentally in our in vitro models.

Publications

Pharmacogenomics of the polyamine analog 3,8,13,18-tetraaza-10,11-[(E)-1,2- cyclopropyl] eicosane tetrahydrochloride, CGC-11093, in the colon adenocarcinoma cell line HCT116

Ignatenko, N. A., Yerushalmi, H. F., Watts, G. S., Futscher, B. W., Stringer, D. E., Marton, L. J., & Gerner, E. W. (2006). Pharmacogenomics of the polyamine analog 3,8,13,18-tetraaza-10,11-[(E)-1,2- cyclopropyl] eicosane tetrahydrochloride, CGC-11093, in the colon adenocarcinoma cell line HCT116. Technology in Cancer Research and Treatment, 5(6), 553-564.

PMID: 17121431;Abstract:

Polyamine analogs are known to inhibit tumorigenesis at least in part by mimicking some of the regulatory roles of natural polyamines. To begin the identification of those signaling pathways that are involved in differential cellular responses to the synthetic conformationally restricted polyamine analog CGC-11093, we conducted gene expression profiling, proteomic, and genome-wide DNA methylation and histone acetylation analyses of the HCT116 colon adenocarcinoma cell line after treatment with this analog. Gene expression analysis was performed using Affymetrix GeneChip human genome U133 Plus 2.0 arrays. Changes in protein expression were evaluated using 2D polyacrylamide gels followed by LCMS/MS. DNA methylation was measured using 6,800 element CpG island microarrays. Treatment of cells with CGC-11093 at concentrations ranging from 0.1 to 10 μM caused inhibition of cell growth and metabolic activity, but only minimally affected cell viability. Gene expression analysis showed concentration-dependent effects of CGC-11093 on the DNA/RNA binding transcription factor, cell cycle, signaling, transport, cytoskeletal/structural, and serine protease genes. Functional gene analysis revealed distinct expression patterns related to inhibition of cell cycle control, TGF beta signaling, proteasome and RNA polymerase pathways, upregulation of the aminoacyl-tRNA synthesis pathway, and perturbations in the MAPK and Wnt signaling pathways. Microarray results were validated for selected genes with real time RT PCR. Proteomics analysis showed correlative changes in the expression of proteins involved in the regulation of proteasome function (proteasome subunit Y) and tRNA synthesis. CGC-11093 treatment did not produce any detectable changes in DNA methylation or histone acetylation in cells. This study validates specific target pathways for a specific conformationally restricted polyamine analog and suggests the utility of combined gene and DNA methylation microarrays along with proteomic analyses as a useful approach to the evaluation of the mechanisms of action of anticancer drugs. ©Adenine Press (2006).

Bernard W Futscher