Christopher Benz

Research Interests

Molecular/cellular understanding of cancer and aging; development therapeutics with a focus on human breast cancer

Research Summary

The translational interest of my human breast cancer research program has been in the area of developmental therapeutics and molecular diagnostics, specifically focused on the cellular and molecular mechanisms by which oncogenes and growth factor receptors result in the most aggressive and treatment resistant forms of breast cancer. (For further details, see Benz lab website: www.buckinstitute.org/benz/Home.htm)
1. Biological and Clinical Significance of Functionally Defective Estrogen Receptors in Human Breast Tumors
We have developed models simulating two types of endocrine resistance: I) loss of ER DNA-binding function induced by endogenous and exogenous factors (e.g. oxidative stress, excess polyamine levels) that can alter secondary or tertiary/qua- ternary structure of the ER DNA-binding domain (ER-DBD, '); and ii) ER-independent growth induced by upregulated phosphokinase-activated transcription factors, like AP-1. Collaborators in these efforts include senior investigators in UCSF's Pharm. Chem. & Mass Spect. Unit, Metabolic Research Unit, Canberra, Austr.NMR Unit, Royal Marsden Hospital (London, UK), and Univ. Basel Kantonsspital, Switzerland.
2. ETS Factors and HER2/NEU (erbB-2) Expression in Breast Cancer
The translational goals of this project are to characterize the biological function of breast cancer-associated Ets factors, investigate Ets-mediated upregulation of the HER2/NEU promoter and develop therapeutic strategies to silence this overactive promoter, and to characterize structure-function relationships associated with specific domains in a novel Ets factor first cloned by our lab (ESX). Collaborators in these efforts include senior investigators in the UCSF Structural Biochemistry group, Frederich Miescher Institute (Basal, Switzerland), Molecular Oncology at the Wistar Cancer Center, and Exp. Therapeutics group at Roswell Park Cancer Center.
3. Development of Immunoliposomes for Targeted Delivery of Drugs and Genes to Breast Tumors
We are developing first- and second-generation immunoliposome (ILs) therapeutics after our proof-of-principle demonstration of their superior therapeutic efficacy and selective intracellular accumulation into HER2/NEU-overexpressing human breast tumor xenografts in vivo. Drug- or gene-encapsulated ILs are coupled to human single chain antibody fragements (scFr), and the resulting agents are being sponsored by the NCI for advancement into clinical trials. Collaborators in these efforts include a number of senior UCSF investigators, colleagues at the Liposome Research Lab at CPMC, NCI/DCTD scientists, and interested co-investigators at various other cancer institutes (e.g. Memorial Sloan-Kettering, University of Colorado).

Selected Publications

Scott GK, Marden C, Xu F, Kirk L, and Benz CC. Transcriptional repression of ErbB2 by histone deacetylase inhibitors detected by a genomically integrated ErbB2 promoter-reporting cell screen. Mol. Cancer Therapeutics 1: 385-392, 2002.

Neve RM, Ylstra B, Chang C-H, Albertson DG, and Benz CC. ErbB2 activation of ESX gene expression. Oncogene 21: 3934-3938, 2002.

Park JW, Hong K, Kirpotin DB, Colbern G, Shalaby R, Baselga J, Shao Y, Nielsen U, Marks J, Moore D, Papahadjopoulos D, Benz CC. Anti-HER2 immunoliposomes: enhanced anticancer efficacy due to targeted delivery. Clin. Cancer Res. 8: 1172-1181, 2002.

Scott GK, Chang C-H, Erny KM, Xu F, Friedericks WI, Rauscher III FJ, Thor AD, Benz CC. Its regulation of the ErbB2 promoter. Oncogene 19: 6490-6502, 2000.

Krauss WC, Park JW, Dirpotia DB, Hong K, Benz CC. Emerging antibody-based HER2 (ErbB2/neu) therapeutics. Breast Disease, 11: 113 -124, 2000.

Whittal RM, Benz CC, Scott G, Semyonov J, Burlingame AL, Baldwin MA. Preferential oxidation of zinc finger 2 in estrogen receptor DNA-binding domain prevents dinierization and hence DNA binding. Biochemistry, 39: 8406-8417, 2000.

Park JW, Kirpotin D, Hong K, Colbern G, Shalaby R, Shao Y, Meyer O, Nielsen U, Marks J, Benz CC, Papahadjopoulos D. Anti-HER2 immunoliposomes for targeted drug delivery. Medical Chemistry Research, 8: 383-391, 1998.

Liang X, Lu B, Scott GK, Chang C-H, Baldwin MA, Benz CC. Oxidant stress impaired DNA-binding of
estrogen receptor from human breast cancer. Mol. Cell. Endocrinol., 146: 151-161, 1998.