APPLICATIONS OF TECHNOLOGY:

	Mina Bissell of Berkeley Lab led the research on TACE inhibition. Dr. Bissell received the 2007 Pezcoller Foundation-AACR International Award for Cancer Research for her pioneering work on the relationship between cancer genetics and the three-dimensional structure of cells and tissues.

• Sensitizing a cancer cell to the effect of an existing EGFR inhibitor therapeutic
• Developing an anti-tumor therapeutic for EGFR-dependent cancers such as breast, lung, kidney, head, neck, bladder, and colorectal cancers
• Adapting existing TACE inhibitors for arthritis to the treatment of cancer

ADVANTAGES:

• Elucidates a new neoplastic tumor signaling pathway for therapeutic targeting
• Promises to enhance the effectiveness of current EGFR treatment
• Targets breast cancers that are high risk and respond poorly to current treatments

ABSTRACT:

Mina Bissell and colleagues at Berkeley Lab have demonstrated that inhibiting the activity of the protease enzyme known as TACE can deprive tumor cells of key growth factors needed for their proliferation.  TNF-Converting Enzyme (TACE, also known as ADAM17 ) is strongly present in a form of high-risk breast cancer that responds poorly to current therapies.

Inhibiting TACE protease in breast cancer cells blocks the shedding of two critical epithelial growth factor receptor (EGFR) ligands and results in inhibition of this key signaling pathway which is involved in regulating cell division, invasion and survival.  Based on analysis of breast cancer cells grown in three-dimensional cultures, the inhibition of TACE results in reversion of the malignant phenotype of these cells and reverts their behavior back to a phenotype reminiscent of non-malignant epithelial cells.

TACE inhibition promises to be a useful therapeutic strategy as a single agent in the treatment of neoplastic diseases in which the tumor cells depend on ongoing stimulation with c-ErbB family ligands.  It may also be used to reduce these ligand levels to enhance the clinical activity of EGFR inhibitors, which are currently effective in very few patients.  TACE can be inhibited using small molecules, peptides, siRNA and antisense oligonucleotides. Others have previosuly targeted TACE to counter inflammation and arthritis.

	Inhibition of TACE activity
					In (A) T4-2 breast cancer cells grown in culture formed continuously proliferating, disorganized, apolar colonies. In (B) T4-2 cells treated with an EGFR inhibitor underwent morphological reversion, forming small, smooth, growth-arrested colonies. In (C) T4-2 cells treated with a broad-spectrum TACE inhibitor underwent morphological reversion similar to that of the EGFR inhibitor–treated cells. (D) shows an absence of tissue polarity in untreated T4-2 cells and (E) shows a restoration of tissue polarity after the cells were treated with the TACE inhibitor.

STATUS:

• Published Patent Application US-2009-0274626-A1 available at USPTO. Available for licensing or collaborative research.

FOR MORE INFORMATION:

Bissell, M.J., Kenny, P.A., Targeting TACE-dependent EGFR ligand shedding in breast cancer, The Journal of Clinical Investigation, Volume 117, Number 2, February 2007, 337-345

REFERENCE NUMBER: IB-2188

SEE THESE OTHER BERKELEY LAB TECHNOLOGIES IN THIS FIELD:

• Prognostic for Invasive and Metastatic Cancers, IB-1637
• Breast Cancer Therapy and Potential Method for Enhancing Radiation Sensitivity via Inhibition of ß1 Integrin, IB-1965
• Non-Transgenic Cell Lines for Identifying Target Premalignant Genes, IB-2023
• Rac1b: A Highly Selective Marker and Target for Cancer, IB-2167
• Protease-based Cancer Screening Using Nanoliter Samples, IB-2240
• High Selectivity Peptides for Cancer Therapy, Screening for Cancer Therapies, and Therapy Sensitization, IB-2489