The Role of cIAPs in breast cancer
Research Team: Apoptosis Team
Project Summary
Apoptosis is an evolutionarily conserved process that is crucial for normal development and homeostasis in multicellular organisms. Imbalances of apoptosis, whereby too many or too few cells die, lead to diverse human pathological conditions such as cancer, neurodegenerative disorders, strokes, myopathies and autoimmune diseases. Certain members of the Inhibitor of Apoptosis (IAP) protein family function as potent anti-apoptotic regulators that can block cell death in response to diverse stimuli. IAPs are highly expressed in many types of cancer and display oncogenic properties. cIAP1 is expressed in most human tissue, and overexpression of cIAP1 and cIAP2 is found in a range of human cancers, including breast cancer. The expression level of cIAPs also correlates with poor clinical prognosis and resistance to chemo- and radiotherapy.
Recently, small pharmacological inhibitors of IAPs, frequently dubbed Smac-mimetic, have been developed to reinstate apoptotic signalling. Such Smac-mimetics are highly effective in killing breast cancer cell lines overexpressing IAPs. Moreover, preliminary pre-clinical studies in animal models also confirm that IAP inhibition may be of significant benefit. Although Smac mimetics kill a variety of cancer cell lines, little is known why certain cells are sensitive to Smac-mimetics, although TNFa–mediated NF-kB activation has been postulated to play a key role. Despite the notion that their mechanisms of action are still somewhat unclear, Smac-mimetic compounds are currently entering Phase I clinical trials. One such example is LBW242.
This project aims to shed light on the physiological function of the Caspase-Recruitment Domain of cIAP’s and identify potential interacting candidates. In addition, it will identify novel mediators of sensitivity and resistance to Smac-mimetic compounds.
Biography
Dr. Lopez has completed her basic medical training as well as just over two years of training as a Medical Oncology Specialist Registrar, most recently at Guys & St Thomas’ Hospital.She graduated from Gonville and Caius College, University of Cambridge in 2001 with BA (Hons) MB BChir MA (Hons), and obtained her MRCP in February 2005.
