Molecular therapy for RDEB associated squamous cell carcinoma (Marinkovich 1)Completed
|Project lead||Prof Peter Marinkovich|
|Organisation||Stanford University, Stanford, USA|
|Project budget||USD 130,945.00|
|Start date / Duration||01. Jan 2011 / 12 months|
|Funder(s) / Co-Funder(s)||DEBRA Austria, MSAP/EBEP Recommended|
|Research area||Skin cancer & fibrosis, Molecular therapy|
Short lay summary
Squamous cell carcinoma (SCC) is a devastating disease which results in a high mortality in patients with recessive dystrophic epidermolysis bullosa (RDEB). We present evidence that SCC tumors rely on two proteins, laminin-332 and collagen VII, to grow and invade. In this project, we intend to study the effects of antibodies to these two proteins for their effects on tumor growth, in a well characterized animal model of human SCC. We have identified several key regions of these proteins, and based on our preliminary evidence, we believe that antibodies to these regions of collagen VII and laminin-332 may selectively inhibit SCC tumor growth but will not interfere with normal skin function in RDEB patients. We propose producing and analyzing this panel of antibodies for effects on normal and RDEB SCC tumor inhibition as well as their effects on normal and RDEB skin in our animal models. We also believe that the regions on laminin-332 and collagen VII may promote SCC tumor formation through separate and distinct mechanisms. If this is true, then it is possible that a combination regimen of more than one antibody could have more benefit towards stopping SCC tumors, compared to one antibody alone. To test this, we will examine the underlying mechanisms as to how each of these antibodies inhibit tumors, looking at the signaling pathways that tumors rely on to grow, resist cell death and to invade into host tissue. In total, these studies plan to characterize a novel group of therapeutic agents which can help to treat RDEB associated SCC. These preclinical studies, if successful, will lead the way towards the future development of these agents for use in clinical trials.
The Aims of this study were directed on the roles of laminins and their receptors in the skin, especially during squamous cell carcinoma (SCC) development in recessive dystrophic epidermolysis bullosa (RDEB) skin. These aims were based upon the premise that laminins and their receptors perform critical functions in the interactions between epithelial cells and the extracellular environment. Efforts to pursue these Aims are reflected in the data described below, generated with various types of EB cells, including RDEB cells. Four manuscripts containing these data, which we are currently preparing, will be soon be submitted to high impact journals.