Molecular therapy for RDEB associated SCC (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|
|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). The team presents evidence that SCC tumors rely on two proteins, laminin-332 and collagen VII, to grow and invade. In this proposal, the team lead by Prof Marinkovich intends 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. They have identified several key regions of these proteins, and based on their preliminary evidence, they 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. The team proposes 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 their animal models. Thay 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, the team 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 were submitted to high impact journals.
It should also be pointed out that as a result of the successful results of this proposal, Bristol-Meyers-Squibb (BMS) and Cephalon Corporation have recognized the therapeutic potential of the laminin targets the team has characterized. Through licensing agreements with the Stanford Office of Technology Licensing, each of these companies have developed and are analyzing therapeutic antibodies to these cancer targets. BMS has already produced polyclonal as well as human monoclonal antibodies to the laminin α3 G45 domain, and Cephalon has also produced both a polyclonal as well as human monoclonal antibodies to the γ2 domain IV-V.
Developing the discoveries obtained into translational applications such as cancer therapy has been a major programmatic goal and our collaborative studies with BMS and Cephalon are currently in the stage of preclinical testing, as a precursor to clinical trials.
One aspect of the studies involves signaling which comes from the molecule laminin-332, that produces changes in the cancer cells leading to invasion and metastasis. The team lead by Prof Marinkovich has identified two key domains of the receptor for laminin 332, called beta 4 integrin. The outside of the receptor, which is the area that binds laminin-332, is critical in transferring the laminin-332 signal inside the cells. After this laminin-332 binding event, the extracellular portion of the beta 4 integrin molecule sends the signal inside the cell, which results in a phosphate group being placed on the intracellular side of the beta 4 integrin molecule. In particular, they have identified a single residue on beta 4 integrin responsible for tumor progression. Phosphorylation of this reside results in a change of shape of this molecule, which appears to be the key mechanism driving the intracellular signaling events. Both the extracellular laminin binding and the intracellular shape change of the beta 4 integrin molecule potentially could be targeted for therapies.
Another aspect of the studies involves the key domains of the laminin-332 molecule which are targeted for therapy with monoclonal antibodies. These domains are removed in normal tissues, but remain present in invasive SCC tumors, including RDEB tumors. Previously they had demonstrated that the G45 domain is involved with cell polarity (orientation) but the current studies with the other laminin domain, the gamma 2 domain IV-V, involve orientation of the cell in a different way, in particular by strongly influencing the direction and rate of cell migration.
When the processing of this domain is inhibited using a nontoxic small molecule, cell migration and cancer cell invasion are both inhibited. Thus the processing of laminin-332 gamma 2 chain appears to be another area which can be potentially targeted for cancer therapy. The data so far suggest that ongoing processing of the laminin gamma 2 chain appears to be a major driver of SCC tumor progression.
What did this project achieve?
Future directions of this work include analysis of the laminin-332 processed domains in a larger array of RDEB SCC tumor samples, from more patients. The was able to obtain a large group of samples in collaboration with Dr. J. Mellerio, from London, and they analyed them in an attempt to correlate level of expression of these domains with microscopic invasiveness of the RDEB tumor samples. The team hopes that by continued work with licensing partners Brostol Meyers Squibb and Cephalon, that we can turn the monoclonal antibodies to laminin domains into useful clinical therapies, though continued preclinical development. Finally
they also are examining the potential of targeting the intracellular and extracellular domains of the laminin receptor, beta 4 integrin, towards the development of small molecules with anti-tumor
effects. All of these proposed therapies would be especially useful for highly invasive tumors such as those found in RDEB patients.