The majority of pharmacological approaches for the treatment of solid tumors suffers from poor selectivity, thus limiting dose escalation. The situation is made more dramatic by the fact that the majority of anticancer drugs accumulate preferentially in normal tissues rather than in neoplastic sites, due to the irregular vasculature and to the high interstitial pressure of solid tumors. One avenue towards the development of more efficacious and better tolerated anti-cancer drugs relies on the targeted delivery of therapeutic agents to the tumor environment, thus sparing normal tissues. The aim of the project was the discovery and validation of selective tumor-associated markers (in particular, markers of the tumor neo-vasculature and tumor stroma), which can be used for the development of ligand-based imaging and therapeutic agents. The platform for this marker discovery activity was based on a novel experimental approach, consisting of an in vivo (or ex vivo, as we will see later) biotinylation procedure for the covalent modification of vascular proteins, followed by purification on streptavidin and identification by means of state-of-the-art mass spectrometric procedures.
In essence, from a scientific point of view, the project aimed at:
- developing a novel methodology for the discovery of novel vascular markers of pathology
- discovering new pharmaceutical targets
- creating information and motivation for the development of specific ligands (e.g., antibodies or globular protein binders) to the pharmaceutical targets mentioned above
Quelles sont les particularités de ce projet?
The aim of this precomeptitive project is the development of an innovative an promising methodolgy in the field of vascular antigen discovery.
A robust methodology has been developed for the reliable identification of vascular proteins in normal mouse organs and at sites of disease (e.g. in tumors). The first results have been published on the cover of Nature Methods in 2005 and in Nature Protocols in 2006. The methodology has also been applied for the discovery of differences between the normal vasculature of the liver and the neo-vasculature in liver metastases.
The methodology has been extended to the ex vivo biotinylation of surgically resected kidney with cancer, thus allowing the discovery (and patenting) of novel vascular markers of renal cell carcinoma. The corresponding article is currently in press in Molecular and Cellular Proteomics (Impact Factor = 9.8).
As expected, the momentum gained by the discovery of novel vascular markers has stimulated entrepreneurial activities. A first company (Philochem AG) is being founded by Dario Neri in Zurich, with the mission to innovate ligand and target discovery in pharmaceutical sciences. A second company (Covagen), corresponding to the work of Dario Neri’s collaborators Julian Bertschinger and Dragan Grabulovski, has received two awards in the Venture 2006 competition (promoted by McKinsey and ETH Zürich) and is currently in negotiation for the first round of financing.
The leadership achieved in the field of vascular antigen discovery, thanks to the methodology funded by Gebert Rüf Stiftung based on biotinylation and mass-spectrometric protein identification, has allowed the group Neri to achieve funding for three Sixth-Framework EU Projects related to vascular targeting (STROMA, 400’000 Euros; DiaNa, 324’000 Euros; ImmunoPDT, 600’000 Euros).
S. Scheurer, J. Rybak, C. Rösli, D. Neri*, G. Elia (2005). “Identification and relative quantification of membrane proteins by surface biotinylation and two-dimensional peptide mapping”. Proteomics, 5, 3035-3039.[* = corresponding author]
M. Silacci, S. Brack, G. Schirru, J. Mårlind, A. Ettorre, A. Merlo, F. Viti, D. Neri (2005) Design, construction, and characterization of a large synthetic human antibody phage display library. Proteomics, 5, 2340-2350
J. Rybak, B. Kaissling, R. Giavazzi, D. Neri*, G. Elia (2005). “In vivo protein biotinylation for the identification of organ-specific antigens accessible from the vasculature”. Nature Methods, 2, 291-298 [* = corresponding author]
D. Neri and R. Bicknell (2005) “Vascular tumor targeting”. Nature Rev. Cancer, 5, 436-446
M. Kaspar, L. Zardi and D. Neri (2006) “Fibronectin as a target for tumor therapy”. Int. J. Cancer, 118, 1331-1339.
C. Rösli, G. Elia and D. Neri (2006) “Two-dimensional mass spectrometric mapping”. Curr. Opin. Chem. Biol., 10, 35-41.
A. Ettorre, C. Rösli, M. Silacci, S. Brack, G. McCombie, R. Knochenmuss, G. Elia, D. Neri (2006) “Recombinant antibodies for the depletion of abundant proteins from human serum” Proteomics, in press.
C. Rösli, D. Neri, J. Rybak (2006) “In vivo protein biotinylation and sample preparation for the proteomic identification of organ- and disease-specific antigens accessible from the vasculature”. Nature Protocols, 1, 192-199.
V. Castronovo, D. Waltregny, P. Kishel, G. Elia, C. Rösli, J. Rybak, D. Neri (2006) "Accessible proteins expressed in kidney cancer". Mol. Cell. Proteomics, in press
Revue de presse
Dernière mise à jour de cette présentation du projet 17.10.2018