SOCIETY

The health issue: Dysregulated angiogenesis is a defining functional feature of several serious human diseases, such as solid tumors and myocardial ischemia. The sporadic success of drugs targeting angiogenesis underscores the need to develop more such molecules.

Current approaches: Thus far, most drug development initiatives have either targeted a handful of known angiogenesis players or used angiogenesis-modulating properties of compounds initially developed for other purposes, hence their overall high toxicity and relatively poor efficacy.

A distinct functional strategy to identify novel angiogenesis modulators and targets:
We intend to harness the chemical diversity and inherent bioactivity potential of natural plant products, by assembling an interdisciplinary partnership with wide-ranging but complementary scientific expertise. As “input” for screening, we will take advantage of the chemical structure diversity and high degree of bioactivity of one unique library composed of ~200 purified natural products from plants endemic mainly in Greece and from synthetic compounds whose structure is based on that of naturally-occurring molecules.

The initial screening process is unbiased regarding the molecular mechanism of action and relies on direct functional end-points, namely endothelial cell growth and creation of vascular-like networks in vitro. Chemical structures with angiogenesis-modulating activity from the second library will be used as a mold to synthesize even more active analogues. Based on the chemical signatures with angiogenesis-modulating activity, we will generate de novo an extract library (~200 entities) from plants rich in molecules structurally resembling these chemical signatures. This new library will be screened in vitro in the same assays. A sub-library of ~30 plant extracts that show activity in the screen will be further investigated by assessing whether they interact with a key angiogenesis player, the Vascular Endothelial Growth Factor (VEGF) receptor.

The receptor protein will be produced by recombinant technology in specially modified microbial systems and immobilized on columns optimized for the protein. Detection and characterization of VEGF-interacting compounds will be performed by cutting-edge FAC-MS technology. Furthermore, DNA microarray technology and bioinformatics analysis of endothelial cells exposed to the most promising candidates will help identify their likely molecular effectors (targets), some of them potentially novel.

Finally, the in vivo bioactivity of the 5 most active molecules will be evaluated in representative pre-clinical angiogenesis models, such as solid tumor growth. Pilot toxicology studies will be also conducted on them. The 2 most potent and safest compounds will undergo optimized formulation.

Overall, by assembling state-of-the-art scientific expertise, by using as screening input two unique libraries of natural products and natural product-inspired molecules and by strategically choosing an unbiased, direct, functional approach, we substantially increase the chances of identifying lead angiogenesis-modulating compounds and novel targetable mechanisms. The expected scientific advances will not only considerably strengthen all participating organizations but, most importantly, may also help address the pressing global therapeutic need in human diseases characterized by dysregulated angiogenesis.