Synthetic Lethality in Cancer
“Development of screening platforms for the identification of new selective anti-tumor compounds through induction of synthetic lethality”
One of the current challenges in the fight against cancer is the identification of drugs as well as the development of therapeutic strategies that allow the elimination of cancer cells with minimum impact on normal cells. One of such strategies that have generated much interest in the last decade is the so-called “synthetic lethality” approach, which takes advantage of mutations in cancer cells to trigger their death. The rationale is that normal cells generally have multiple mechanisms to achieve a given function, implying that selective inhibition of one mechanism tends to be compensated by other mechanisms. In contrast, the inhibition of the same mechanism in cancer cells may trigger lethality due to the loss of compensatory mechanisms by mutations.
This project relies on the fact that tumor cells tend to lose some DNA repair pathways and to exacerbate others, thus leading to tumorigenesis, drug-resistance and tumor progression. We are particularly interested in homologous recombination (HR) because several types of cancer with high incidence (for instance breast cancers deficient in the proteins BRCA1 and BRCA2) are HR-deficient.
The general aim of our group is to identify compounds that behave as inducers of synthetic lethality in HR-deficient contexts in order to find candidate molecules for the development of selective anti-cancer drugs. To achieve this goal we develop phenotypic screenings platforms based on HR-deficient tumor cells, allowing the identification of synthetic lethality inducers.
Our specific aims include:
1) Generate high-throughput screening platforms using both “top down” strategies (unknown target) and “bottom up” strategies (target related).
2) Use those platforms to carry out screenings with commercial libraries of natural products as well as collections of compounds and complete extracts from plants, algae and fungi from Argentina and South America.
3) Validate the identified compounds in cell culture and models resembling the disease.
4) Study the mechanism of action of the more promising compounds in order to identify their molecular target.
Dr. Soria authored 12 publications in prestigious international journals, obtaining around 600 citations and reaching an h-index of 11. Details in the following link: