Anna Huguet Ninou - ESR 14
Name: Anna Huguet Ninou
Nationality: Catalan (Spanish)
Main Host Institution: Kancera AB in collaboration with The Helleday Laboratory, Karolinska
M.Sc. Drug Discovery and Safety Assessment (Major in molecular toxicology),
Vrije Universiteit Amsterdam.
B.Sc. Cellular and Molecular Biotechnology, Universitat Autònoma of Barcelona.
Project title: Inhibition of PFKFB3 for therapeutic targeting of ovarian cancer.
Project background: Ovarian cancer is the sixth most common cancer among European women and one of the most malignant ones. Considering that approximately 50% of patients that suffer this cancer do not survive, looking for new and effective therapeutic strategies is of main interest. Current chemotherapy consists on using drugs that damage DNA (platinum compounds and taxanes). However, these drugs are noxious in healthy tissues and that limits their therapeutic potential.
The development of targeted therapies that selectively kill cancer cells with harmless effects on healthy cells offers the possibility to tackle this scenario. Since proteins that help to repair damaged DNA (such as BRCA1, BRCA2 and RAD51) do not function correctly in ovarian tumor cells due to mutations in their genes, synthetic lethal interactions can be exploited compromising the stability of cancer cell’s genetic material. This is the case of PARP inhibitors, drugs that inhibit an alternative mechanism by which BRCA-deficient tumor cells rely to repair DNA damage and, thus, constitute an effective targeted therapy for ovarian cancer.
In most ovarian tumors, there is a physiological lack of oxygen because an imbalance between the formation of blood vessels and the tumor mass growth. To cope with this oxygen-deficient situation, the tumor adjusts its metabolism so that it primarily uses glycolysis (breakdown of sugar) independently of how much oxygen is available, also known as the Warburg effect. PFKFB3 is an enzyme responsible of regulating the first step of glycolysis. This key regulator of sugar metabolism has been found overexpressed in ovarian tumors compared to normal tissues. It is believed that PFKFB3 contributes to the so-called Warburg effect by promoting energy supply from glucose and supporting specifically cancer cell proliferation. Strikingly, PFKFB3 has been recently localized in the cell nucleus (while glycolysis occurs in the cytoplasm), indicating that this enzyme may play an unexpected role.
Project Aim: The aim of the project is to characterize the nuclear function of PFKFB3 in relation to the DNA damage response and DNA repair in ovarian cancer cells. We seek to study the mechanism of action of novel small inhibitors designed at Kancera AB, with emphasis on their effect on genetic instability.
Expected outcome: The study of synthetic lethal interactions when inhibiting PFKFB3 will contribute to rationally design targeted therapy for ovarian cancer that specifically kill cancer cells but not healthy cells. Throughout the four-year project we expect to validate potent PFKFB3 inhibitors to further assess the feasibility of targeting this enzyme when translated into the clinic.
Contact: Kancera or Helleday Lab, Karolinska