I currently hold a position of PhD Student in Dr Xavier Salvatella’s laboratory at IRB Barcelona. My projects focus on different steps of early drug discovery processes from target validation to lead optimisation. I work in the field of small molecules targeting intrinsically disordered proteins (IDPs). For this position I have secured an MSCA co-fund PREBIST PhD fellowship that, apart from funding, provides me with various forms of high-end training.
I hold a double master degree in Biomedical Engineering from Grenoble Institute of Technology, Grenoble, France (INP Grenoble) and AGH Institute of Science and Technology, Cracow, Poland, which I finished with the highest distinction and among 5% top graduates. For this degree I was awarded a French Government Scholarship by the French Embassy in Warsaw, Poland.
During my studies I completed several internships both in fundamental and applied sciences. I worked at Bioaster Microbiology Technology Institute in Paris, France, under co-supervision of Dr Christophe Védrine and Dr Patrick Lécine on novel multiplex in vitro diagnostic test. I also finished an internship at the laboratory of Dr Isabelle Tardieux at the Institute for Advanced Biosciences in Grenoble, France, where I worked with the state-of-the-art real-time microscopy to understand the dynamics of Toxoplasma gondii during the host invasion.
Throughout my career I have participated in many important scientific and outreach initiatives. This includes co-chairing Scientific Organising Committee for ENABLE Conference 2021 and a teaching practice as a tutor within “Crazy about Biomedicine” programme for excellent high school students.
After completing my PhD I intend to continue working on the verge of technological advances in drug discovery to push the frontiers of knowledge and bring therapies from the bench to the bedside.
Role of transcription factor condensation in transactivation: opportunities for therapeutic intervention
Prostate cancer is the second leading cause of cancer in men and is responsible for the yearly death of ca. 35,000/40,000 American/European patients. A key driver of the tumour progression is the androgen receptor (AR), a transcription factor that has three domains: the N-terminal domain (NTD), the DNA-binding domain (DBD) and the ligand binding domain (LBD). AR belongs to the family of nuclear receptors and is activated by the androgens binding to the LBD, such as dihydrotestosterone. The first line prostate cancer treatment is based on inhibiting AR by decreasing androgen levels, which can be achieved by androgen deprivation therapy that is based on surgical/chemical castration and/or blocking androgen binding to the LBD of AR.
Unfortunately, all patients treated with androgen deprivation therapy become refractory to these treatments and reach an incurable stage of the disease known as castration resistant prostate cancer (CRPC). This is due to mechanisms such as AR gene amplification, gain-of-function mutations, and, especially, the expression of constitutionally active splice variants of AR lacking the ligand binding domain. The NTD, a domain indispensable for transactivation, is present in all splice variants and therefore could be considered as a perfect target for CRPC therapies. Nevertheless, the NTD is intrinsically disordered, thus lacking persistent binding pockets for small molecules. Although this would classify it as undruggable, a family of small molecule inhibitors was identified by phenotypic screening (Andersen et al, Cancer Cell, 2010), indicating that it is a challenging but validated target.
The subject of my thesis is focused mainly on two projects, both of them aiming at advancing the new therapeutic strategies to treat CRPC. The first project is based on using a peptide derived from an NTD motif to inhibit the interaction with its binding partner RAP74. RAP74 is a globular domain of the general transcription factor IIF and its binding to the NTD is essential for the AR-driven transcription (De Mol, Szulc et al, Struct, 2018). The goal of this project is to validate RAP74 as a CRPC target and give the patients a new therapeutic opportunity. In the second main project I develop a rational screening strategy to identify new inhibitors that modulate the biophysical properties of the NTD. This approach might open a new avenue for targeting AR, as well as other targets, and bring a new potential therapy to the market.