[FPU2019] Cell Cycle & Cancer Biomarkers

1.- Identification of new resistance mechanisms for Plk1 inhibitors, in order to define new associated Plk1 therapeutic biomarkers:Alterations in cell cycle progression, high rates of cell proliferation and chromosomal instability are common features of multiple tumors. Numerous cell cycle regulators are overexpressed in tumors and very often this correlates with poor clinical prognosis. Nevertheless, proper identification of reliable biomarkers related to cell cycle, which not only correlate to prognosis but also provide a therapeutic value, is still lacking. One of the essential regulators for cell division, frequently overexpressed in cancer, is the Plk1 kinase. Plk1 is a promising therapeutic target against many types of tumors, and Plk1 inhibitors are already in advanced clinical stages. Although the molecular mechanisms of Plk1 kinase are well known, some of the new specific drugs do not achieve their preclinical efficacy when translated into clinical response in human trials. Therefore, being able to define sensitivity or resistance mechanisms for Plk1 inhibitors, can help to determine specific therapeutic strategies for each drug. 

2.- Identification of the molecular mechanisms by which Plk1 can act either as an oncogene or as a tumor suppressor:“Cancer is not a single disease, but approximately 200 different". This claim is now widely accepted and it means that a patient of a certain type of cancer may benefit from a particular therapy, and the same therapy may be completely useless in other patients. This applies even for patients suffering from a similar type of cancer. Therefore, there is currently an effort in research seeking for biomarkers that can tell what type of therapy is the most appropriate for each patient. This concept is the so called "personalized medicine". In the case of the Plk1 kinase, there is a dichotomy in its function since Plk1 can play as an oncogene or as a tumor suppressor, depending on the cancer type or even the tumor subtype. Therefore, being able to know, when the Plk1 expression will confer an advantage or a disadvantage to the patient is very challenging, and an extremely valuable tool in order to define diagnostic and therapeutic biomarkers. Finally, we want also to explore possible unexpected mechanisms for Plk1 in the tumoral context. We have recently described a role for Plk1 in vascular homeostasis. Plk1 expression can be found in post-mitotic arteria walls upon stress induction. This surprising feature led us to reconsider the angiogenesis events that take place inside the tumoral mass, and propose a challenging hypothesis: Can Plk1 play a role in angiogenesis? Both goals encounter the same general interest for this project: to describe the oncogenic molecular mechanisms associated with the mitotic kinase Plk1. References:https://www.ncbi.nlm.nih.gov/myncbi/guillermo.de%20carcer.1/bibliograph…