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• genetics, genomics and molecular biology
• cancer/oncology

• Medicine

• Haematology
• Oncology
• Pharmacology

The work in our laboratory focus on studying the mechanisms of DNA replication in cancer cells at the molecular level and exploiting the results in this field for therapeutic purposes. We use a combination of modern technologies in genome editing, genomics, cellular and molecular biology to address the fundamental question of how normal and cancer cells multiply and to devise novel and more effective strategies to limit cancer growth. We have specific interest in breast cancer and onco-hematology.
Recent work of from our lab has been published on top journals including Cancer Research, NAR and Nature Chemical Biology.

1. McGarry, E. et al. The Deubiquitinase USP9X Maintains DNA Replication Fork Stability and DNA Damage Checkpoint Responses by Regulating CLASPIN during S-Phase. Cancer Res. 76, 2384?2393 (2016).
2. Wu, K. Z. L. et al. DDK dependent regulation of TOP2A at centromeres revealed by a chemical genetics approach. Nucleic Acids Res. (2016). doi:10.1093/nar/gkw626
3. Montagnoli, A. et al. A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nat. Chem. Biol. 4, 357?365 (2008).

Several projects in the area of molecular targeted therapy in cancer are available, please contact for more information. As an example:

Identification of molecular determinant for the activity of novel DNA replication kinase inhibitors

Background:
CDC7 kinase is considered a key switch for DNA replication and its depletion by siRNA causes cancer cells to stop DNA synthesis and to die in a p53 independent manner. Many institutions are developing CDC7 inhibitors (CDC7i), which block its enzymatic activity by competing with ATP, as potential agents for refractory p53 deficient cancers. Some CDC7i have excellent antitumor activity and are approaching clinical trials. On the contrary, others compounds equally able to inhibit CDC7, only have marginal effect on DNA synthesis and proliferation. Such striking differences in cellular responses to CDC7 inhibition can be due to 1) off-target effects of siRNA and drugs or 2) existence of mechanisms that can compensate for loss of CDC7 activity.

Aims:
The overarching question is ?How cancer cells respond to CDC7 kinase inhibition and what are the genetic determinants that affect response?? Specific objectives are:
1) Develop genetic cellular models that will unequivocally allow characterization of cellular phenotypes associated with rapid and specific inhibition of CDC7.
2) Identify cellular factors that modulate the response to CDC7i.

Techniques and Methodology:
1) Exploiting the concept of the ?analogue sensitive kinase?, we will generate cellular models in which CDC7 activity can be rapidly and efficiently modulated, with minimal off-target effects. This will be accomplished using CRISPR/CAS9 gene editing technology.
2) Using lentivirus sgRNA pooled libraries, we will perform large-scale loss-of function screens to identify cellular factors that increase the efficacy of CDC7i.

Impact on cancer research:
This work will validate the use of CDC7i indicating which genes are involved in determining the sensitivity to CDC7i and it will advance understanding of cell-cycle regulation.