Prof Corrado Santocanale

Ph.D

 
researcher
 

Biography

Professor Corrado Santocanale received his Ph.D. in Cellular and Molecular Biology at the University of Milan, Italy, in 1993. His early work focused on the characterization of enzymes required for the duplication of the DNA in the yeast S. cerevisiae. He was then awarded an EU Marie Curie postdoctoral fellowship to work on the molecular mechanisms that control initiation of DNA replication at the Clare Hall Laboratories, Cancer Research UK, London. He spent eight years in the pharmaceutical industry at the Oncology R&D site in Nerviano, Italy (former Pharmacia/Pfizer and now Nerviano Medical Sciences) both as a group and as a project leader developing protein kinase inhibitors for the treatment of human cancers. He returned to academia  in 2007. The major achievement in Cancer Drug Discovery was to propose and lead a program through all the stages of the pre-clinical drug discovery process delivering a compound with a novel mechanism of action that entered clinical trials. The major achievements in basic cancer research include: - Identification and characterization of the "origin firing checkpoint", a biochemical pathway that is activated in response to the inhibition of DNA replication elongation thus preventing the activation of new replication origins. - Identification of the second "cyclin like" regulatory subunit of the human Cdc7 kinase. - The identification of a biochemical pathway, altered in cancer cells, responding to the inhibition of the Cdc7 kinase. Identification of the gene encoding the first eukaryotic DNA primase large subunit. 

Research Interests

The process of DNA replication is the biggest threat for genome stability in all proliferating cells. Cancer cells in particular are subjected to replication stress after activation of proto-oncogenes into their oncogenic forms or due to deficiency in specific factors required for genome duplication. Thus aberrant DNA replication contributes to initiating and maintaining the cancerous state, while drugs targeting DNA synthesis have potent antitumor activity and are key component of current and novel chemotherapeutic regimens.

Our laboratory is studying the mechanisms that regulate genome replication in human cells with particular emphasis on the Cell Division Cycle 7 kinase (CDC7). CDC7 acts as a molecular switch for DNA synthesis and is also thought to participate in several other processes that regulate normal cell cycle progression and chromosome dynamics.We have adopted chemical biology and gene editing approaches to characterize the molecular processes in which CDC7 is involved and to detect new substrates of the kinase. We are performing genome-wide CRISPR/Cas9 screens to identify genes that alter the cellular responses and make cells more sensitive or resistant to CDC7 inhibition.This information will be pivotal in understanding in what disease context emerging CDC7 inhibitors may be used for the cancer treatment, and in developing novel biomarkers, thus providing valuable information and tools for rationally driving patient selection and devising combination therapies in preclinical and clinical settings.

We are also interested in understanding the roles of the Ubiquitin Specific Protease 9X (USP9X) which in context dependent manner can act as either an oncogene or a tumour suppressor. We have recently discovered that USP9X contributes to genome stability by promoting forks stability and efficient DNA repair, but by different mechanisms. 

In the past we have established a technique for the purification and characterization of proteins associated to newly replicated DNA that we called DNA mediated chromatin pull down (Dm-ChP).  This technique has been particularly useful in understanding which proteins acts at forks during unperturbed replication, upon replication stress and in different genetic backgrounds.

Cell Cycle, DNA replication, Cancer therapeutics
 

Research Projects

  Project Start Date End Date
Cellular responses to ATP competitive CDC7 kinase inhibitors 01-FEB-16 31-JAN-23
CDC7 REGULATION OF CLASPIN STABILITY AND ITS EFFECT ON CELL CYCLE CHECKPOINT FUNCTION C SANTOCANALE 01-APR-13 31-DEC-19
CDC7 AND CLASPIN IN THE REGULATION OF DNA REPLICATION IN BREAST CANCER CELLS BREAST CANCER CAMPAIGN CORRADO SANTOCANALE 01-NOV-12 31-JAN-16
GUAN NAN WANG IRCSET EMPOWER POSTDOC CORRADO SANTOCANALE 01-JUL-12 19-OCT-15
ESI HEA PRTLI5 MMI CTRSP EDEL MCGARRY 01-MAR-11 25-OCT-18
EHA ASH RESEARCH EXCH AWRD MARK COYNE 01-JUL-10 30-NOV-12
UNDERSTAND EXPLOIT MOLECULAR DNA 08/IN.1/B2064 - C SANTOCANALE 01-SEP-09 05-JAN-17
REGULATION BY MICRORNAS AND ITS IMPACT IN CANCER 01-OCT-08 30-SEP-12
SFI CDC7 KINASE IN CANCER CELLS EXPOSED TO S-PHASE 01-SEP-08 31-AUG-11

Teaching Interests

Involved in the education of second and third year Biochemistry and Medicine students. Also contributing to several post-graduate courses. 

Recent Postgraduate Students

  Graduation Name Degree Primary Supervisor
2012 Anna Kliszczak PhD Y
2012 Raffaella D'Auria Msc Y
2015 Kevin Wu PhD Y
2014 Mark Coyne PhD Y
2016 Edel McGarry PhD Y
2015 Ashton Scully Msc Y

Internal Collaborators

  Name Description of Collaboration
Internal Collaborators
Prof Michael O'Dwyer.Dr Heinz Peter Nasheuer.

External Collaborators

  Name Organisation / Institute Country Description of Collaboration
External Collaborators
Dr Stefan Knap, Structural Genomic Consortium, University of Oxford, UK. Dr Achille Peliccioli, Dipartimento di Scienze Biomolecolari e Biotecnologie University of Milan, Italy. Dr Andrea Musacchio,  Max-Planck Institute of Molecular Physiology, Dortmund, Germany.