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.
October 1989-September 1993: Ph.D. degree in Cellular and Molecular Biology, University of Milan.
December 1988: University degree in Biology at the University of Milan with the highest rate (110/110 cum laude).
2004-2007 Principal Research Scientist and Project Leader. Nerviano Medical Sciences-Oncology, Nerviano, Italy.
2002-2004 Principal Research Scientist and Project Leader. Pfizer Oncology R&D, Nerviano, Italy
2000-2002 Principal Research Scientist and Project Leader. Pharmacia Corporation Oncology R&D, Nerviano, Italy
1999-2000 Research Scientist and Group leader, Pharmacia and Upjohn Oncology R&D, Nerviano, Italy
1994 to 1999: Post-doctoral fellow in the laboratory of Dr. John Diffley, ICRF (now Cancer Research UK) Clare Hall Laboratories, South Mimms, UK,
1993-1994: Postdoctoral fellow in the laboratory of Prof. Paolo Plevani and Prof. Giovanna Lucchini, University of Milan, funded by the University of Milan.
Research in my lab is centered on studying the mechanisms of DNA replication in cancer cells and exploiting the results of this research for therapeutic purposes. Active projects focus on understanding the cellular functions and regulation of Cdc7 kinase (A) and on characterizing inhibitors of Cdc7 kinase activity in Multiple Myeloma and Chronic Lymphocytic Leukaemia (B). Recently we have developed a technique that will allow us to study how chromatin assembly is coupled with the duplication of DNA (C).
A) 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. Human Cdc7 has two cyclin-like binding partners which form either a Cdc7/Dbf4 complex or a Cdc7/Drf1 complex-their reciprocal roles are not yet defined. Biochemical, structural and functional approaches are employed to characterize the role of human Cdc7. Specific goals are:
- Define reciprocal roles of the Dbf4 and Drf1 regulatory subunits
- Identify new roles/substrates of the kinase
- Determine the structure of kinase active site and other structural domains
- Determine the impact of miRNA on Cdc7 activity
Key to these projects is the access to a MS/proteomic facility. A great effort was put into the development of in house infrastructure that can currently support both protein ID and phosphosite ID. This resource and protocols are made available to NUIG researchers.
B) Cdc7 inhibitors have shown antitumor activity in broad spectrum of preclinical cancer models including solid and leukemia xenografts, carcinogen induced and transgenic models. Phase I clinical studies are ongoing. A key question for this new class of drugs is to identify those cancer types in which they may be more efficacious. Together with Micheal O'Dwyer (Prof. of Hematology and Hospital consultant) we have been testing the activity and mechanism of action of Cdc7 inhibitors in cells from MM and CLL patents. Cellular co-culture systems that mimic the protective microenvironment niche of the lymph nodes have been developed for this purpose.
C) Replication of DNA and duplication of the epigenetic information are critical to the transmission of the genetic material from the parental cell to the two daughter cells and for specifying cell-type identity of the two daughter cells. To investigate how these processes are regulated and coordinated, it is important to determine the identity of the proteins that are either stably or transiently associated with newly synthesized DNA. We have devised an experimental procedure that allows newly synthesized chromatin to be efficiently captured and analyzed. We have termed this DNA mediated chromatin pull-down (Dm-ChP). Dm-ChP is a highly specific and flexible technique. Current work is focused on identifying the protein component of newly synthesized chromatin and in assessing qualitative and quantitative changes in this protein fraction caused by the normal temporal program of DNA replication as well as by perturbation of the DNA replication machinery.
OPEN ACCESS/ download at http://www.nature.com/srep/2011/110919/srep00095/full/srep00095.html
Mechanisms of Action of a Dual Cdc7/Cdk9 Kinase Inhibitor against Quiescent and Proliferating CLL Cells.
Mol Cancer Ther. 2011 Sep;10(9):1624-34. Epub 2011 Jul 18.
4) Alessia Montagnoli, Barbara Valsasina, Valter Croci, Maria Menichincheri, Sonia Rainoldi, Vanessa Marchesi, Marcello Tibolla, Pierluigi Tenca, Deborah Brotherton, Clara Albanese, Veronica Patton, Rachele Alzani, Antonella Ciavolella, Francesco Sola, Antonio Molinari, Daniele Volpi, Nilla Avanzi, Francesco Fiorentini, Marina Cattoni, Sandra Healy, Dario Ballinari, Enrico Pesenti, Antonella Isacchi, Jurgen Moll, Aaron Bensimon, Ermes Vanotti & Corrado Santocanale.
A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity.
Nature Chemical Biology 4, 357 - 365 (2008)
5) Tenca P., Brotherton D., Montagnoli A., Rainoldi S., Albanese C. and Santocanale C.
Cdc7 is an active kinase in human cancer cells undergoing replication stress.
Journal of Biological Chemistry (2007) 282, 208-215
6) Montagnoli A.,Tenca P., Sola F., Carpani D., Brotherton D., Albanese C., Santocanale, C.
Cdc7 inhibition reveals a new p53 dependent replication checkpoint that is defective in cancer cells.
Cancer Res. (2004); 64, 7110-6
7) Montagnoli A, Bosotti R, Villa F, Rialland M, Brotherton D, Mercurio C, Berthelsen J, and Santocanale C.
Drf1, a novel regulatory subunit for human Cdc7 kinase.
EMBO J. (2002); 21, 3171-81.
8) Santocanale, C. and Diffley J.F.X.
A Mec1- and Rad53- dependent checkpoint controls late-firing origins of DNA replication.
Nature, (1998), 395, 615-618.
January 2012: Ania pass her VIVA
We are proud of you !
Summer 2011: ALAN is awarded an HRB fellowship to perform a short project in our group...
...and in September he gets a GOLD medal for the best research project talk in the School of Medicine !
LAB Dinner Party August 2010
From the left: