Molecular Oncology and Mouse Models
Andrea Alimonti, MD (group leader)
Alberto Toso, PhD (postdoc)
Abdullah Alajati, PhD (postdoc)
Ilaria Guccini, PhD (postdoc)
Diletta Di Mitri, PhD (postdoc)
JingJing Chen (phd student)
Ajinkya Revandkar (phd student)
Madhuri Kalathur (phd student)
Cellular senescence is an irreversible cell growth arrest, observed in response to various insults including an abnormally high activity of oncogenes, suboptimal cells growth conditions and DNA damage. After its discovery and molecular characterization in vitro, it has only recently been recognized to specifically oppose tumor formation in various tissues, both in humans and in mice. Given the limited number of therapeutic approaches currently at our disposal in the fight against cancer, it is wise to explore the usefulness of a pro-senescence alternative for cancer therapy.
Our research is focused on the characterization of a novel type of cellular senescence response which is elicited by complete loss of the tumor suppressor PTEN, and on the identification of novel compounds with pro-senescence activity. Our aim is to develop the concept of pro-senescence therapy for cancer, from experimental evidences to clinic, investigating the efficacy of “pro-senescence” compounds in phase I clinical trials. This will also allow for the identification of senescence markers in human tumor samples to be used in clinic.
ERC Project: PICS Therapy
A project 'PICS therapy' (Pten loss Induced Cellular Senescence therapy) is funded under the ERC starting grant from the European Union. The project aims to find a new kind of cancer therapy, especially against prostate cancer. The therapy focuses on PTEN, a protein that regulates cell growth and division. If a cell has not enough of this protein, for example 80% of normal, the cell grows and divides beyond control - which means cancer. Paradoxically, however, if the level drops to 0%, the cell reacts by “getting old”: it does not grow and divide anymore at all. PICS therapy screens several thousands of compounds that potentiate this effect on cancer cells and, eventually, will try selected compounds in clinical tests.
- A. Alimonti, A. Carracedo, J. G. Clohessy, C. Nardella, L. C. Trotman, C. Nardella, A. Egia, L. Salmena, K. Sampieri, E. Brogi, J. Zhang, A. Richardson and P. P. Pandolfi. Subtle variations in PTEN dose determine breast cancer susceptibility. Nat Genet. 2010 May;42(5):454-8.
- A. Alimonti, C. Nardella, Z. Chen, J. G. Clohessy, L. C. Trotman, A. Carracedo, K. Cheng, S. Varmeh-Ziaie, M. B. Kastan, S.C. Kozma, G. Thomas, E. Rosivatz, R. Woscholski,F.Cognetti, H.I. Scher and P. P. Pandolfi. Modulation of cellular senescence response for ‘pro-senescence’ therapy in cancer. J Clin Invest. 2010 Mar;120(3):681-93.
- L.C. Trotman, A. Alimonti, P.P. Scaglioni, J.A. Koutcher, C. Cordon-Cardo and P.P. Pandolfi. Identification of a tumour suppressor network opposing nuclear AKT function.Nature, 441:523-7 2006.
- L.C. Trotman, X. Wang, A. Alimonti, Z. Chen, J. Teruya-Feldstein, S-G. Chi, H-J. Kim, H. Yang, N.P. Pavletich, B.S. Carver, H. Erdjument-Bromage, P. Tempst, C. Cordon-Cardo, T. Misteli. X. Jiang and P.P. Pandolfi. Ubiquitination regulates nuclear PTEN import and tumor suppression as revealed by inherited mutation. Cell. 2007 Jan 12; 128(1): 141-56.
- X. Wang, L. Trotman, T. Koppie, A. Alimonti, Z. Gao, J. Wang, H. Erdjument-Bromage, P. Tempst, C. Cordon-Cardo, P.P. Pandolfi and X. Jiang. NEDD 4-1 is the Proto-oncogenic Ubiquitin ligase for PTEN. Cell. 2007 Jan 12;128(1):129-39.