Project

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Manipulation of senescence pathways for cancer therapy: from experimental models to clinic

Applicant Alimonti Andrea
Number 136612
Funding scheme Ambizione
Research institution Fondazione per l'Istituto Oncologico di Ricerca (IOR) Istituto di Ricerca in Biomedicina
Institution of higher education Università della Svizzera italiana - USI
Main discipline Experimental Cancer Research
Start/End 01.02.2012 - 31.01.2015
Approved amount 558'704.00
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All Disciplines (3)

Discipline
Experimental Cancer Research
Molecular Biology
Clinical Cancer Research

Keywords (3)

Senescence; PTEN loss; Targeted therapy

Lay Summary (English)

Lead
Senescence is an irreversible cell growth arrest which opposes tumor formation by blocking tumor proliferation and triggering an immune tumor clearance. Aim of this Score project is to identify novel pro-senescence compounds for cancer therapy. We have recently developed a screening platform for the identification of novel pro-senescence compounds (PICS assay) by using the Pten loss induced cellular senescence model. Compounds will be selected by taking advantage of bioinformatics, chemogenomic and drug repositioning approaches and will be screened in the PICS assay and in the Pten mouse model. Identified leads will be validated in human cancer cell lines and quiescent cancer stem cells. This study model will lead to the appropriate development of pro-senescence compounds from in vitro to the pre-clinical and clinical phase.
Lay summary
Senescence is an irreversible cell growth arrest which opposes tumor formation  by blocking tumor proliferation and triggering an immune tumor clearance. Aim of this Score project is to identify novel pro-senescence compounds for cancer therapy. We have recently developed a screening platform for the identification of novel pro-senescence compounds (PICS assay) by using  the Pten loss induced cellular senescence model. Compounds will be selected by taking advantage of bioinformatics, chemogenomic and drug repositioning approaches and will be screened in the PICS assay and in the Pten mouse model. Identified leads will be validated in human cancer cell lines and quiescent cancer stem cells. This study model will lead to the appropriate development of pro-senescence compounds from in vitro to the pre-clinical and clinical phase.
Direct link to Lay Summary Last update: 12.03.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity.
Toso Alberto, Revandkar Ajinkya, Di Mitri Diletta, Guccini Ilaria, Proietti Michele, Sarti Manuela, Pinton Sandra, Zhang Jiangwen, Kalathur Madhuri, Civenni Gianluca, Jarrossay David, Montani Erica, Marini Camilla, Garcia-Escudero Ramon, Scanziani Eugenio, Grassi Fabio, Pandolfi Pier Paolo, Catapano Carlo V, Alimonti Andrea (2014), Enhancing chemotherapy efficacy in Pten-deficient prostate tumors by activating the senescence-associated antitumor immunity., in Cell reports, 9(1), 75-89.
Marine sponge Cribrochalina vasculum compounds activate intrinsic apoptotic signaling and inhibit growth factor signaling cascades in non-small cell lung carcinoma.
Zovko Ana, Viktorsson Kristina, Hååg Petra, Kovalerchick Dimitry, Färnegårdh Katarina, Alimonti Andrea, Ilan Micha, Carmeli Shmuel, Lewensohn Rolf (2014), Marine sponge Cribrochalina vasculum compounds activate intrinsic apoptotic signaling and inhibit growth factor signaling cascades in non-small cell lung carcinoma., in Molecular cancer therapeutics, 13(12), 2941-54.
Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer.
Di Mitri Diletta, Toso Alberto, Chen Jing Jing, Sarti Manuela, Pinton Sandra, Jost Tanja Rezzonico, D'Antuono Rocco, Montani Erica, Garcia-Escudero Ramon, Guccini Ilaria, Da Silva-Alvarez Sabela, Collado Manuel, Eisenberger Mario, Zhang Zhe, Catapano Carlo, Grassi Fabio, Alimonti Andrea (2014), Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer., in Nature, 515(7525), 134-7.
Targeting tumor infiltrating myeloid derived suppressor cells (MDSCs) for cancer therapy
Diletta Di Mitri, Alberto Toso, Andrea Alimonti, Targeting tumor infiltrating myeloid derived suppressor cells (MDSCs) for cancer therapy, in Clinical Cancer Research.
A combined chemogenomic and shRNA-screening platform identifies CK2 as a novel target for pro-senescence therapy in PTEN null tumors
Madhuri Kalathur, Alberto Toso, Jingjing Chen, Ajinkya Revandkar, Andrea Alimonti, A combined chemogenomic and shRNA-screening platform identifies CK2 as a novel target for pro-senescence therapy in PTEN null tumors, in Nature Communications.
Enhancing chemotherapy efficacy by reprogramming the senescence-associated secretory phenotype of prostate tumors. “A way to reactivate the anti-tumor immunity"
Alberto Toso, Diletta Di Mitri, Andrea Alimonti, Enhancing chemotherapy efficacy by reprogramming the senescence-associated secretory phenotype of prostate tumors. “A way to reactivate the anti-tumor immunity", in Oncoimmunology.
Tumour infiltrating myeloid cells drive senescence evasion and chemoresistance in cancer
Diletta Di Mitri, Alberto Toso, Andrea Alimonti, Tumour infiltrating myeloid cells drive senescence evasion and chemoresistance in cancer, in Oncoimmunology.

Collaboration

Group / person Country
Types of collaboration
Jiangwen Zhang, Faculty of Arts and Sciences (FAS), Center for Systems Biology, Harvard University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Lorenzo Pinna, University of Pavia Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Alessandro Padova, Head of Department Medicinal Chemistry and Molecular Informatics, Siena Biotech Italy (Europe)
- Publication
- Research Infrastructure
Ian Frew, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Signal trasduction_ESMO meeting Talk given at a conference PTEN 01.03.2014 Sidges, Spain Alimonti Andrea;
Manipulation of senescence pathways for cancer therapy Talk given at a conference Manipulation of senescence pathways for cancer therapy 30.10.2013 Cologne, Germany Alimonti Andrea;
Sino-Swiss conference Talk given at a conference SASP reprogramming for cancer therapy 02.10.2013 Beijin, China Alimonti Andrea;
“Immune –senescence” therapy for cancer Talk given at a conference “Immune –senescence” therapy for cancer 02.11.2012 Lousanne CHUV, Switzerland Alimonti Andrea;


Awards

Title Year
J. Steiner Cancer Research Award 2015
Fellowship 2012

Associated projects

Number Title Start Funding scheme
145038 Acquisition of a 2-Photon microscope for intravital analysis 01.12.2012 R'EQUIP

Abstract

Recent papers, including ours, have demonstrated the relevance of cellular senescence in restricting tumorigenesis in vivo, opening up new potential opportunities for cancer treatment. This proposal aims to harness a novel type of cellular senescence that we have identified in response to activation of the PI3K pathway by complete loss of the tumor suppressor PTEN, and which we believe offers a radical therapeutic approach to target prostate cancer cells including quiescent prostate cancer stem cells. In characterizing the mechanisms and features of PI3K-Induced Cellular Senescence (PICS), we have discovered that PICS is distinct from other forms of cellular senescence including oncogene-induced senescence (OIS) and replicative senescence. These distinct differences are characterized by a lack of DNA damage and hyper-replication in PICS, breaking the current dogma for senescence induction. In addition, we have found that PICS can be evoked even in non proliferating cells. This senescence pathway is therefore the result of a genuine signalling short circuit that is driven by a novel Akt-mTOR-p53 pathway. The ability to induce senescence in cells by targeting PTEN signalling, without a requirement for hyper replication and DNA damage, opens up the possibility of targeting quiescent cells including quiescent cancer initiating cells. Due to the fact that partial functional PTEN loss as a consequence of heterozygous mutation/deletion or protein down regulation is associated with the vast majority of tumours at presentation, this approach has tremendous therapeutic potential and represents one of the most exciting developments for the advancement of cancer prevention and therapy in recent years. We have in fact already identified drugs that potentiate PICS and that we will test in pre-clinical trials, while, at the same time, we propose to identify novel PICS enhancing drugs through the manipulation of senescence induction pathways in gene expression-based small molecule screenings using our previously characterized PICS in vitro assay. In addition, we aim to validate the efficacy of pro-senescence therapy in human prostate quiescent cancer stem cells (qCICs). We will use bioinformatics and systems biology approaches to unify the data derived from our small molecule screening and to generate in silico models of senescence relevant signalling that will lead to the molecular characterization of cellular senescence and to the identification of pro-senescence compounds. Finally we have developed unique prostate cancer mouse models to study, in a preclinical setting, the biology of the prostate qCICs, in response to PICS and PICS enhancing drugs. This study model will lead to the appropriate development of compounds with pro-senescence potential from in vitro to the pre-clinical and clinical phase.
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