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.
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.
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.
Diletta Di Mitri, Alberto Toso, Andrea Alimonti, Targeting tumor infiltrating myeloid derived suppressor cells (MDSCs) for cancer therapy, in Clinical Cancer Research
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
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
Diletta Di Mitri, Alberto Toso, Andrea Alimonti, Tumour infiltrating myeloid cells drive senescence evasion and chemoresistance in cancer, in Oncoimmunology
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.