PRO-SENESCENCE AND SENOLYTICS
Our laboratory mainly focusses on characterizing and subsequently manipulating pathways involved in induction of senescence, as a novel therapeutic approach in treatment of PTEN-deficient prostate tumors.
Prostate cancer (PCa) at advanced stage is extremely irresponsive to conventional and targeted therapies, where chemotherapy remains of palliative benefit. These tumors often harbor PTEN-loss, which results in poor prognosis and therapy-resistance. While acute loss of PTEN induces senescence response both in vitro and in vivo, termed Pten-loss induced cellular senescence (PICS), we aim to identify novel enhancers and their target genes involved in modulating PICS. Importantly, even though senescence is demonstrated to restrict tumorigenesis in vivo, prolonged accumulation of such senescent tumor cells, have been reported to have a negative impact on the tumor microenvironment thereby allowing its progression. Thus, we aim to identify small molecule inhibitors that can selectively eliminate senescent-tumor cells. Our final aim is to implement, in tandem, a ‘Pro-senescence approach’ followed by ‘Senolytic 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. The final 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.
Ongoing activities
- Identification of Salvia haenkei as gerosuppressant agent
- Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence
- Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer
- IL-23 secreted by myeloid cells drives castration-resistant prostate cancer
- Development of senolytic compounds for prostate cancer therapy
- Pre-clinical validation of SH extract as anti-aging agent
- Development of senolytic compounds for the treatment of aging-related disorders
- Montopoli M, Zumerle S, Vettor R, Rugge M, Zorzi M, Catapano CV, Carbone GM, Cavalli A, Pagano F, Ragazzi E, Prayer-Galetti T, Alimonti A. Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2: a population-based study (n=4532). Ann Oncol. 2020 May 4:S0923-7534(20)39797-0.
- Alajati A, D'Ambrosio M, Troiani M, Mosole S, Pellegrini L, Chen J, Revandkar A, Bolis M, Theurillat JP, Guccini I, Losa M, Calcinotto A, De Bernardis G, Pasquini E, D'Antuono R, Sharp A, Figueiredo I, Nava Rodrigues D, Welti J, Gil V, Yuan W, Vlajnic T, Bubendorf L, Chiorino G, Gnetti L, Torrano V, Carracedo A, Camplese L, Hirabayashi S, Canato E, Pasut G, Montopoli M, Rüschoff JH, Wild P, Moch H, De Bono J, Alimonti A. CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo. J Clin Invest. 2020 May 1;130(5):2435-24
- Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, Campisi J, Collado M, Evangelou K, Ferbeyre G, Gil J, Hara E, Krizhanovsky V, Jurk D, Maier AB, Narita M, Niedernhofer L, Passos JF, Robbins PD, Schmitt CA, Sedivy J, Vougas K, von Zglinicki T, Zhou D, Serrano M, Demaria M. Cellular Senescence: Defining a Path Forward. Cell. 2019 Oct 31; 179(4):813-827
- Di Mitri D, Mirenda M, Vasilevska J, Calcinotto A, Delaleu N, Revandkar A, Gil V, Boysen G, Losa M, Mosole S, Pasquini E, D'Antuono R, Masetti M, Zagato E, Chiorino G, Ostano P, Rinaldi A, Gnetti L, Graupera M, Martins Figueiredo Fonseca AR, Pereira Mestre R, Waugh D, Barry S, De Bono J, Alimonti A. Re-education of Tumor-Associated Macrophages by CXCR2 Blockade Drives Senescence and Tumor Inhibition in Advanced Prostate Cancer. Cell Rep. 2019 Aug 20;28(8):2156-2168.e5
- Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria M, Alimonti A. Cellular Senescence: Aging, Cancer, and Injury. Physiol Rev. April 2019 99(2):1047-1078.
- Rodrigues DN, Rescigno P, Liu D, Yuan W, Carreira S, Lambros MB, Seed G, Mateo J, Riisnaes R, Mullane S, Margolis C, Miao D, Miranda S, Dolling D, Clarke M, Bertan C, Crespo M, Boysen G, Ferreira A, Sharp A, Figueiredo I, Keliher D, Aldubayan S, Burke KP, Sumanasuriya S, Fontes MS, Bianchini D, Zafeiriou Z, Mendes LST, Mouw K, Schweizer MT, Pritchard CC, Salipante S, Taplin ME, Beltran H, Rubin MA, Cieslik M, Robinson D, Heath E, Schultz N, Armenia J, Abida W, Scher H, Lord C, D'Andrea A, Sawyers CL, Chinnaiyan AM, Alimonti A, Nelson PS, Drake CG, Van Allen EM, de Bono JS. J. Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer. Clin Invest 2018 Nov 128(11):5185.
- Sgrignani J, Chen J, Alimonti A, Cavalli A. How phosphorylation influences E1 subunit pyruvate dehydrogenase: A computational study. Sci Rep. Oct 2018 8(1):14683
- Calcinotto A, Spataro C, Zagato E, Di Mitri D, Gil V, Crespo M, De Bernardis G, Losa M, Mirenda M, Pasquini E, Rinaldi A, Sumanasuriya S, Lambros MB, Neeb A, Lucianò R, Bravi CA, NavaRodrigues D, Dolling D, Prayer-Galetti T, Ferreira A, Briganti A, Esposito A, Barry S, Yuan W, Sharp A, de Bono J, Alimonti A. IL-23 secreted by myeloid cells drives castration-resistant prostate cancer. Nature 2018 559(7714):363-36
- Chen J, Guccini I, Di Mitri D, Brina D, Revandkar A, Sarti M, Pasquini E, Alajati A, Pinton S, Losa M, Civenni G, Catapano CV, Sgrignani J, Cavalli A, D'Antuono R, Asara JM, Morandi A, Chiarugi P,Crotti S, Agostini M, Montopoli M, Masgras I, Rasola A, Garcia-Escudero R, Delaleu N, Rinaldi A, Bertoni F, Bono J, Carracedo A, Alimonti A. Compartmentalized activities of the pyruvate dehydrogenase complex sustain lipogenesis in prostate cancer. Nat Genet 2018 50(9):1343
- Revandkar A, Perciato ML, Toso A, Alajati A, Chen J, Gerber H, Dimitrov M, Rinaldi A, Delaleu N, Pasquini E, D'Antuono R, Pinton S, Losa M, Gnetti L, Arribas A, Fraering P, Bertoni F, Nepveu A, Alimonti A. Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence. Nat Commun 2016 7:13719
- Matic I, Revandkar A, Chen J, Bisio A, Dall'Acqua S, Cocetta V, Brun P, Mancino G, Milanese M, Mattei M, Montopoli M, Alimonti A. Identification of Salvia haenkei as gerosuppressant agent by using an integrated senescence-screening assay. Aging (Albany NY) 2016 8(12):3223-3240
ANDREA ALIMONTI
- Full Professor, Department of Medicine, University of Padua, Padua, Italy (2017)
- Full Professor, USI (Università della Svizzera Italiana), Lugano, Switzerland (2017)
- Clinical Oncology Specialization, Regina Elena National Cancer Institute, Rome, Italy (2004)
- Group leader: Venetian Institute of Molecular Medicine (VIMM), Padova, Italy (since 2012)
- Medicine M.D..University of Rome “La Sapienza”, Rome, Italy (2000)
Selected Awards
- 2015-2019, Steiner award, J.Steiner Foundation
- 2016-2019, EMBO Young Investigator Programme, EMBO (European Molecular Biology Organization)
- 2010-2013, Swiss Bridge Award, Swiss Bridge Foundation
- 2009-2010, Award in translational research, ESMO (European Society of Medical Oncology)
Current funding
- Fondazione CARIPARO
- Fondazione AIRC