NUOVI APPROCCI TERAPEUTICI NEL CARCINOMA PROSTATICO Alfredo Berruti Dipartimento di Scienze Cliniche e Biologiche Università di Torino Azienda Ospedaliero Universitaria San Luigi di Orbassano

N Engl J Med 2004;351:1502-12.

Lancet 2010; 376: 1147–54

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CASTRATE RESISTANT PROSTATE CANCER Gain-of-function in AR. Mutations occurring in the AR ligand–binding domain AR gene amplification Cross-talk with growth factors and growth factor receptors Changes in the balance of steroid receptor coregulators Availability of androgens in tumor microenvironment Enzymatic conversion of other steroids to androgens in the local tumor environment, leading to an increase in the concentration and availability of androgens for the tumor. Sharifi N et al. Clin Cancer Res 2009

Low AR High AR 6

Low AR High AR 7

AR MDV 3100 ABIRATERONE LHRH-A BICALUTAMIDE KETOCONAZOLO FLUTAMIDE CIPROTERONE LHRH-A ABIRATERONE KETOCONAZOLO AR ANDROGENI

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Chemotherapy pretreated patients!!! 11

Mechanism of MDV3100 Lancet Oncol 2009; 10: 981–91 Yu Chen, Nicola J Clegg, Howard I Scher Lancet Oncol 2009; 10: 981–91

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only patients with asymptomatic disease were enrolled!!!

SIPULEUCEL-T TREATMENT FLOW

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Trattamenti medici per il carcinoma prostatico “castrate resistant” Ormonoterapia Abiraterone MDV3100 Vaccini Sipoleucel ? Farmaci a bersaglio molecolare Chemioterapia Cabazitaxel Inibitori del riassorbimento osseo Ac Zoledronico Denosumab

Sternberg C 2007 Disease Median Chemotherapy Burden survival indicated Rising PSA only 4 years? NO Asymptomatic 18 to 24 months Case by case Metastases (limited) Asymptomatic 18 months YES (extensive) Symptomatic 9 to 18 months YES PSA=prostate specific antigen Sternberg C 2007

Quale strategie nel prossimo futuro? Ormono terapia I linea LHRH-A Ormono terapia II linea Abiraterone o MDV3100 Ormono terapia III linea Abiraterone o MDV3100 Paziente asintomatico Paziente sintomatico Vaccino Chemioterapia

Quale strategie nel prossimo futuro? Farmaci aventi come bersaglio il tumore Farmaci aventi come bersaglio il microambiente

Bone marrow are a reservoir of cancer cells that eventually metastasize elsewhere. Clin Cancer Res 2008

ANTINEOPLASTIC AGENTS BISPHOSPHONATES AS ANTINEOPLASTIC AGENTS may create an unfavorable microenvironment for the survival and activity of cancer stem cell in bone

Lancet 2011; 377: 813–22