nuovi approcci terapeutici nel carcinoma prostatico alfredo berruti dipartimento di scienze cliniche...
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NUOVI APPROCCI TERAPEUTICINEL CARCINOMA PROSTATICO
Alfredo Berruti
Dipartimento di Scienze Cliniche e Biologiche
Università di Torino Azienda Ospedaliero UniversitariaSan Luigi di Orbassano
N Engl J Med 2004;351:1502-12.
Lancet 2010; 376: 1147–54
Gain-of-function in AR.
AR gene amplification
Cross-talk withgrowth factors and growth factor receptors
Changes in the balance of steroid receptorcoregulators
Mutations occurring in the AR ligand–binding domain
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.
Availability of androgens in tumor microenvironment
Sharifi N et al. Clin Cancer Res 2009
CASTRATE RESISTANT PROSTATE CANCER
Low AR
High AR
High AR
Low AR
AR
LHRH-A
ABIRATERONEKETOCONAZOLO
ANDROGENI
MDV 3100
BICALUTAMIDEFLUTAMIDECIPROTERONE
Chemotherapy pretreated patients!!!
Mechanism of MDV3100
Yu Chen, Nicola J Clegg, Howard I Scher
Lancet Oncol 2009; 10: 981–91
only patients with asymptomatic disease were enrolled!!!
SIPULEUCEL-T TREATMENT FLOW
Trattamenti medici per il carcinoma prostatico “castrate resistant”
OrmonoterapiaAbirateroneMDV3100
ChemioterapiaCabazitaxel
VacciniSipoleucel
Farmaci a bersaglio molecolare
Inibitori del riassorbimento osseoAc ZoledronicoDenosumab
?
Disease Median ChemotherapyBurden survival indicated
Rising PSA only 4 years? NO
Asymptomatic 18 to 24 months Case by caseMetastases(limited)
Asymptomatic 18 months YESMetastases(extensive)
Symptomatic 9 to 18 months YESMetastases
PSA=prostate specific antigenSternberg 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
Chemioterapia
Paziente asintomatico
Vaccino
Paziente sintomatico
Quale strategie nel prossimo futuro?
Farmaci aventicome bersaglio il tumore
Farmaci aventicome bersaglio il microambiente
Bone marrow are a reservoir of cancer cells that eventually metastasize elsewhere.
Clin Cancer Res 2008
Drugs that killcancer stem cells, or block their self-renewal Tumor looses its
ability to generatenew cells
Tumor degenerates,patient is cured
Drugs thatkill cancer cellsbut not CSCs
CSCs regenaratetumor
CSC
CSC
CSC
Tumor regresses
Tumor recursReya et al., Nature 2003
Implications of the cancer stem cell model for treatment
may create an unfavorable microenvironment for the survival and activity of cancer stem cell in bone
BISPHOSPHONATES AS ANTINEOPLASTIC AGENTS
2 7
P r o s ta te C a n c e r S u r v iv a l
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2 0
4 0
6 0
8 0
1 0 0
0 1 2 0 2 4 0 3 6 0 4 8 0 6 0 0 7 2 0 8 4 0 9 6 0
D a y s *
Per
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t su
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M e d ia n , d a y s P v a lu e
Z O M E T A ® 4 m g 5 4 6 .1 0 3P la c e b o 4 6 9
* T im e a f te r s ta r t o f s tu d y d r u g .
Z o l 4 m g 2 1 4 1 6 2 1 1 3 5 6 1 0P la c e b o 2 0 8 1 4 8 9 4 4 0 5
Lancet 2011; 377: 813–22