NUOVI APPROCCI TERAPEUTICI NEL CARCINOMA PROSTATICO Alfredo Berruti Dipartimento di Scienze Cliniche...

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

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Lancet 2011; 377: 813–22