SnapShot: Prostate Cancer LaMont J. Barlow and Michael M. Shen Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA See online version for legend and references. 400 Cancer Cell 24, September 9, 2013 ©2013 Elsevier Inc. DOI http://dx.doi.org/10.1016/j.ccr.2013.08.033 DHT Preclinical disease Elevated PSA or abnormal DRE Followed by biopsy Definitive treatment after active surveillance Post-ADT Failed treatment or immediate progression Active surveillance (low-risk or short life expectancy) Definitive treatment No evidence of disease (undetectable or stable low PSA) Luminal cells Adenocarcinoma Castration-resistant prostate cancer Basal cells Neuroendocrine cell transformed luminal cells transformed basal cells luminal differentiation treatment failure Chromoplexy Deleted segments SPINK1 overexpressed SPOP mutated 5q - /6q - 10q (PTEN) 17p (TP53) 3p (FOXP1, RYBP, SHQ1) 6q - 7q + 16q - CHD1 deleted ERG rearranged Normal Tumor “Backdoor” pathway 5α-androstane- dione pathway Canonical pathway Cholesterol Pregnenolone 17OH- pregnenolone DHEA Androstenediol Androstenedione 5α-androstanedione Androsterone Androstanediol Testosterone Estradiol Dihydrotestosterone 17OH- progesterone 17OH-Dihydro- progesterone 17OH-Allo- pregnanolone Progesterone Dihydro- progesterone Allo- pregnanolone CYP11A1 CYP17A1 CYP17A1 3βHSD1,2 3βHSD2 3βHSD2 3βHSD1,2 SRD5A1,2 SRD5A1 SRD5A1 17βHSD3 17βHSD3 AKR1C3 AKR1C3 17βHSD3 AKR1C3 17βHSD6 AKR1C2 17βHSD3 AKR1C3 AKR1C2 AKR1C2 CYP17A1 SRD5A1 AKR1C2 CYP17A1 CYP19A1 CYP17A1 CYP17A1 CYP17A1 CYP17A1 Abiraterone TAK700 Abiraterone TAK700 Dutasteride Finasteride Dutasteride Treatment Options for Castration-Resistant Prostate Cancer (CRPC) Treatment Observation Mild symptoms Combine with other palliative measures Pre- or postdocetaxel treatment Postdocetaxel (studies ongoing for predocetaxel use) Asymptomatic or minimally symptomatic Postdocetaxel Bone metastases only To symptomatic sites +/- +/- +/- +/- +/- -/(+) + + + + + + + + + + + - Secondary hormone therapy Docetaxel Abiratirone Enzalutamide Sipuleucel-T Cabazitaxel Radium-223 Palliative radiation therapy Indication M S Other Selected Genetically Engineered Mouse Models Cell Types of Origin for Prostate Cancer Name TRAMP Hi-Myc Progression from PIN to invasive adenocarcinoma and metastasis Rapid progression to metastatic and castration resistant disease with neuroendocrine phenotype Develops PIN but not cancer Progression from PIN to adenocarcinoma Nkx3.1-/- Pb-Cre4;Ptenflox/flox Rapid progression from PIN to invasive adenocarcinoma Rapid progression from PIN to invasive adenocarcinoma with patches of neuroendocrine differentiation Pb-Cre4;Ptenflox/flox; p53flox/flox Pb-Cre4;Ptenflox/flox; Rosa26LSL-ERG/LSL-ERG Rapid progression from PIN to invasive adenocarcinoma and castration-resistant disease with high frequency of metastasis Nkx3.1CreERT2/+; Ptenflox/flox;KrasLSL-G12D/+ Phenotype Risk Stratification for Recurrence after Prostatectomy for Local Disease, D’Amico Criteria Clinical Progression of Prostate Cancer Chromosomal Rearrangements and Molecular Subtypes Androgen Biosynthesis Pathways and Inhibitors Cross-talk between AR, PI3K, and MAPK Pathways Risk group PSA Gleason score Clinical stage 10-year recurrence rate Low risk <10 >20 10-20 17% 71% 54% 7 T1-T2a (nonpalpable tumor or palpable, confined to less than half of one lobe) T2c or highter (palpable, involving both lobes and/or beyond prostate) T2b (palpable, involving more than half of one lobe) Intermediate risk High risk <6 >8 Locally advanced, hormone sensitive Metastatic, hormone sensitive Locally advanced, castration resistant Metastatic, castration resistant Clinically localized Biochemical relapse (rising PSA); Disease progression Stable disease Benign High-grade PIN Gleason 2 Gleason 3 Gleason 4 Gleason 5 ADT: androgen-deprivation therapy Definitive treatment: surgery or radiation, before or after ADT Reproduced with permission from Epstein et al., 2005 and R. Cardiff, unpublished Patients are assigned to the highest catorgory of three variables M: metastatic S: symptomatic PSA: prostate-specific antigen DRE: digital rectal exam RTK RAS DHT DHT DHT DHT AR AR AR RAF MEK ERK PI3K BKM120 MK2206 BEZ235 Everolimus Temsirolimus Enzalutamide ARN-509 PTEN AKT TSC1/2 RHEB TORC1 TORC2 PHLPP FKBP5 S6K AR cofactors 4EBP1
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