Snapshot: Prostate Cancer Lamont J

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SnapShot: Prostate Cancer LaMont J. Barlow and Michael M. Shen Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA

Clinical Progression of Prostate Cancer

No evidence of disease Locally advanced, Locally advanced, Deﬁnitive Deﬁnitive treatment after (undetectable hormone sensitive castration resistant Elevated treatment or stable low active surveillance PSA or abnormal PSA) Biochemical relapse Preclinical DRE Clinically Benign High-grade PIN Gleason 2 (rising PSA); Post-ADT disease localized Followed Failed treatment Disease progression by biopsy or immediate progression

Active surveillance Stable (low-risk or short Metastatic, Metastatic, life expectancy) disease hormone sensitive castration resistant Gleason 3 Gleason 4 Gleason 5 PSA: prostate-speci c antigen ADT: androgen-deprivation therapy Reproduced with permission from Epstein et al., 2005 and R. Cardiff, unpublished DRE: digital rectal exam De nitive treatment: surgery or radiation, before or after ADT Treatment Options for Castration-Resistant Prostate Cancer (CRPC) Risk Stratiﬁcation for Recurrence after Prostatectomy for Local Disease, D’Amico Criteria Indication Treatment Gleason 10-year MS Other Risk group PSA score Clinical stage recurrence rate Observation +/- - T1-T2a (nonpalpable tumor or palpable, con ned to less than half of + - + - Mild symptoms Low risk <10 <6 17% Secondary hormone therapy / / one lobe) Docetaxel + + Combine with other palliative measures Intermediate risk 10-20 7 T2b (palpable, involving more than half of one lobe) 54% Abiratirone + +/- Pre- or postdocetaxel treatment High risk >20 >8 T2c or highter (palpable, involving both lobes and/or beyond prostate) 71% Enzalutamide + +/- Postdocetaxel (studies ongoing for predocetaxel use) Patients are assigned to the highest catorgory of three variables Sipuleucel-T + -/(+) Asymptomatic or minimally symptomatic Cabazitaxel + + Postdocetaxel Chromosomal Rearrangements and Molecular Subtypes Radium-223 + + Bone metastases only To symptomatic sites Normal Tumor SPINK1 overexpressed Palliative radiation therapy + + SPOP mutated M: metastatic S: symptomatic 5q-/6q- Chromoplexy CHD1 deleted Cross-talk between AR, PI3K, and MAPK Pathways 6q- 7q+ 16q-

ERG rearranged RTK 10q (PTEN) DHT 17p (TP53) Deleted segments 3p (FOXP1, RYBP, SHQ1)

Androgen Biosynthesis Pathways and Inhibitors RAS PTEN PI3K BKM120 Cholesterol Abiraterone Abiraterone TAK700 Dutasteride CYP11A1 TAK700 MK2206 AKT BEZ235 DHT RAF β SRD5A1 Dihydro- AKR1C2 Allo- Pregnenolone 3 HSD2 Progesterone progesterone pregnanolone PHLPP TSC1/2 TORC2

CYP17A1 CYP17A1 CYP17A1 CYP17A1 MEK AR RHEB “Backdoor” pathway AKR1C2 17OH- 3βHSD2 17OH- SRD5A1 17OH-Dihydro- 17OH-Allo- Everolimus TORC1 pregnenolone progesterone progesterone pregnanolone ERK Temsirolimus

CYP17A1 CYP17A1 CYP17A1 CYP17A1 FKBP5 DHT Canonical pathway AR 4EBP1 S6K 3βHSD1,2 SRD5A1 AKR1C2 DHEA Androstenedione 5α-androstanedione Androsterone

17βHSD3 17βHSD3 5α-androstane- 17βHSD3 17βHSD3 DHT AR AKR1C3 AKR1C3 dione pathway AKR1C3 AKR1C3 Enzalutamide ARN-509 AR cofactors 17βHSD6 Androstenediol Testosterone Dihydrotestosterone Androstanediol β 3 HSD1,2 SRD5A1,2 DHT AKR1C2

CYP19A1 Selected Genetically Engineered Mouse Models Dutasteride Estradiol Finasteride Name Phenotype TRAMP Rapid progression to metastatic and Luminal cells Cell Types of Origin for Prostate Cancer castration resistant disease with transformed neuroendocrine phenotype luminal cells Hi-Myc Progression from PIN to invasive adenocarcinoma and metastasis Castration-resistant Nkx3.1-/- Develops PIN but not cancer Adenocarcinoma prostate cancer treatment Pb-Cre4;Ptenflox/flox Progression from PIN to adenocarcinoma failure Pb-Cre4;Ptenflox/flox; Rapid progression from PIN to invasive p53flox/flox adenocarcinoma Rapid progression from PIN to invasive transformed Pb-Cre4;Ptenflox/flox; basal cells adenocarcinoma with patches of Rosa26LSL-ERG/LSL-ERG luminal neuroendocrine differentiation differentiation Nkx3.1CreERT2/+; Rapid progression from PIN to invasive Basal cells adenocarcinoma and castration-resistant Ptenflox/flox;KrasLSL-G12D/+ Neuroendocrine cell disease with high frequency of metastasis

See online version for 400 Cancer Cell 24, September 9, 2013 ©2013 Elsevier Inc. DOI http://dx.doi.org/10.1016/j.ccr.2013.08.033 legend and references. SnapShot: Prostate Cancer LaMont J. Barlow and Michael M. Shen Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA

Prostate cancer (PCa) is the most commonly diagnosed cancer in men, with an estimated 238,000 new cases in the United States this year. It is the second highest cause of cancer-related death; nearly 30,000 men in the U.S. die from PCa each year. The discovery of prostate-specific antigen (PSA) as a biomarker for PCa has made it possible to detect the disease in early stages. It is estimated that there is often a lag-time of 15 years or more from initially detectable PSA elevation to clinically manifested PCa. In recent years, there has been considerable debate about the benefits versus risks of PSA screening, as there is a potential to over-treat indolent disease that may never have caused symptoms during a patient’s lifetime. However, novel tumor markers and new mechanistic insights into disease progression may improve prognostic abilities.

Clinical Progression of Prostate Cancer and Histopathology Most patients are diagnosed after presenting with elevated PSA or abnormal digital rectal exam, followed by a biopsy. Definitive treatments for clinically localized disease are surgery and radiation, but patients with low-risk disease or a shorter life expectancy can be managed with active surveillance, which consists of PSA assays and repeat biopsies at regular intervals until there is evidence of disease progression. Patients who progress may develop locally advanced or metastatic disease, which is initially treated primarily with androgen-deprivation therapy (ADT). However, almost all advanced prostate cancer progresses to castration-resistant disease after a period of ADT. Histologic grading is based on the Gleason system, which ranges from grade 1 (most differentiated) to 5 (least differentiated). Each specimen is assigned a Gleason score based on their most prevalent and second-most prevalent histologic grades. The combination of the two grades gives the total score (ranging from 2 to 10, with most cancers falling between 6 and 8). When malignant cells are confined to the prostate acini and the basal cell layer remains at least partially intact, it is defined as prostatic intraepithelial neoplasia (PIN). High-grade PIN is an established precursor to adenocarcinoma, which is distinguished by an absence of the basal epithelial layer.

Cell Types of Origin, Genetic Alterations, and Molecular Subtypes Prostate adenocarcinoma can derive from luminal or basal epithelial cells of the prostatic acini. While malignancies may arise from a single mutation followed by clonal propa- gation, many prostate cancers contain multiple foci with varying genetic alterations. Tumor heterogeneity at the molecular, cellular, and architectural levels makes it difficult to distinguish between synchronous tumors developing from independent oncogenic events versus clonally derived tumors whose cells become highly divergent. Unlike most cancers that are commonly associated with specific point mutations, PCa involves large-scale genomic rearrangements and extensive copy number alterations involving multiple chromosomes. This phenomenon of chromoplexy often leads to loss of one or both copies of critical tumor suppressor genes such as PTEN, NKX3.1, TP53, and CDKN1B as well as oncogenic fusions such as TMPRSS2-ERG, which is observed in ~50% of prostate tumors. Exome and whole-genome sequencing studies have provided evidence for distinct molecular subtypes of PCa categorized by specific alterations such as CHD1 deletions, ERG rearrangements, and SPOP mutations.

Chemoprevention Because of the high prevalence and prolonged latency period of prostate cancer, chemoprevention approaches have been of particular interest. The most promising agents are the 5-alpha reductase inhibitors finasteride and dutasteride, which inhibit the conversion of testosterone to dihydrotestosterone, the most active prostatic androgen. Although data suggest that finasteride and dutasteride may reduce PCa risk overall, concerns of a potential increased risk of high-grade cancer have hindered their use in chemoprevention.

Mechanisms of Castration Resistance and Advances in Treatment of Castration-Resistant Prostate Cancer Virtually every patient treated with ADT will eventually develop resistance with subsequent rise in PSA or clinical progression. Although the pathways that lead to castration resistance are not fully understood, potential mechanisms include (1) intratumoral androgen biosynthesis, (2) androgen receptor (AR) pathway hypersensitivity via AR gene amplification, (3) AR activation by noncognate ligands such as corticosteroids (often mediated by AR mutations), (4) growth factor-mediated increase in AR transcription activity, (5) expression of variant AR isoforms that are ligand independent, (6) activation of alternative survival pathways that bypass the AR pathway, and (7) selection of pre-existing castration-resistant epithelial stem cells. Castration resistance may involve several of these processes simultaneously as well as undiscovered mechanisms. The available treatments for castration-resistant prostate cancer (CRPC) have traditionally been limited to cytotoxic chemotherapeutics and palliative measures. However, recent novel therapies with proven survival benefits have broadened the armamentarium for this disease state. In particular, Abiraterone is an oral agent that blocks androgen production in tumors as well as testis and adrenal gland through irreversible inhibition of products of the CYP17A1 gene. Abiraterone prolongs overall survival in men with CRPC previously treated with docetaxel as well as in chemotherapy naive patients. Enzalutamide, another oral agent, blocks AR function by inhibition of androgen binding to AR, nuclear translocation of AR, and AR association with nuclear DNA, and also prolongs survival in men with metastatic CRPC after docetaxel treatment. Activation of the PI3K-AKT-mTOR pathway is likely to play a key role in castration resistance, particularly through its complex regulation involving cross-talk with the AR and MAPK pathways. Agents that block various steps in the PI3K-AKT-mTOR pathway are currently being investigated as novel therapeutics for advanced PCa. Such agents may be used in the context of combinatorial treatments with agents that target the AR and/or MAPK pathways to counteract positive feedback loops that are activated when only a single pathway is targeted.

Mouse Models of Prostate Cancer Genetically engineered autochthonous mouse models of prostate cancer have played important roles in the elucidation of molecular mechanisms for cancer initiation and progression. Newer models that display castration-resistant phenotypes are now being used for analyses of drug response and resistance mechanisms.

Acknowledgments

We thank R. Cardiff for images, and N. Sharifi, K. Kelly, B. Carver, E. Gelmann, and C. Abate-Shen for comments. This work was supported by the NIH and the Urology Care Foundation.

References

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