Molecular landscape of prostate cancer: Implications for current clinical trials

Cancer Treatment Reviews xxx (2015) xxx–xxx

Contents lists available at ScienceDirect

Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

Anti-Tumour Treatment

Molecular landscape of prostate cancer: Implications for current clinical trials Galina Khemlina a,⇑, Sadakatsu Ikeda b, Razelle Kurzrock b a b

Department of Geriatrics, University of California, San Diego, United States Department of Medicine, Division of Hematology/Oncology, and Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, United States

a r t i c l e

i n f o

Article history: Received 10 May 2015 Received in revised form 30 June 2015 Accepted 2 July 2015 Available online xxxx Keywords: Prostate cancer Molecular targeted therapy Next-generation sequencing Genetic aberrations

a b s t r a c t Castration-resistant prostate cancer (CRPC) is a lethal disease, and improvement with androgen-deprivation therapy has plateaued. Next-generation sequencing studies have led to significant advances in our understanding of genomic alterations in prostate cancer. The most common genomic aberrations in this malignancy are the transcription factor fusion of TMPRSS2–ETS, and mutations in TP53, AR, RB1 and PTEN/PIK3CA. Some of these alterations are actionable by drugs available in the clinic. In addition, it was recently shown that aberrations in DNA repair genes, such as BRCA2 and ATM, are present in both somatic and germline form in a significant minority of prostate cancer; these abnormalities can be targeted by drugs such as platinums and PARP inhibitors. In the era of tumour profiling, targeting molecular alterations may provide an opportunity for new therapeutic approaches. Although there are promising new agents to attack a variety of genomic signal abnormalities, biomarker-matched therapy (other than for androgens) have been utilised in only 2.0% of clinical trials (September 2011 through September 2014; https://clinicaltrials.gov) for prostate cancer. Enhanced efforts to define subsets of patients with prostate cancer based on their molecular anomalies, and match them with cognate therapies, warrant investigation. Ó 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction Prostate cancer continues to be the most frequently occurring cancer in men in the United States, and the second leading cause of cancer-related deaths in men [1,2]. Although the 10-year disease-specific survival rate of low-risk, localised prostate cancer patients is more than 90%, the prognosis for the 10–20% of patients who develop castration-resistant prostate cancer (CRPC) remains poor [3,4]. Therefore, novel therapeutic approaches for prostate cancer are needed. There are 19 Food and Drug Administration (FDA)-approved agents for prostate cancer (Table 1) [5–26]. The majority of these agents (N = 9 (47%)) are hormonal modulators targeting the androgen pathway. Gonadotropin-releasing agonists (goserelin acetate, leuprolide acetate, histrelin acetate, or triptorelin pamoate), and androgen-receptor blockers (flutamide, and bicalutamide) were approved by the FDA before 2000, and have been the backbone of prostate cancer treatment [5–11]. However, advanced prostate cancer ultimately develops resistance to androgen-deprivation ⇑ Corresponding author at: UC San Diego, 9500 Gilman Drive, #9111, La Jolla, CA 92093-9111, United States. E-mail address: [email protected] (G. Khemlina).

therapy. Newer agents, such as abiraterone and enzalutamide, are effective in CRPC [16]. Abiraterone inhibits CYP17, a critical enzyme in the synthesis of testosterone, and therefore decreases androgen synthesis in adrenal glands, testes, and tumour cells [12,13]. Enzalutamide is a newer androgen-receptor (AR) blocker, which has greater affinity for the receptor, and it inhibits the nuclear translocation of the AR, DNA binding, and co-activator [15]. Although abiraterone and enzalutamide showed survival benefit in castrate-resistant disease, prostate cancer cells eventually develop resistance [13–15]. Therefore, androgen deprivation alone is not sufficient to control prostate cancer. Phase III studies demonstrate survival benefits with chemotherapeutic agents (docetaxel and cabazitaxel) and improved quality of life (mitoxantrone) [16–19]. However, their effectiveness is not long lasting, and toxicity eventually becomes a challenge in the prostate cancer patient population. Sipuleucel-T, a novel cancer vaccine, was associated with prolonged overall survival compared to that seen in a sham-treated control [25,26]. Bone-seeking radiopharmaceuticals use unique properties of specific radioisotopes to target metastatic disease in the bone. Strontium-89 and samarium-153 are beta particle emitters, and they are effective in relieving bone-related symptoms; they do not, however, improve survival [20,24]. Radium-223 was the first

http://dx.doi.org/10.1016/j.ctrv.2015.07.001 0305-7372/Ó 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Khemlina G et al. Molecular landscape of prostate cancer: Implications for current clinical trials. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.07.001

2

G. Khemlina et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

Table 1 FDA-approved agents for prostate cancer [5–26]. Class

Name

Year of FDA approval

Mechanism of action

Refs.

Hormonal agents

Goserelin acetate Leuprolide acetate Histrelin acetate Bicalutamide Flutamide Triptorelin pamoate Degarelix Abiraterone Enzalutamide

1989 1989 1991 1995 1989 2000 2008 2011 2012

GnRH agonist GnRH agonist GnRH agonist Androgen receptor blocker Androgen receptor blocker GnRH agonist GnRH antagonist CYP17 inhibitor Androgen receptor blocker

[5] [6] [7] [8] [9] [10] [11] [12,13] [14,15]

Chemotherapy

Estramustine Mitoxantrone Docetaxel Cabazitaxel

1981 1996 2004 2010

Microtubules inhibitor Alkylating agent and TOPOII inhibitor Microtubules inhibitor Microtubules inhibitor

[16] [17] [17,18] [17,19]

Bone-seeking radiopharmaceuticals

Strontium-89 Samarium-153 Radium 223

1993 1997 2013

Beta particle emitter Beta particle emitter Alpha particle emitter

[12,20] [12,24] [21,22]

Bone-directed agents

Zoledronic acid Denosumab

2002 2013

Osteoclast inhibition RANK ligand inhibitor

[16,23] [16,23]

Immunotherapy

Sipuleucel-T

2010

Cancer vaccine

[25,26]

Abbreviations: GnRH = gonadotropin-releasing hormone; RANK = receptor activator of nuclear factor kappa-B.

bone-seeking radioisotope that showed an overall survival benefit [21,22]. Other bone-directed agents, zoledronic acid and denosumab, attenuated skeletal-related events [23]. Taken together, most of the progress in the past decade in prostate cancer treatment has been made possible by the development of newer androgen pathway-targeted therapy. As mentioned, nine therapies that manipulate androgen levels have been approved for prostate cancer (Table 1). These treatments are not without side effects, including hot flashes, fatigue, sexual dysfunction, and osteoporosis [27]. Although there are well-known genomic alternations in prostate cancer, molecular-targeted therapy for this malignancy has not been extensively studied in the clinic. We review the genomic landscape of prostate cancer and implications for clinical research in this disease. Genomic aberrations in prostate cancer Prostate cancer shows biological heterogeneity, which likely reflects underlying genomic diversity. The oncogenic landscape of prostate cancer has become clearer after next-generation sequencing and microarray-based interrogation [28–33]. Common genomic aberrations in prostate cancer include: transcription factor fusion of TMPRSS2–ETS, and mutations and copy number alterations of TP53, AR, RB1 and PTEN/PIK3CA, as well as alterations in DNA repair genes such as BRCA2 and ATM (Table 2) [33–55].

fusion-positive disease, including a randomized study with veliparib, in which patients with prostate cancer are stratified based on the fusion status of ETS (NCT01576172) [38]. Other PARP1 inhibitors being assessed as monotherapy in CRPC include olaparib (AZD-2281/KU-0059436; phase II, clinicaltrials.gov identifier NCT01682772) and niraparib (MK-4827; phase I expansion cohort in prostate cancer, NCT00749502) [38]. TP53 Approximately 3–47% of prostate cancer specimens harbour TP53 mutations, and 2–15% contain homozygous deletion [28–31,33]. The tumour suppressor p53 plays a key role in maintaining genomic stability and preventing tumourigenesis [59]. A previous study demonstrated that the TP53R270H mutation was sufficient to induce prostate cancer in mice [60]. Mutation or deletion of TP53 was associated with increased risk of recurrence [61]. Wee-1 inhibitors, such as MK-1775, can target TP53 mutated malignancy [62]. The TP53 gene also regulates the expression of VEGF, and anti-angiogenic agents, such as bevacizumab, were associated with improved survival in patients harbouring TP53-mutant tumours, in a retrospective study [41,63,64]. A phase III randomized trial comparing docetaxel/prednisone with or without bevacizumab in CRPC patients found no difference in overall survival [65]. However, this study did not screen patients based on the TP53 mutation, and their TP53 mutation status was not investigated.

TMPRSS2–ETS fusion Androgen receptor (AR) Transmembrane protease, serine 2 (TMPRSS2) is a serine protease regulated by androgens [34–36,56]. ERG and ETV1 belong to the ETS transcription factor family, and are fused with TMPRSS2 in approximately 50–79% cases of prostate cancer [28–32,36]. TMPRSS2–ETS fusion is associated with a poor prognosis in localised prostate cancer [57]. Recent preclinical studies have identified targetable cofactors, such as PARP1, DNAPK, and HDAC1, and inhibition of these cofactors has conferred preferential sensitivity in ETS-positive malignancies in preclinical models [37,38,58]. A number of phase I studies of PARP1, DNAPK, or HDAC1 inhibitors have been done in patient populations including those with ERG fusion-positive malignancies [38]. Ongoing phase II studies have focused on the inhibition of PARP1 as a strategy to target ETS

From 2–18% of prostate cancer specimens harbour androgen receptor (AR) mutations, and 5–52% demonstrate amplification [28–31,33]. Amplification occurs rarely in untreated primary prostate cancers, with the observed frequency between 0% and 5% [66,67,69,70]. However, amplification of the AR was found in 20– 52% of hormone-refractory prostate cancers [28–31,66–71]. The AR belongs to the steroid hormone group of nuclear receptors and acts as a ligand-dependent transcription factor that controls the expression of specific genes. Prostate cancer initially responds to androgen-deprivation therapy, but it eventually becomes castration-resistant. The AR remains a key regulator in CRPC [42]. There are several proposed mechanisms of resistance. An AR

Please cite this article in press as: Khemlina G et al. Molecular landscape of prostate cancer: Implications for current clinical trials. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.07.001

3

G. Khemlina et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx Table 2 Commonly aberrant genes in prostate adenocarcinoma [28–55]. Gene

Aberration frequency [28–36]

Pathway

Function

Examples of targeted agent

TMPRSS2– ETS

Gene fusion: 50–79%

Androgen receptor pathway, epigenetic regulation, DNA repair pathway

Plays a critical role in prostate cancer progression by disrupting the AR lineage-specific differentiation programme, and mediating invasion [35]; regulates the epigenetic programme; interacts with PARP1 [37]

PARP1 inhibitors: veliparib (NCT01576172) Olaparib (AZD-2281/KU-0059436; phase II, NCT01682772) Niraparib (MK-4827; phase I expansion in prostate cancer, NCT00749502) [38]

TP53

Mutation: 3–47% Loss: 2–15%

P53 pathway

Tumour suppressor and regulator of the expression of target genes, inducing cell cycle arrest, apoptosis, senescence, DNA repair [39]

MK-1775 (Wee-1 inhibitor) [40] Patients with TP53 mutations may have better outcomes with bevacizumab [41]

AR

Mutation: 2–18% Amplification: 5–52% (early-stage 0–5%, castrate-resistant 20–52%)

Nuclear receptor transcription pathway

Ligand-dependent transcription factor that controls the expression of specific genes [42]

Abiraterone Enzalutamide Newer CYP17 inhibitor, such as CFG-920, VT-464[43,44] Newer anti-androgen, such as ODM-201, AZD-3514 [43,44]

PTEN

Mutation: 2–14% Loss: 12–41%

PI3K pathway

Tumour suppressor. Negative regulator of the phosphatidylinositol-PI3K pathway [45]

mTOR inhibitor, everolimus [46] PI3K inhibitor AZD8186 and AKT inhibitor AZD5363 [47]

PIK3CA

Mutation: 3–4% Amplification: 4–10%

PI3K pathway

Responsible for coordinating a diverse range of cell functions including proliferation, cell survival, degranulation [39]

TORC1 inhibitor rapamycin and its analogues: everolimus, temsirolimus, and ridaforolimus [48–50]

RB1

Mutation: 1–14% Loss: 5–23%

Cell cycle pathway

Tumour suppressor Key regulator of entry into cell division [39]

Azacitidine [51]

APC

Mutation: 3–10%

Wnt-signalling pathway

Encodes a tumour suppressor protein that acts as an antagonist of the Wnt signalling pathway [39]

CHD1

Mutation: 2–8% Loss: 5–20%

Chromatin regulation pathway

ATP-dependent chromatin-remodelling factor. Regulates negatively DNA replication [39]

MYC

Amplification: 2–20%

Cell cycle pathway

Plays a role in cell cycle progression, apoptosis and cellular transformation [39]

MYC and aurora kinase A (AURKA) coamplified prostate cancer was sensitive to AURKA inhibitors in vitro and in vivo [91]

BRCA2

Mutation: 9% Loss: 3%

DNA repair

Germline mutation in 2–6% of patients [33]

Confers sensitivity to platinums and PARP inhibitors [33,53,54]

ATM

Mutation: 5%

DNA repair

Germline mutation in 1% of patients [33]

Confers sensitivity to platinums and PARP inhibitors [33,55]

F876L mutation was identified in a clone resistant to enzalutamide [72]. An AR splice variant 7 (AR-V7) was associated with resistance to abiraterone and enzalutamide with poor survival [73]. Another study found that an AR splice variant and its amplification status appear to be able to determine whether sequencing AR-targeted therapies was a feasible strategy [43]. In addition to approved AR-targeting therapy (Table 1), there are multiple new AR-directed therapies in early stages of clinical development including: (i) CFG-920, a nonsteroidal CYP17 inhibitor; (ii) VT-464, a nonsteroidal selective inhibitor of 17,20-lyase; (iii) ODM-201, an anti-androgen; (iv) AZD-3514, a small molecule that inhibits nuclear translocation of the AR and down-regulates of its expression; (v) ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression [43,44,74]; (vi) EPI-001, a small molecule that is antagonistic to the amino-terminus of the AR [75], and Galentinon, a dual androgen receptor blocker and CYP17 inhibitor, which may have effects in patients with AR-V7 variant (NCT01709734 and NCT02438007) [76]. The PTEN/PI3K/AKT/mTOR pathway The signalling pathway involving PTEN, PI3K and AKT plays a central role in the regulation of cell growth and death [77]. The PI3K/AKT/mTOR pathway is fundamental to the metastatic potential of prostate cancer, providing a strong rationale for targeting the PI3K/AKT/mTOR pathway in this disease [46]. Supporting the view that PTEN and PIK3CA genes act in the same signalling pathway,

genetic alterations of these genes in prostate cancer were largely mutually exclusive [77]. Approximately 2–14% of prostate cancer specimens harbour PTEN mutations, and 12–41% have copy number loss [28–31,33]. Mutations in PIK3CA were observed in 3–4% of patients, and amplifications were reported in 4–10% of cases. The PTEN gene is a negative regulator of the PI3K/AKT signalling pathway [45]. A combination of PTEN and TP53 deficiency in prostate cancer cells synergistically leads to robustly elevated hexokinase 2 expression, which fuels aggressive prostate cancer growth in vivo [78]. The loss of PTEN was found to be associated with a poor prognosis [79]. Dysregulation of the PI3K pathway due to PTEN or PIK3CA aberrations can conceivably be targeted by mTOR inhibitors, such as everolimus. Everolimus demonstrated PSA response in 11% of patients with CRPC in a non-biomarker selected population [48]. The PSA response to everolimus was correlated with a PTEN deletion by FISH [48]. Everolimus was safely combined with bicalutamide and docetaxel [80,81]. Novel inhibitors are under development, for examples: AKT inhibitor AZD5363, and a PI3Kb/d inhibitor AZD8186 [47]. Both agents showed potent anti-tumour activity in multiple prostate cancer preclinical models, and they were equally effective in vivo in a PTEN-deleted model [47]. In addition, targeting of the AKT and androgen receptor pathways with AZD5363 and enzalutamide significantly delayed the development of enzalutamide-resistant prostate cancer in preclinical models [82].

Please cite this article in press as: Khemlina G et al. Molecular landscape of prostate cancer: Implications for current clinical trials. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.07.001

4

G. Khemlina et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

RB Approximately 1–14% of prostate cancer specimens harbour RB1 mutations, and 5–23% of prostate cancers demonstrated loss of RB1 [28–31,33]. The RB1 gene is a tumour suppressor, and impairment of RB function is sufficient to upregulate the androgen receptor output and confer castration resistance [83]. The RB1 gene is frequently deleted and methylated in CRPC, which points to a possible therapeutic option with hypomethylating agents, such as 5-azacytidine [51]. Azacytidine resulted in some PSA reduction in a phase II study of non-biomarker-selected CRPC [84]. Also, an animal study demonstrated higher sensitivity to cabazitaxel in CRPC tumour with loss of RB [85]. APC From 3–10% percent of prostate cancer specimens harbour APC mutations [28–31,33]. The APC gene encodes a tumour suppressor protein, which acts as an antagonist of the Wnt signalling pathway. It is also involved in other processes, including cell migration and adhesion, transcriptional activation, and apoptosis [39]. A high-level of APC promoter methylation was shown to be an independent predictor of a poor prognosis in prostate cancer [86]. Wnt inhibitors are in clinical development. CHD1 Approximately 2–8% of prostate cancer specimens harbour CHD1 mutations, and 5–20% contain deletions [28–31,33]. CHD1 genes alter gene expression, possibly by modification of chromatin structure, thus altering access of the transcriptional apparatus [39]. A focal deletion or mutation of CHD1 (CHD1 ) was identified that was significantly associated with the fusion-negative (ETS ) status of the ETS gene family [29]. The CHD1 deletion may be responsible for cell invasiveness in a subset of prostate cancer and play a possible novel role in altered chromatin remodelling in prostate tumourigenesis [87]. Currently, there is no targeted therapy for CHD1 aberrations. MYC Approximately 2–20% of prostate cancer specimens exhibit MYC amplification [28–31,33]. The protein encoded by MYC is multi-functional, and plays a role in cell cycle progression, apoptosis and cellular transformation [39]. The MYC gene has previously been validated as a driver of prostate cancer [88,89]. Targeting of MYC could be a critical strategy against PTEN-deficient prostate cancer [90]. Co-amplification of MYC and aurora kinase A (AURKA) resulted in sensitivity to aurora kinase inhibitors in vitro and in vivo, thereby providing a rationale for trials of this molecular and histologic subset [52,91]. DNA repair genes Aberrations in DNA repair genes such as BRCA2 and ATM have been recently shown to be present in both somatic and germline form in a significant minority of prostate cancers [33,39,92] (Table 2). These aberrations can be targeted by platinums and PARP inhibitors [53–55]. BRCA2 Approximately 9% of prostate cancer specimens exhibit BRCA2 mutations, including 2–6% pathogenic germline BRCA2 mutations [33,92]. Biallelic loss was observed in 3% of patients [33]. BRCA2 is involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair

[39]. BRCA2 germline mutations not only confer a high risk of prostate cancer, but are also an independent prognostic factor for cause-specific survival in all stages of prostate cancer including localised disease [93,94]. CRPC affected individuals with biallelic BRCA2 loss experienced clinical benefit from poly(-ADP-ribose) polymerase (PARP) inhibition, providing evidence of clinical actionability [33,53,54]. ATM Approximately 5% of prostate cancer specimens exhibit somatic ATM alterations including some 1% of pathogenic germline mutations [33]. ATM acts a controller of cell cycle checkpoint signalling pathways that are required for cell response to DNA damage and for genome stability [39]. ATM has been reported to be highly activated in prostatic intraneoplasia and some missense variants of the ATM gene confer a moderate increased risk of prostate cancer [95], ATM mutations were observed in affected individuals who achieved clinical responses to PARP inhibition and predicted to benefit from this therapy [33,55]. Clinical trials for prostate cancer A search of clinicaltrials.gov for new prostate cancer protocols registered during the past 3 years identified 761 protocols (search criteria: search term = prostate cancer; study type = interventional; first received = from 09/01/2011 to 09/01/2014) [96]. The 761 protocol summaries were manually reviewed, and protocols for radiation, procedure, imaging, diagnostic tests, prevention, and life style modification interventions were excluded. The drug interventional studies total 357. Of these 357 protocols, only 5 (2.0%) used selective inclusion criteria to identify a subset of patients based upon laboratory molecular/biomarker data and treatment with a cognate therapy that was believed to impact or biologically match the biomarker. There were 73 (20.4% of 357) targeted therapy trials, but these trials did not use biomarker or genomic alterations for screening patients. The remainder of the studies were: hormonal therapy (123 trials, 34.5%), chemotherapy (48 trials, 13.4%), immunotherapy/vaccine trials (52 trials, 14.6%), and others such as radium-223, or statins (54 trials, 15.1%). These results suggest that there is still a remarkable paucity of trials addressing molecular/biomarker stratification in prostate cancer. Conclusions Despite the progress in the past decades, prostate cancer remains a major cause of death in the U.S. Pharmaceutical research has emphasised AR modulation, and 9 agents approved by the FDA for prostate cancer target the AR pathway. Multiple newer AR-modulating agents are in development. These drugs are not without side effects including impotence, hot flashes, osteoporosis, fatigue, loss of muscle mass and anemia [97]. Recent studies have also suggested multiple escape mechanisms that lead to renewed AR signalling under castration levels of androgens [13,98,99]. Therefore, understanding the molecular mechanisms leading to CRPC and identifying alternative targets are important to identify more effective treatments for CRPC [100]. In other tumour types such as BRAF-mutant melanoma [101], and EGFR- or ALK-aberrant non-small cell lung cancer [102–104], significant improvements have been achieved by matching targeted agents to tumours harbouring the cognate molecular abnormality. Several theoretically ‘actionable’ aberrations exist in prostate cancer, including PTEN, and PIK3CA. Indeed, aberrations in the PI3K/AKT/mTOR pathway have been discerned in a substantial subset of patients with prostate cancer. These aberrations can

Please cite this article in press as: Khemlina G et al. Molecular landscape of prostate cancer: Implications for current clinical trials. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.07.001

G. Khemlina et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

be targeted by cognate inhibitors. DNA repair genes such as BRCA2 and ATM are also altered in prostate cancer (with a subset of patients having germline mutations). PARP inhibitors and platinums can effectively target these abnormalities in several cancers, and merit further exploration in BRCA2- and ATM-aberrant prostate cancer [33,105]. Despite the number of aberrations that can be targeted, relatively few have been addressed in clinical trials of prostate cancer, with only 2.0% of clinical trials (posted on clinicaltrials.gov in the last 3 years; September 1, 2011, through September 1, 2014) employing a biomarker-based patient selection strategy. Efforts to target biomarker-defined subsets of patients with prostate cancer and to expand current research beyond androgen inhibition is needed. Conflict of interest Dr. Kurzrock has consultant fees from Sequenom and has ownership interest in RScueRx Inc. as well as research funding from Merck Serono, Genentech, Pfizer, and Foundation Medicine. The other authors declare that they have no conflict of interest. Acknowledgement Funded in part by the Joan and Irwin Jacobs Fund. References [1] Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69–90. [2] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5–29. [3] Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract 2011;65:1180–92. [4] Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med 2012;367:203–13. [5] Debruyne FM, Dijkman GA, Lee DCH, Witjes WPJ. A new long acting formulation of the luteinizing hormone-releasing hormone analogue, goserelin: results of studies in prostate cancer. J Urol 1996;155:1352–4. [6] Iacopino F, Lama G, Angelucci C, Sica G. Leuprorelin acetate affects ERK1/2 activity in prostate cancer cells. Int J Oncol 2006;29:237–47. [7] Shore N, Cookson MS, Gittelman MC. Long-term efficacy and tolerability of once-yearly histrelin acetate subcutaneous implant in patients with advanced prostate cancer. BJU Int 2012;109:226–32. [8] Osguthorpe DJ, Hagler AT. Mechanism of androgen receptor antagonism by bicalutamide in the treatment of prostate cancer. Biochemistry 2011;50:4105–13. [9] Flutamide approved for prostate cancer. Oncology (Williston Park) 1989;3:135. [10] Millar JL. Triptorelin approved for prostate cancer treatment. Am J Health Syst Pharm 2000;57:1386. [11] Steinberg M. Degarelix: a gonadotropin-releasing hormone antagonist for the management of prostate cancer. Clin Ther 2009;31(Pt. 2):2312–31. [12] Ruch JM, Hussain MH. Evolving therapeutic paradigms for advanced prostate cancer. Oncology (Williston Park) 2011;25(496–504):508. [13] de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995–2005. [14] Bahl A, Masson S, Birtle A, et al. Second-line treatment options in metastatic castration-resistant prostate cancer: a comparison of key trials with recently approved agents. Cancer Treat Rev 2014;40:170–7. [15] Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187–97. [16] D’Amico AV. US Food and Drug Administration approval of drugs for the treatment of prostate cancer: a new era has begun. J Clin Oncol 2014;32:362–4. [17] Galsky MD, Small AC, Tsao CK, Oh WK. Clinical development of novel therapeutics for castration-resistant prostate cancer: historic challenges and recent successes. CA Cancer J Clin 2012;62:299–308. [18] Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502–12. [19] de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010;376:1147–54. [20] Porter AT, McEwan AJ, Powe JE, et al. Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys 1993;25:805–13.

5

[21] Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369:213–23. [22] Abi-Ghanem AS, McGrath MA, Jacene HA. Radionuclide therapy for osseous metastases in prostate cancer. Semin Nucl Med 2015;45:66–80. [23] Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377:813–22. [24] Sartor O, Reid RH, Hoskin PJ, et al. Samarium-153–lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology 2004;63:940–5. [25] Singh BH, Gulley JL. Therapeutic vaccines as a promising treatment modality against prostate cancer: rationale and recent advances. Ther Adv Vaccines 2014;2:137–48. [26] Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363:411–22. [27] Holzbeierlein JM, Castle EP, Thrasher JB. Complications of androgendeprivation therapy for prostate cancer. Clin Prostate Cancer 2003;2:147–52. [28] Taylor BS, Schultz N, Hieronymus H, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010;18:11–22. [29] Grasso CS, Wu YM, Robinson DR, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012;487:239–43. [30] Baca SC, Prandi D, Lawrence MS, et al. Punctuated evolution of prostate cancer genomes. Cell 2013;153:666–77. [31] Barbieri CE, Baca SC, Lawrence MS, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet 2012;44:685–9. [32] Berger MF, Lawrence MS, Demichelis F, et al. The genomic complexity of primary human prostate cancer. Nature 2011;470:214–20. [33] Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015;161:1215–28. [34] Tomlins SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005;310:644–8. [35] Yu J, Mani RS, Cao Q, et al. An integrated network of androgen receptor, polycomb, and TMPRSS2–ERG gene fusions in prostate cancer progression. Cancer Cell 2010;17:443–54. [36] Tu JJ, Rohan S, Kao J, et al. Gene fusions between TMPRSS2 and ETS family genes in prostate cancer: frequency and transcript variant analysis by RT-PCR and FISH on paraffin-embedded tissues. Mod Pathol 2007;20:921–8. [37] Brenner JC, Ateeq B, Li Y, et al. Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell 2011;19:664–78. [38] Feng FY, Brenner JC, Hussain M, Chinnaiyan AM. Molecular pathways: targeting ETS gene fusions in cancer. Clin Cancer Res 2014;20:4442–8. [39] Safran M, Dalah I, Alexander J, et al. GeneCards version 3: the human gene integrator. Database (Oxford) 2010;2010:baq020. [40] Bridges KA, Hirai H, Buser CA, et al. MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clin Cancer Res 2011;17:5638–48. [41] Said R, Hong DS, Warneke CL, et al. P53 mutations in advanced cancers: clinical characteristics, outcomes, and correlation between progression-free survival and bevacizumab-containing therapy. Oncotarget 2013;4:705–14. [42] Tan ME, Li J, Xu HE, et al. Androgen receptor: structure, role in prostate cancer and drug discovery. Acta Pharmacol Sin 2015:3–23. [43] Kim W, Ryan CJ. Quo vadis: advanced prostate cancer – clinical care and clinical research in the era of multiple androgen receptor-directed therapies. Cancer 2014. [44] Loddick SA, Ross SJ, Thomason AG, et al. AZD3514: a small molecule that modulates androgen receptor signaling and function in vitro and in vivo. Mol Cancer Ther 2013;12:1715–27. [45] Huret JL, Ahmad M, Arsaban M, et al. Atlas of genetics and cytogenetics in oncology and haematology in 2013. Nucleic Acids Res 2013;41:D920–4. [46] Bitting RL, Armstrong AJ. Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. Endocr Relat Cancer 2013;20:R83–99. [47] Marques RB, Aghai A, de Ridder CM, et al. High efficacy of combination therapy using PI3K/AKT inhibitors with androgen deprivation in prostate cancer preclinical models. Eur Urol 2014. [48] Templeton AJ, Dutoit V, Cathomas R, et al. Phase 2 trial of single-agent everolimus in chemotherapy-naive patients with castration-resistant prostate cancer (SAKK 08/08). Eur Urol 2013;64:150–8. [49] Piatek CI, Raja GL, Ji L, et al. Phase I clinical trial of temsirolimus and vinorelbine in advanced solid tumors. Cancer Chemother Pharmacol 2014;74:1227–34. [50] Zhang W, Haines BB, Efferson C, et al. Evidence of mTOR activation by an AKTindependent mechanism provides support for the combined treatment of PTEN-deficient prostate tumors with mTOR and AKT inhibitors. Transl Oncol 2012;5:422–9. [51] Friedlander TW, Roy R, Tomlins SA, et al. Common structural and epigenetic changes in the genome of castration-resistant prostate cancer. Cancer Res 2012;72:616–25. [52] Roychowdhury S, Chinnaiyan AM. Advancing precision medicine for prostate cancer through genomics. J Clin Oncol 2013;31:1866–73. [53] Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009;361:123–34. [54] Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015;33:244–50.

Please cite this article in press as: Khemlina G et al. Molecular landscape of prostate cancer: Implications for current clinical trials. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.07.001

6

G. Khemlina et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx

[55] Stratifying prostate patients for olaparib. Cancer Discov 2015;5:568–9. [56] Lin B, Ferguson C, White JT, et al. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res 1999;59:4180–4. [57] Demichelis F, Fall K, Perner S, et al. TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 2007;26:4596–9. [58] Bjorkman M, Iljin K, Halonen P, et al. Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer. Int J Cancer 2008;123:2774–81. [59] Liu J, Zhang C, Wang XL, et al. E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis. Cell Death Differ 2014. [60] Vinall RL, Chen JQ, Hubbard NE, et al. Initiation of prostate cancer in mice by Tp53R270H: evidence for an alternative molecular progression. Dis Model Mech 2012;5:914–20. [61] Kluth M, Harasimowicz S, Burkhardt L, et al. Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer. Int J Cancer 2014;135:1369–80. [62] Leijen S, Beijnen JH, Schellens JH. Abrogation of the G2 checkpoint by inhibition of Wee-1 kinase results in sensitization of p53-deficient tumor cells to DNA-damaging agents. Curr Clin Pharmacol 2010;5:186–91. [63] Farhang Ghahremani M, Goossens S, Haigh JJ. The p53 family and VEGF regulation: ‘‘It’s complicated’’. Cell Cycle 2013;12:1331–2. [64] Schwaederle M, Vladimir L, Validire P, et al. VEGF-A expression correlates with TP53 mutations in non-small cell lung cancer: implications for antiangiogenesis therapy. Cancer Res 2015. [65] Kelly WK, Halabi S, Carducci M, et al. Randomized, double-blind, placebocontrolled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. J Clin Oncol 2012;30:1534–40. [66] Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev 2004;25:276–308. [67] Bubendorf L, Kononen J, Koivisto P, et al. Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays. Cancer Res 1999;59:803–6. [68] Qu X, Randhawa G, Friedman C, et al. A three-marker FISH panel detects more genetic aberrations of AR, PTEN and TMPRSS2/ERG in castration-resistant or metastatic prostate cancers than in primary prostate tumors. PLoS One 2013;8:e74671. [69] Miyoshi Y, Uemura H, Fujinami K, et al. Fluorescence in situ hybridization evaluation of c-myc and androgen receptor gene amplification and chromosomal anomalies in prostate cancer in Japanese patients. Prostate 2000;43:225–32. [70] Visakorpi T, Hyytinen E, Koivisto P, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet 1995;9:401–6. [71] Linja MJ, Savinainen KJ, Saramaki OR, et al. Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res 2001;61:3550–5. [72] Joseph JD, Lu N, Qian J, et al. A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov 2013;3:1020–9. [73] Antonarakis ES, Lu C, Wang H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014;371:1028–38. [74] Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res 2012;72:1494–503. [75] Andersen RJ, Mawji NR, Wang J, et al. Regression of castrate-recurrent prostate cancer by a small-molecule inhibitor of the amino-terminus domain of the androgen receptor. Cancer Cell 2010;17:535–46. [76] Yaqub F. Galeterone activity in castration-resistant prostate cancer. Lancet Oncol 2015;16:e10. [77] Sun X, Huang J, Homma T, et al. Genetic alterations in the PI3K pathway in prostate cancer. Anticancer Res 2009;29:1739–43. [78] Wang L, Xiong H, Wu F, et al. Hexokinase 2-mediated Warburg effect is required for PTEN- and p53-deficiency-driven prostate cancer growth. Cell Rep 2014;8:1461–74. [79] Heselmeyer-Haddad KM, Berroa Garcia LY, Bradley A, et al. Single-cell genetic analysis reveals insights into clonal development of prostate cancers and indicates loss of PTEN as a marker of poor prognosis. Am J Pathol 2014;184:2671–86. [80] Pan C-x, Chow H, Ghosh P, et al. Everolimus plus bicalutamide in men with castration-resistant prostate cancer (CRPC): final results of a phase II trial. ASCO Meet Abstr 2014;32:5028.

[81] Courtney KD, Manola JB, Elfiky AA, et al. A phase I study of everolimus and docetaxel in patients with castration-resistant prostate cancer. Clin Genitourin Cancer 2014. [82] Toren P, Kim S, Cordonnier T, et al. Combination AZD5363 with enzalutamide significantly delays enzalutamide-resistant prostate cancer in preclinical models. Eur Urol 2014. [83] Sharma A, Yeow WS, Ertel A, et al. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest 2010;120:4478–92. [84] Sonpavde G, Aparicio AM, Zhan F, et al. Azacitidine favorably modulates PSA kinetics correlating with plasma DNA LINE-1 hypomethylation in men with chemonaive castration-resistant prostate cancer. Urol Oncol 2011;29:682–9. [85] de Leeuw R, Berman-Booty LD, Schiewer MJ, et al. Novel actions of nextgeneration taxanes benefit advanced stages of prostate cancer. Clin Cancer Res 2015;21:795–807. [86] Henrique R, Ribeiro FR, Fonseca D, et al. High promoter methylation levels of APC predict poor prognosis in sextant biopsies from prostate cancer patients. Clin Cancer Res 2007;13:6122–9. [87] Huang S, Gulzar ZG, Salari K, et al. Recurrent deletion of CHD1 in prostate cancer with relevance to cell invasiveness. Oncogene 2012;31:4164–70. [88] Ellwood-Yen K, Graeber TG, Wongvipat J, et al. Myc-driven murine prostate cancer shares molecular features with human prostate tumors. Cancer Cell 2003;4:223–38. [89] Kim J, Roh M, Doubinskaia I, et al. A mouse model of heterogeneous, c-MYCinitiated prostate cancer with loss of Pten and p53. Oncogene 2012;31:322–32. [90] Cho HJ, Herzka T, Zheng W, et al. RapidCaP, a novel GEM model for metastatic prostate cancer analysis and therapy, reveals Myc as a driver of Pten-mutant metastasis. Cancer Discov 2014;4:318–33. [91] Beltran H, Rickman DS, Park K, et al. Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov 2011;1:487–95. [92] Edwards SM, Kote-Jarai Z, Meitz J, et al. Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 2003;72:1–12. [93] Castro E, Goh C, Leongamornlert D, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol 2014. [94] Castro E, Goh C, Olmos D, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol 2013;31:1748–57. [95] Chiu YT, Liu J, Tang K, et al. Inactivation of ATM/ATR DNA damage checkpoint promotes androgen induced chromosomal instability in prostate epithelial cells. PLoS One 2012;7:e51108. [96] Clinicaltrials.gov. In: Bethesda MNLoM. Clinicaltrials.gov. Bethesda, MD: National Library of Medicine (accessed 09.07.2015). [97] Miyamoto H, Messing EM, Chang C. Androgen deprivation therapy for prostate cancer: current status and future prospects. Prostate 2004;61:332–53. [98] Attard G, Richards J, de Bono JS. New strategies in metastatic prostate cancer: targeting the androgen receptor signaling pathway. Clin Cancer Res 2011;17:1649–57. [99] Wang Q, Li W, Zhang Y, et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 2009;138:245–56. [100] Yokoyama NN, Shao S, Hoang BH, et al. Wnt signaling in castration-resistant prostate cancer: implications for therapy. Am J Clin Exp Urol 2014;2:27–44. [101] Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012;379:1893–901. [102] Steuer CE, Khuri FR, Ramalingam SS. The next generation of epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of lung cancer. Cancer 2014. [103] Sgambato A, Casaluce F, Maione P, et al. The role of EGFR tyrosine kinase inhibitors in the first-line treatment of advanced non small cell lung cancer patients harboring EGFR mutation. Curr Med Chem 2012;19:3337–52. [104] Cappuzzo F, Moro-Sibilot D, Gautschi O, et al. Management of crizotinib therapy for ALK-rearranged non-small cell lung carcinoma: an expert consensus. Lung Cancer 2015;87:89–95. [105] O’Sullivan CC, Moon DH, Kohn EC, Lee JM. Beyond breast and ovarian cancers: PARP inhibitors for BRCA mutation-associated and BRCA-like solid tumors. Front Oncol 2014;4:42.

Please cite this article in press as: Khemlina G et al. Molecular landscape of prostate cancer: Implications for current clinical trials. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.07.001