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Targeting intratumoral androgens: statins and beyond:

Targeting intratumoral androgens: statins and beyond: 647962 TAM0010.1177/1758834016647962Therapeutic Advances in Medical OncologyMT Schweizer and EY Yu research-article2016 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Targeting intratumoral androgens: statins 2016, Vol. 8(5) 388 –395 DOI: 10.1177/ and beyond © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ Michael T. Schweizer and Evan Y. Yu journalsPermissions.nav Abstract: While initially effective, androgen deprivation therapy (ADT) is not curative, and nearly all men with advanced prostate cancer will eventually progress to the more resistant, and ultimately lethal form of the disease, so called castration-resistant prostate cancer (CRPC). The maintenance of androgens within the prostate cancer microenvironment likely represents one of the key mechanisms by which this transition from hormone- sensitive to CRPC occurs. This can be accomplished either through intratumoral androgen biosynthesis or the active transport of androgens and androgenic precursors into the tumor microenvironment. More recently, preclinical and clinical data supported therapeutic strategies that seek to target these two mechanisms, either through the use of drugs that impair androgen biosynthesis (e.g. inhibiting the steroidogenic enzymes CYP17 and AKR1C3 with abiraterone and indomethacin, respectively) or drugs that inhibit the SLCO transporters responsible for importing androgens (e.g. statins). Keywords: androgen receptor, castration-resistant prostate cancer, drug resistance, microenvironment, prostate cancer, statin, steroidogenesis Correspondence to: Introduction phenotype [Titus et  al. 2005; Mostaghel et  al. Michael Schweizer, MD Even in its most resistant form, the vast majority 2007]. Key sources of these persistent androgens Division of Oncology, Department of Medicine, of prostate cancers remain dependent on andro- are intratumoral steroidogenesis through overex- University of Washington/ gen receptor (AR) signaling [Schweizer and Yu, pressing steroidogenic enzymes (e.g. AKR1C3, Fred Hutchinson Cancer Research Center, Seattle, 2015]. Indeed, prostate cancer’s reliance on 3βHSD and CYP17), and the active transport of WA 98109, USA androgens has been recognized since the 1940s, androgens into the tumor microenvironment schweize@u.washington. edu and inhibiting AR signaling with androgen depri- [Montgomery et al. 2008; Cai et al. 2011; Sharifi, Evan Yu, MD vation therapy (ADT) (i.e. surgical castration, 2013; Liu et  al. 2015]. Notably, the recognition Division of Oncology, luteinizing hormone-releasing hormone (LHRH) that CRPC is largely driven by persistent AR Department of Medicine, University of Washington/ analogues) represent the first example of a ‘tar- signaling led to the development of the next gen- Fred Hutchinson Cancer geted’ cancer therapy [Huggins and Hodges, eration AR-directed therapies abiraterone [a Research Center, Seattle, WA, USA 2002]. Consequently, a number of adaptive cytochrome P450 17 (CYP17) inhibitor] and changes occur whereby prostate cancer cells are enzalutamide (a potent AR antagonist), both able to survive in spite of low circulating andro- capable of disrupting the A–ligand interaction gen levels, many of which involve the AR (abiraterone through ligand depletion and enzal- [Robinson et al. 2015; Schweizer and Yu, 2015]. utamide through directly antagonizing the recep- Tumor outgrowth while on ADT represents a key tor) [De Bono et al. 2011; Scher et al. 2012; Ryan transition point from hormone-sensitive to a more et al. 2013; Beer et al. 2014]. aggressive, and ultimately lethal form of the dis- ease: castration-resistant prostate cancer (CRPC). Abiraterone, a CYP17 inhibitor, was largely devel- oped to target the production of persistent extrago- While there are varied mechanisms by which AR nadal (i.e. adrenal and intratumoral) androgens, signaling is able to persist in a castration-resistant and is United States Food and Drug Administration state, the maintenance of intratumoral androgens approved for men with metastatic CRPC on the at levels sufficient to drive tumor growth likely basis of phase III data, indicating that it affords an represent an important driver of the CRPC overall survival benefit [De Bono et al. 2011; Ryan 388 http://tam.sagepub.com MT Schweizer and EY Yu et al. 2013]. Perhaps not surprising, the androgenic the androgen precursor DHEAS into testosterone precursor dehydroepiandrosterone sulfate and DHT, has been shown to mediated steroido- (DHEAS) has been found to persist within the genesis, leading to resistance to AR signaling prostate following neoadjuvant treatment with abi- inhibitors [Desmond et al. 2003; Cai et al. 2011; raterone plus LHRH agonist therapy, which may Liedtke et al. 2013; Liu et al. 2015]. Conversely, in theory be sufficient to drive continued tumor indomethacin, a nonsteroidal drug that has the growth [Tamae et  al. 2015]. Steroid transporters off-target effect of inhibiting AKR1C3, has been have been implicated as mediators of persistent shown to synergize with abiraterone and enzalu- androgens within the tumor microenvironment, tamide in resistant prostate cancer cell lines [Cai and would in theory not be affected by CYP17 et al. 2011; Liu et al. 2015]. As such, clinical trials inhibition. To that end, drugs that impair these designed to more completely impair AR signaling transporters’ activity, such as statins, have begun by including an AKR1C3 inhibitor are currently to be explored [Harshman et  al. 2015]. In this under development. review, we will summarize the role of intratumoral androgens in driving CRPC cell growth, with a Another key steroidogenic enzyme, 3βHSD, also focus on the role of androgen biosynthesis and plays an important role in catalyzing the conver- steroid transporters. sion of androgen precursors (i.e. androstenediol) to more potent androgens (i.e. testosterone), with its enzymatic activity mediating the rate-limiting Intracrine androgen production step that leads to the conversion of DHEA to Data from CRPC studies from both localized DHT [Sharifi, 2013]. Interestingly, a 3βHSD prostate and rapid autopsy tissues have supported gain-of-function mutation, which may be selected the hypothesis that intracrine androgen produc- for in a castration-resistant state, has been shown tion may drive castration-resistant growth to lead to increased DHT production [Chang [Mohler et  al. 2004; Montgomery et  al. 2008]. et  al. 2013]. Furthermore, increased 3βHSD Mohler and colleagues compared tissue androgen activity can result in persistent intratumoral levels in biopsies from men with locally recurrent androgen production in the face of CYP17 inhibi- prostate cancer on ADT with androgen levels in tion, potentially driving abiraterone resistance. benign prostate specimens from untreated men Whether targeting 3βHSD is a viable treatment [Mohler et  al. 2004]. They found that testoster- strategy remains to be seen; however, efforts to one levels were comparable between these samples, effectively target its activity are likely forthcoming while dihydrotestosterone (DHT) levels were [Evaul et  al. 2010]. It should be noted that pre- lower in CRPC specimens. Given that persistent clinical data demonstrate that abiraterone is a prostate-specific antigen (PSA) expression was weak 3βHSD inhibitor, and one strategy being observed in the CRPC specimens, it was con- pursued to target persistent intratumoral andro- cluded that intratumoral androgen levels were gen production entails the administration of dose- sufficient to activate the AR transcriptional pro- escalated abiraterone [ClinicalTrials.gov gram. Montgomery and colleagues have shown identifier: NCT01503229] [Scher et al. 2012]. that in men who died with CRPC, androgen levels within metastatic deposits were significantly higher Speaking to the complexity of the metabolic pro- compared with normal (i.e. benign) control tissue cesses at play within the tumor microenviron- obtained from the same patients [Montgomery ment, 3βHSD has also recently been shown to et al. 2008]. In addition, when mRNA transcript catalyze the conversion of abiraterone to Δ abira- levels of steroidogenic enzymes were compared terone (D4A), a compound able to potently between primary prostate tumors obtained from inhibit the steroidogenic enzymes CYP17, eugonadal men and metastatic tumors from men 3βHSD and SRD5A, and to effectively antago- with CRPC, upregulation of several important nize the AR (at a level comparable to enzaluta- enzymes (i.e. 3βHSD, CYP17A1, AKR1C3 and mide) [Li et  al. 2015]. Given that 3βHSD has SRD5A2) were observed. been implicated in resistance to abiraterone implies that the scales may be tipped towards In vitro and in vivo models of CRPC have lent 3βHSD catalyzing more DHT production rela- further support to the putative role intracrine hor- tive to D4A; however, more research to under- mone production plays in maintaining intratu- stand the relative contribution of DHT and D4A moral androgens, and thus sustaining AR in promoting resistance and response, respec- activation. AKR1C3, an enzyme able to convert tively, are needed. http://tam.sagepub.com 389 Therapeutic Advances in Medical Oncology 8(5) Androgen transporters SNPs in the SLCO2B1 gene (rs12422149G>A, Organic anion-transporting polypeptides rs1789693A>T and rs1077858A>G) were found (OATPs), which are encoded by SLCO genes, are to associate with time to PSA progression in uni- a family of transport proteins that are responsible variate and multivariate analyses. Of these SNPs, for the influx of a number of substrates, including only SLCO2B1 rs12422149G>A (Arg312Gln) is androgens and other steroids, bile acids, peptides exonic. To explore the biologic function of this and a number of pharmaceutical agents [Sissung SNP, LNCaP cells were transfected with either et al. 2010; Pressler et al. 2011]. In total, there are SLCO2B1-312Gln or SLCO2B1-312Arg, and 11 OATPs, which are classified into six families their respective DHEAS uptake efficiency was and subfamilies [Obaidat et al. 2012]. OATPs are characterized. While both SLCO2B1 variants were ubiquitously expressed normal tissues, and have able to transport DHEAS, the SLCO2B1-312Arg been found to be upregulated in several malig- variant was able to do so more efficiently. Because nancies, including prostate cancer, and to associ- DHEAS is a precursor of the potent androgens ate with clinical outcomes in patients with prostate DHT and testosterone, its influx into prostate can- cancer [Obaidat et al. 2012]. cer cells may be an important mechanism by which intracrine androgen production is mediated, thus The OATP1B3 (encoded by SLCO1B3) and providing a plausible biologic explanation for the OATP2B1 (encoded by SLCO2B1) transporters association observed between this SNP and dimin- have both been shown to actively transport ished time to PSA progression [Tamae et al. 2015]. androgens and androgenic substrates. Not sur- prisingly, SLCO genes are more highly expressed by tumors from men with CRPC compared with Statins and androgen transporter activity primary specimens, and SLCO polymorphisms As mentioned above, the OATP transporters that associate with enhanced androgen uptake have a number of substrates in addition to andro- have been shown to associate with prostate can- gens. Notably, statins are also substrates of the cer clinical outcomes [Hamada et  al. 2008; SLCO2B1 transporter, an observation that pro- Mostaghel et  al. 2010; Wright et  al. 2011; Yang vided the motivation for evaluating if there was an et al. 2011]. These observations are both consist- association between statin use and time to PSA ent with the hypothesis that OATP transporters progression with frontline ADT [Harshman et al. may be able to maintain intratumoral androgen 2015]. Harshman and colleagues evaluated the concentrations, thus sustaining AR signaling. effect of a number of statins (i.e. atorvastatin, flu- For instance, in one study cos-7 cells were trans- vastatin, pravastatin, and simvastatin) on DHEAS fected with either wild type (WT) SLCO1B3 uptake in LNCaP and 22RV1 cells, both andro- (334T/699G) or various combinations of the gen responsive and expressing the SLCO2B1 allelic variants 334T>G and 699G>A, which transporter. They found that pravastatin more were identified through genotyping NCI-60 cell effectively inhibited DHEAS transport in both lines. Testosterone influx was then determined cell lines in vitro; although all of the statins tested for the T/G, G/G, T/A and G/A variants, with were able to inhibit DHEAS influx to some diminished androgen transport activity observed extent. Atorvastatin, the most commonly pre- only in cells expressing the SLCO1B3 G/A variant scribed statin, was also shown to inhibit DHEAS- [Hamada et  al. 2008]. To assess for the clinical induced prostate cancer cell growth in vitro. importance of this finding, genotyping was per- Importantly, a separate group was able to show formed on germline DNA from 180 patients with that oral simvastatin administration was associ- CRPC enrolled onto several prospective clinical ated with decreased castration-resistant progres- trials. Those possessing the SLCO1B3 GG/AA sion and lower intratumoral androgen levels in haplotype were shown in this post hoc analysis to LNCaP xenografts compared with controls have improved survival compared with those with [Gordon et al. 2016]. the TT/AA or TG/GA haplotypes (10-year sur- vival: 42% versus 23%, p < 0.023), consistent To evaluate for a potential clinical effect of statin with preclinical experiments. use on prostate cancer growth, Harshman and colleagues next performed a retrospective analy- A larger study assessed for an association between sis to assess for an association between statin use 18 SLCO single nucleotide polymorphisms (SNPs) and time to PSA progression. Using an institu- and clinical outcomes [Yang et al. 2011]. From a tionally maintained database of patients with cohort of 538 patients treated with ADT, three prostate cancer, a cohort of 926 men receiving 390 http://tam.sagepub.com MT Schweizer and EY Yu ADT was assembled. They found that the median time of diagnosis was associated with decreased time to PSA progression for those taking a statin prostate cancer specific mortality [Geybels et al. was 27.5 months versus 17.4 for those not receiv- 2013]. In contrast, a meta-analysis from 27 large ing one (p < 0.001). Importantly, this association randomized statin trials did not find that statin persisted after multivariate analysis adjusted for use was associated with a decreased cancer risk, predefined prognostic factors. calling into question the result of several obser- vation studies, and raising the possibility that While there is a strong suggestion that the clinical the chemoprotective benefits of statins may be correlation between statin use and delayed time to merely a reflection of the inherent bias associ- PSA progression is a result of interfering with ated with retrospective studies [Emberson et  al. SLCO2B1-mediated DHEAS uptake, the possi- 2012]. bility remains that this effect could be due to lowering cholesterol levels, a substrate for all Several epidemiologic and retrospective studies steroid hormones, through inhibiting 3-hydroxy- have been completed to specifically evaluate for 3-methylglutaryl-coenzyme A (HMG-CoA) an association between statin use and the devel- reductase activity [Ramos and Yu, 2015]. A retro- opment of prostate cancer [Flick et  al. 2007; spective analysis by Allott and colleagues specifi- Boudreau et  al. 2008; Chang et  al. 2011; Allott cally evaluated the risk of biochemical recurrence et al. 2014; Jespersen et al. 2014; Chan et al. 2015; (i.e. PSA relapse) following prostatectomy in 843 Cuaron et al. 2015; Kantor et al. 2015; Luo et al. patients who had never received statins prior to 2015; Sun et al. 2015; Zapata et al. 2015]. In gen- their surgery. They found that elevated triglycer- eral, these studies have supported the notion that ides were associated with increased risk of recur- statins may function as a prostate cancer chemo- rence for the entire cohort, and that an elevated protective agent; however, some data conflict total cholesterol level was associated with an with this assertion. increased risk for those with hyperlipidemia [Allott et  al. 2014]. While this finding is consistent with To further explore for a potential association statins exerting a beneficial antitumor effect between statin use and the development of pros- through lowering lipids, it does not specifically tate cancer, two large meta-analyses were con- address whether or not statins modulate SLCO ducted [Bonovas et al. 2008; Bansal et al. 2012]. transporter activity. Ultimately, a prospective ran- Bansal and colleagues reported the results of a domized study will be needed to evaluate the abil- meta-analysis combining 27 observational studies ity of statins to impair intratumoral androgen that assessed the association between statin use transporters and to determine if they are a useful and the risk of developing prostate cancer, and adjunctive prostate cancer treatment. included 1,893,571 men in their final analysis [Bansal et  al. 2012]. They found that statin use was associated with a reduction in total [relative Statin use and cancer risk risk (RR) = 0.93, 95% confidence interval (CI): Because statins are generally well tolerated and 0.87–0.99, p = 0.03) and advanced prostate can- have documented health benefits, there is consid- cer (RR = 0.80, 95% CI: 0.70–0.90, p < 0.001) erable motivation to explore their use as repur- risk. In contrast, Bonovas and colleagues ana- posed chemopreventive agents. In addition to lyzed the data from six randomized controlled tri- lowering the risk of major vascular events, epide- als and 13 observation studies, which included miologic data indicate that they may be effective over 880,000 male subjects [Bonovas et al. 2008]. at preventing a number of malignancies [Poynter This study did not find an association between et  al. 2005; Mihaylova et  al. 2012; Nielsen et  al. statin use and total prostate cancer incidence (RR 2012]. For instance, a population-based observa- = 0.95, 95% CI: 0.73–1.23). The authors noted tional study out of Denmark evaluated the effect that there was high heterogeneity between the of statin use on a subsequent cancer diagnosis. observational studies, and those studies that were Upon multivariate analysis, they found that statin specifically designed to examine statin use in rela- use was associated with a 15% risk reduction in tion to the risk of developing advanced prostate all-cause and cancer-specific mortality, including cancer found that statin use had a protective asso- prostate cancer [Nielsen et al. 2012]. Similarly, a ciation (RR = 0.77, 95% CI: 0.64–0.93). These prospective population-based cohort study (n = conflicting results highlight the need for rand- 1001) evaluating the effect of statin use on pros- omized studies to evaluate the utility of statin as a tate cancer outcomes found that statin use at the chemoprotective agent. http://tam.sagepub.com 391 Therapeutic Advances in Medical Oncology 8(5) Table 1. Ongoing or planned trials evaluating statins in men with prostate cancer. ClinicalTrials. Target population Study Sample Treatment Primary endpoint gov identifier phase size NCT01821404 Preprostatectomy Phase II 160 A: atorvastatin A: tissue effects (i.e. apoptosis, B: placebo Ki-67 expression, histological inflammation) B: change in PSA pre/ post treatment (prior to prostatectomy) NCT02534376 Preprostatectomy Phase 0 70 A: ezetimibe + Ex vivo growth of Gleason 3 simvastatin prostate cancer obtained from prostatectomy specimens NCT00572468 Preprostatectomy Phase II 44 A: simvastatin Effect of treatment on B: placebo mevalonate pathway synthesis and target activation NCT01992042 Preprostatectomy Phase II 40 A: fluvastatin Pre-/post-treatment effect on B: pimonidazole Ki-67 index NCT01759836 Preprostatectomy Phase II 354 A: atorvastatin Rate of biochemical recurrence B: placebo postprostatectomy NCT02497638 Biochemically recurrent Phase II 110 A: metformin + Time to progression (PSA rise patients following local atorvastatin >10 ng/ml or development of therapy B: placebo metastases) NCT01220973 Patients with biochemically Phase II 27 PSA response A: atorvastatin + recurrent disease following celecoxib local therapy PSA, prostate-specific antigen. Future directions phenotype [Mohler et  al. 2004; Montgomery A number of strategies are being explored to tar- et al. 2008]. Additional studies evaluating the role get intracrine androgen synthesis or transporter- of statins, ideally in combination with other mediated androgen influx into the tumor inhibitors of intratumoral steroidogenesis (e.g. microenvironment. Compelling preclinical data abiraterone or indomethacin), in treating CRPC supported both of these strategies and a number are therefore justified. of the drugs in our current ‘therapeutic toolbox’ may allow us to accomplish these goals, thus decreasing the long lead-in time required to Conclusion launch most translational clinical trials. As men- While the availability of statins may tempt one to tioned above, agents warranting further clinical proceed with prescribing them off label in an investigation include high-dose abiraterone, indo- effort to more effectively treat prostate cancer, methacin and, as a class, the statins. caution should be taken. Even in the face of com- pelling preliminary data, randomized trials are Indeed, a query of ClinicalTrials.gov demon- still needed to establish new treatment standards. strates that a number of trials evaluating the ther- This point was highlighted by the SELECT trial: apeutic effect of statins on prostate cancer have a large (n = 35,533), randomized chemopreven- either recently been activated or are planned to tion trial testing vitamin E with or without sele- open in the near future (Table 1). It should be nium versus placebo [Lippman et al. 2009; Klein noted that the majority of studies are being devel- et al. 2011]. This study was launched on the basis oped in the presurgical or biochemically recurrent of prior randomized trials that reported improved space. While there is certainly a rationale for prostate cancer outcomes for those on vitamin E developing statins as a therapy for hormone- and selenium as a secondary outcome, presuma- sensitive prostate cancer, available evidence indi- bly due to their antioxidant effects. Ultimately, cates that steroidogenesis may be key mechanism this trial reported that vitamin E was associated underlying the emergence of a castration-resistant with the unintended consequence of increasing 392 http://tam.sagepub.com MT Schweizer and EY Yu Cai, C., Chen, S., Ng, P., Bubley, G., Nelson, P., the risk of developing prostate cancer. Given their Mostaghel, E. et al. (2011) Intratumoral de novo long safety track record, it seems unlikely that a steroid synthesis activates androgen receptor in randomized prostate cancer trial testing statins castration-resistant prostate cancer and is upregulated would result in such an unexpected outcome; by treatment with CYP17A1 inhibitors. Cancer Res 71: however, exposure to unnecessary medications 6503–6513. should be limited whenever possible due to the Chan, J., Kenfield, S., Paciorek, A., Platz, E., potential for side effects (e.g. rhabdomyolysis, Giovannucci, E. and Stampfer, M. (2015) liver function test abnormalities). Postdiagnostic statin use and the risk of lethal prostate cancer in the health professionals follow-up study. Prostate cancer is a worthy foe, constantly adapt- Cancer Epidemiol Biomarkers Prev 24: 1638–1640. ing to maintain persistent AR signaling. Our understanding of the intracrine and other micro- Chang, C., Ho, S., Chiu, H. and Yang, C. (2011) Statins increase the risk of prostate cancer: a environmental processes that can lead to persis- population-based case-control study. Prostate 71: tent intratumoral androgens is still in its infancy; 1818–1824. however, mounting evidence supports the asser- tion that these are viable targets by which prostate Chang, K., Li, R., Kuri, B., Lotan, Y., Roehrborn, cancer growth can be further attacked. With C., Liu, J. et al. (2013) A Gain-of-function mutation drugs like statins readily available, clinical trials to in DHT synthesis in castration-resistant prostate cancer. Cell 154: 1074–1084. formally assess the utility of impairing the mecha- nisms that sustain intratumoral androgens should Cuaron, J., Pei, X., Cohen, G., Cox, B., Yamada, Y., proceed without delay. Zelefsky, M. et al. (2015) Statin use not associated with improved outcomes in patients treated with Funding brachytherapy for prostate cancer. 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Targeting intratumoral androgens: statins and beyond:

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647962 TAM0010.1177/1758834016647962Therapeutic Advances in Medical OncologyMT Schweizer and EY Yu research-article2016 Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Targeting intratumoral androgens: statins 2016, Vol. 8(5) 388 –395 DOI: 10.1177/ and beyond © The Author(s), 2016. Reprints and permissions: http://www.sagepub.co.uk/ Michael T. Schweizer and Evan Y. Yu journalsPermissions.nav Abstract: While initially effective, androgen deprivation therapy (ADT) is not curative, and nearly all men with advanced prostate cancer will eventually progress to the more resistant, and ultimately lethal form of the disease, so called castration-resistant prostate cancer (CRPC). The maintenance of androgens within the prostate cancer microenvironment likely represents one of the key mechanisms by which this transition from hormone- sensitive to CRPC occurs. This can be accomplished either through intratumoral androgen biosynthesis or the active transport of androgens and androgenic precursors into the tumor microenvironment. More recently, preclinical and clinical data supported therapeutic strategies that seek to target these two mechanisms, either through the use of drugs that impair androgen biosynthesis (e.g. inhibiting the steroidogenic enzymes CYP17 and AKR1C3 with abiraterone and indomethacin, respectively) or drugs that inhibit the SLCO transporters responsible for importing androgens (e.g. statins). Keywords: androgen receptor, castration-resistant prostate cancer, drug resistance, microenvironment, prostate cancer, statin, steroidogenesis Correspondence to: Introduction phenotype [Titus et  al. 2005; Mostaghel et  al. Michael Schweizer, MD Even in its most resistant form, the vast majority 2007]. Key sources of these persistent androgens Division of Oncology, Department of Medicine, of prostate cancers remain dependent on andro- are intratumoral steroidogenesis through overex- University of Washington/ gen receptor (AR) signaling [Schweizer and Yu, pressing steroidogenic enzymes (e.g. AKR1C3, Fred Hutchinson Cancer Research Center, Seattle, 2015]. Indeed, prostate cancer’s reliance on 3βHSD and CYP17), and the active transport of WA 98109, USA androgens has been recognized since the 1940s, androgens into the tumor microenvironment schweize@u.washington. edu and inhibiting AR signaling with androgen depri- [Montgomery et al. 2008; Cai et al. 2011; Sharifi, Evan Yu, MD vation therapy (ADT) (i.e. surgical castration, 2013; Liu et  al. 2015]. Notably, the recognition Division of Oncology, luteinizing hormone-releasing hormone (LHRH) that CRPC is largely driven by persistent AR Department of Medicine, University of Washington/ analogues) represent the first example of a ‘tar- signaling led to the development of the next gen- Fred Hutchinson Cancer geted’ cancer therapy [Huggins and Hodges, eration AR-directed therapies abiraterone [a Research Center, Seattle, WA, USA 2002]. Consequently, a number of adaptive cytochrome P450 17 (CYP17) inhibitor] and changes occur whereby prostate cancer cells are enzalutamide (a potent AR antagonist), both able to survive in spite of low circulating andro- capable of disrupting the A–ligand interaction gen levels, many of which involve the AR (abiraterone through ligand depletion and enzal- [Robinson et al. 2015; Schweizer and Yu, 2015]. utamide through directly antagonizing the recep- Tumor outgrowth while on ADT represents a key tor) [De Bono et al. 2011; Scher et al. 2012; Ryan transition point from hormone-sensitive to a more et al. 2013; Beer et al. 2014]. aggressive, and ultimately lethal form of the dis- ease: castration-resistant prostate cancer (CRPC). Abiraterone, a CYP17 inhibitor, was largely devel- oped to target the production of persistent extrago- While there are varied mechanisms by which AR nadal (i.e. adrenal and intratumoral) androgens, signaling is able to persist in a castration-resistant and is United States Food and Drug Administration state, the maintenance of intratumoral androgens approved for men with metastatic CRPC on the at levels sufficient to drive tumor growth likely basis of phase III data, indicating that it affords an represent an important driver of the CRPC overall survival benefit [De Bono et al. 2011; Ryan 388 http://tam.sagepub.com MT Schweizer and EY Yu et al. 2013]. Perhaps not surprising, the androgenic the androgen precursor DHEAS into testosterone precursor dehydroepiandrosterone sulfate and DHT, has been shown to mediated steroido- (DHEAS) has been found to persist within the genesis, leading to resistance to AR signaling prostate following neoadjuvant treatment with abi- inhibitors [Desmond et al. 2003; Cai et al. 2011; raterone plus LHRH agonist therapy, which may Liedtke et al. 2013; Liu et al. 2015]. Conversely, in theory be sufficient to drive continued tumor indomethacin, a nonsteroidal drug that has the growth [Tamae et  al. 2015]. Steroid transporters off-target effect of inhibiting AKR1C3, has been have been implicated as mediators of persistent shown to synergize with abiraterone and enzalu- androgens within the tumor microenvironment, tamide in resistant prostate cancer cell lines [Cai and would in theory not be affected by CYP17 et al. 2011; Liu et al. 2015]. As such, clinical trials inhibition. To that end, drugs that impair these designed to more completely impair AR signaling transporters’ activity, such as statins, have begun by including an AKR1C3 inhibitor are currently to be explored [Harshman et  al. 2015]. In this under development. review, we will summarize the role of intratumoral androgens in driving CRPC cell growth, with a Another key steroidogenic enzyme, 3βHSD, also focus on the role of androgen biosynthesis and plays an important role in catalyzing the conver- steroid transporters. sion of androgen precursors (i.e. androstenediol) to more potent androgens (i.e. testosterone), with its enzymatic activity mediating the rate-limiting Intracrine androgen production step that leads to the conversion of DHEA to Data from CRPC studies from both localized DHT [Sharifi, 2013]. Interestingly, a 3βHSD prostate and rapid autopsy tissues have supported gain-of-function mutation, which may be selected the hypothesis that intracrine androgen produc- for in a castration-resistant state, has been shown tion may drive castration-resistant growth to lead to increased DHT production [Chang [Mohler et  al. 2004; Montgomery et  al. 2008]. et  al. 2013]. Furthermore, increased 3βHSD Mohler and colleagues compared tissue androgen activity can result in persistent intratumoral levels in biopsies from men with locally recurrent androgen production in the face of CYP17 inhibi- prostate cancer on ADT with androgen levels in tion, potentially driving abiraterone resistance. benign prostate specimens from untreated men Whether targeting 3βHSD is a viable treatment [Mohler et  al. 2004]. They found that testoster- strategy remains to be seen; however, efforts to one levels were comparable between these samples, effectively target its activity are likely forthcoming while dihydrotestosterone (DHT) levels were [Evaul et  al. 2010]. It should be noted that pre- lower in CRPC specimens. Given that persistent clinical data demonstrate that abiraterone is a prostate-specific antigen (PSA) expression was weak 3βHSD inhibitor, and one strategy being observed in the CRPC specimens, it was con- pursued to target persistent intratumoral andro- cluded that intratumoral androgen levels were gen production entails the administration of dose- sufficient to activate the AR transcriptional pro- escalated abiraterone [ClinicalTrials.gov gram. Montgomery and colleagues have shown identifier: NCT01503229] [Scher et al. 2012]. that in men who died with CRPC, androgen levels within metastatic deposits were significantly higher Speaking to the complexity of the metabolic pro- compared with normal (i.e. benign) control tissue cesses at play within the tumor microenviron- obtained from the same patients [Montgomery ment, 3βHSD has also recently been shown to et al. 2008]. In addition, when mRNA transcript catalyze the conversion of abiraterone to Δ abira- levels of steroidogenic enzymes were compared terone (D4A), a compound able to potently between primary prostate tumors obtained from inhibit the steroidogenic enzymes CYP17, eugonadal men and metastatic tumors from men 3βHSD and SRD5A, and to effectively antago- with CRPC, upregulation of several important nize the AR (at a level comparable to enzaluta- enzymes (i.e. 3βHSD, CYP17A1, AKR1C3 and mide) [Li et  al. 2015]. Given that 3βHSD has SRD5A2) were observed. been implicated in resistance to abiraterone implies that the scales may be tipped towards In vitro and in vivo models of CRPC have lent 3βHSD catalyzing more DHT production rela- further support to the putative role intracrine hor- tive to D4A; however, more research to under- mone production plays in maintaining intratu- stand the relative contribution of DHT and D4A moral androgens, and thus sustaining AR in promoting resistance and response, respec- activation. AKR1C3, an enzyme able to convert tively, are needed. http://tam.sagepub.com 389 Therapeutic Advances in Medical Oncology 8(5) Androgen transporters SNPs in the SLCO2B1 gene (rs12422149G>A, Organic anion-transporting polypeptides rs1789693A>T and rs1077858A>G) were found (OATPs), which are encoded by SLCO genes, are to associate with time to PSA progression in uni- a family of transport proteins that are responsible variate and multivariate analyses. Of these SNPs, for the influx of a number of substrates, including only SLCO2B1 rs12422149G>A (Arg312Gln) is androgens and other steroids, bile acids, peptides exonic. To explore the biologic function of this and a number of pharmaceutical agents [Sissung SNP, LNCaP cells were transfected with either et al. 2010; Pressler et al. 2011]. In total, there are SLCO2B1-312Gln or SLCO2B1-312Arg, and 11 OATPs, which are classified into six families their respective DHEAS uptake efficiency was and subfamilies [Obaidat et al. 2012]. OATPs are characterized. While both SLCO2B1 variants were ubiquitously expressed normal tissues, and have able to transport DHEAS, the SLCO2B1-312Arg been found to be upregulated in several malig- variant was able to do so more efficiently. Because nancies, including prostate cancer, and to associ- DHEAS is a precursor of the potent androgens ate with clinical outcomes in patients with prostate DHT and testosterone, its influx into prostate can- cancer [Obaidat et al. 2012]. cer cells may be an important mechanism by which intracrine androgen production is mediated, thus The OATP1B3 (encoded by SLCO1B3) and providing a plausible biologic explanation for the OATP2B1 (encoded by SLCO2B1) transporters association observed between this SNP and dimin- have both been shown to actively transport ished time to PSA progression [Tamae et al. 2015]. androgens and androgenic substrates. Not sur- prisingly, SLCO genes are more highly expressed by tumors from men with CRPC compared with Statins and androgen transporter activity primary specimens, and SLCO polymorphisms As mentioned above, the OATP transporters that associate with enhanced androgen uptake have a number of substrates in addition to andro- have been shown to associate with prostate can- gens. Notably, statins are also substrates of the cer clinical outcomes [Hamada et  al. 2008; SLCO2B1 transporter, an observation that pro- Mostaghel et  al. 2010; Wright et  al. 2011; Yang vided the motivation for evaluating if there was an et al. 2011]. These observations are both consist- association between statin use and time to PSA ent with the hypothesis that OATP transporters progression with frontline ADT [Harshman et al. may be able to maintain intratumoral androgen 2015]. Harshman and colleagues evaluated the concentrations, thus sustaining AR signaling. effect of a number of statins (i.e. atorvastatin, flu- For instance, in one study cos-7 cells were trans- vastatin, pravastatin, and simvastatin) on DHEAS fected with either wild type (WT) SLCO1B3 uptake in LNCaP and 22RV1 cells, both andro- (334T/699G) or various combinations of the gen responsive and expressing the SLCO2B1 allelic variants 334T>G and 699G>A, which transporter. They found that pravastatin more were identified through genotyping NCI-60 cell effectively inhibited DHEAS transport in both lines. Testosterone influx was then determined cell lines in vitro; although all of the statins tested for the T/G, G/G, T/A and G/A variants, with were able to inhibit DHEAS influx to some diminished androgen transport activity observed extent. Atorvastatin, the most commonly pre- only in cells expressing the SLCO1B3 G/A variant scribed statin, was also shown to inhibit DHEAS- [Hamada et  al. 2008]. To assess for the clinical induced prostate cancer cell growth in vitro. importance of this finding, genotyping was per- Importantly, a separate group was able to show formed on germline DNA from 180 patients with that oral simvastatin administration was associ- CRPC enrolled onto several prospective clinical ated with decreased castration-resistant progres- trials. Those possessing the SLCO1B3 GG/AA sion and lower intratumoral androgen levels in haplotype were shown in this post hoc analysis to LNCaP xenografts compared with controls have improved survival compared with those with [Gordon et al. 2016]. the TT/AA or TG/GA haplotypes (10-year sur- vival: 42% versus 23%, p < 0.023), consistent To evaluate for a potential clinical effect of statin with preclinical experiments. use on prostate cancer growth, Harshman and colleagues next performed a retrospective analy- A larger study assessed for an association between sis to assess for an association between statin use 18 SLCO single nucleotide polymorphisms (SNPs) and time to PSA progression. Using an institu- and clinical outcomes [Yang et al. 2011]. From a tionally maintained database of patients with cohort of 538 patients treated with ADT, three prostate cancer, a cohort of 926 men receiving 390 http://tam.sagepub.com MT Schweizer and EY Yu ADT was assembled. They found that the median time of diagnosis was associated with decreased time to PSA progression for those taking a statin prostate cancer specific mortality [Geybels et al. was 27.5 months versus 17.4 for those not receiv- 2013]. In contrast, a meta-analysis from 27 large ing one (p < 0.001). Importantly, this association randomized statin trials did not find that statin persisted after multivariate analysis adjusted for use was associated with a decreased cancer risk, predefined prognostic factors. calling into question the result of several obser- vation studies, and raising the possibility that While there is a strong suggestion that the clinical the chemoprotective benefits of statins may be correlation between statin use and delayed time to merely a reflection of the inherent bias associ- PSA progression is a result of interfering with ated with retrospective studies [Emberson et  al. SLCO2B1-mediated DHEAS uptake, the possi- 2012]. bility remains that this effect could be due to lowering cholesterol levels, a substrate for all Several epidemiologic and retrospective studies steroid hormones, through inhibiting 3-hydroxy- have been completed to specifically evaluate for 3-methylglutaryl-coenzyme A (HMG-CoA) an association between statin use and the devel- reductase activity [Ramos and Yu, 2015]. A retro- opment of prostate cancer [Flick et  al. 2007; spective analysis by Allott and colleagues specifi- Boudreau et  al. 2008; Chang et  al. 2011; Allott cally evaluated the risk of biochemical recurrence et al. 2014; Jespersen et al. 2014; Chan et al. 2015; (i.e. PSA relapse) following prostatectomy in 843 Cuaron et al. 2015; Kantor et al. 2015; Luo et al. patients who had never received statins prior to 2015; Sun et al. 2015; Zapata et al. 2015]. In gen- their surgery. They found that elevated triglycer- eral, these studies have supported the notion that ides were associated with increased risk of recur- statins may function as a prostate cancer chemo- rence for the entire cohort, and that an elevated protective agent; however, some data conflict total cholesterol level was associated with an with this assertion. increased risk for those with hyperlipidemia [Allott et  al. 2014]. While this finding is consistent with To further explore for a potential association statins exerting a beneficial antitumor effect between statin use and the development of pros- through lowering lipids, it does not specifically tate cancer, two large meta-analyses were con- address whether or not statins modulate SLCO ducted [Bonovas et al. 2008; Bansal et al. 2012]. transporter activity. Ultimately, a prospective ran- Bansal and colleagues reported the results of a domized study will be needed to evaluate the abil- meta-analysis combining 27 observational studies ity of statins to impair intratumoral androgen that assessed the association between statin use transporters and to determine if they are a useful and the risk of developing prostate cancer, and adjunctive prostate cancer treatment. included 1,893,571 men in their final analysis [Bansal et  al. 2012]. They found that statin use was associated with a reduction in total [relative Statin use and cancer risk risk (RR) = 0.93, 95% confidence interval (CI): Because statins are generally well tolerated and 0.87–0.99, p = 0.03) and advanced prostate can- have documented health benefits, there is consid- cer (RR = 0.80, 95% CI: 0.70–0.90, p < 0.001) erable motivation to explore their use as repur- risk. In contrast, Bonovas and colleagues ana- posed chemopreventive agents. In addition to lyzed the data from six randomized controlled tri- lowering the risk of major vascular events, epide- als and 13 observation studies, which included miologic data indicate that they may be effective over 880,000 male subjects [Bonovas et al. 2008]. at preventing a number of malignancies [Poynter This study did not find an association between et  al. 2005; Mihaylova et  al. 2012; Nielsen et  al. statin use and total prostate cancer incidence (RR 2012]. For instance, a population-based observa- = 0.95, 95% CI: 0.73–1.23). The authors noted tional study out of Denmark evaluated the effect that there was high heterogeneity between the of statin use on a subsequent cancer diagnosis. observational studies, and those studies that were Upon multivariate analysis, they found that statin specifically designed to examine statin use in rela- use was associated with a 15% risk reduction in tion to the risk of developing advanced prostate all-cause and cancer-specific mortality, including cancer found that statin use had a protective asso- prostate cancer [Nielsen et al. 2012]. Similarly, a ciation (RR = 0.77, 95% CI: 0.64–0.93). These prospective population-based cohort study (n = conflicting results highlight the need for rand- 1001) evaluating the effect of statin use on pros- omized studies to evaluate the utility of statin as a tate cancer outcomes found that statin use at the chemoprotective agent. http://tam.sagepub.com 391 Therapeutic Advances in Medical Oncology 8(5) Table 1. Ongoing or planned trials evaluating statins in men with prostate cancer. ClinicalTrials. Target population Study Sample Treatment Primary endpoint gov identifier phase size NCT01821404 Preprostatectomy Phase II 160 A: atorvastatin A: tissue effects (i.e. apoptosis, B: placebo Ki-67 expression, histological inflammation) B: change in PSA pre/ post treatment (prior to prostatectomy) NCT02534376 Preprostatectomy Phase 0 70 A: ezetimibe + Ex vivo growth of Gleason 3 simvastatin prostate cancer obtained from prostatectomy specimens NCT00572468 Preprostatectomy Phase II 44 A: simvastatin Effect of treatment on B: placebo mevalonate pathway synthesis and target activation NCT01992042 Preprostatectomy Phase II 40 A: fluvastatin Pre-/post-treatment effect on B: pimonidazole Ki-67 index NCT01759836 Preprostatectomy Phase II 354 A: atorvastatin Rate of biochemical recurrence B: placebo postprostatectomy NCT02497638 Biochemically recurrent Phase II 110 A: metformin + Time to progression (PSA rise patients following local atorvastatin >10 ng/ml or development of therapy B: placebo metastases) NCT01220973 Patients with biochemically Phase II 27 PSA response A: atorvastatin + recurrent disease following celecoxib local therapy PSA, prostate-specific antigen. Future directions phenotype [Mohler et  al. 2004; Montgomery A number of strategies are being explored to tar- et al. 2008]. Additional studies evaluating the role get intracrine androgen synthesis or transporter- of statins, ideally in combination with other mediated androgen influx into the tumor inhibitors of intratumoral steroidogenesis (e.g. microenvironment. Compelling preclinical data abiraterone or indomethacin), in treating CRPC supported both of these strategies and a number are therefore justified. of the drugs in our current ‘therapeutic toolbox’ may allow us to accomplish these goals, thus decreasing the long lead-in time required to Conclusion launch most translational clinical trials. As men- While the availability of statins may tempt one to tioned above, agents warranting further clinical proceed with prescribing them off label in an investigation include high-dose abiraterone, indo- effort to more effectively treat prostate cancer, methacin and, as a class, the statins. caution should be taken. Even in the face of com- pelling preliminary data, randomized trials are Indeed, a query of ClinicalTrials.gov demon- still needed to establish new treatment standards. strates that a number of trials evaluating the ther- This point was highlighted by the SELECT trial: apeutic effect of statins on prostate cancer have a large (n = 35,533), randomized chemopreven- either recently been activated or are planned to tion trial testing vitamin E with or without sele- open in the near future (Table 1). It should be nium versus placebo [Lippman et al. 2009; Klein noted that the majority of studies are being devel- et al. 2011]. This study was launched on the basis oped in the presurgical or biochemically recurrent of prior randomized trials that reported improved space. While there is certainly a rationale for prostate cancer outcomes for those on vitamin E developing statins as a therapy for hormone- and selenium as a secondary outcome, presuma- sensitive prostate cancer, available evidence indi- bly due to their antioxidant effects. Ultimately, cates that steroidogenesis may be key mechanism this trial reported that vitamin E was associated underlying the emergence of a castration-resistant with the unintended consequence of increasing 392 http://tam.sagepub.com MT Schweizer and EY Yu Cai, C., Chen, S., Ng, P., Bubley, G., Nelson, P., the risk of developing prostate cancer. Given their Mostaghel, E. et al. (2011) Intratumoral de novo long safety track record, it seems unlikely that a steroid synthesis activates androgen receptor in randomized prostate cancer trial testing statins castration-resistant prostate cancer and is upregulated would result in such an unexpected outcome; by treatment with CYP17A1 inhibitors. Cancer Res 71: however, exposure to unnecessary medications 6503–6513. should be limited whenever possible due to the Chan, J., Kenfield, S., Paciorek, A., Platz, E., potential for side effects (e.g. rhabdomyolysis, Giovannucci, E. and Stampfer, M. (2015) liver function test abnormalities). Postdiagnostic statin use and the risk of lethal prostate cancer in the health professionals follow-up study. Prostate cancer is a worthy foe, constantly adapt- Cancer Epidemiol Biomarkers Prev 24: 1638–1640. ing to maintain persistent AR signaling. Our understanding of the intracrine and other micro- Chang, C., Ho, S., Chiu, H. and Yang, C. (2011) Statins increase the risk of prostate cancer: a environmental processes that can lead to persis- population-based case-control study. Prostate 71: tent intratumoral androgens is still in its infancy; 1818–1824. however, mounting evidence supports the asser- tion that these are viable targets by which prostate Chang, K., Li, R., Kuri, B., Lotan, Y., Roehrborn, cancer growth can be further attacked. With C., Liu, J. et al. (2013) A Gain-of-function mutation drugs like statins readily available, clinical trials to in DHT synthesis in castration-resistant prostate cancer. Cell 154: 1074–1084. formally assess the utility of impairing the mecha- nisms that sustain intratumoral androgens should Cuaron, J., Pei, X., Cohen, G., Cox, B., Yamada, Y., proceed without delay. Zelefsky, M. et al. (2015) Statin use not associated with improved outcomes in patients treated with Funding brachytherapy for prostate cancer. 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Journal

Therapeutic Advances in Medical Oncology – SAGE

Published: May 11, 2016

Keywords: androgen receptor; castration-resistant prostate cancer; drug resistance; microenvironment; prostate cancer; statin; steroidogenesis

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