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Redefining hormone resistance in prostate cancer:

Redefining hormone resistance in prostate cancer: Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Redefining hormone resistance in (2010) 2(2) 107123 DOI: 10.1177/ prostate cancer ! The Author(s), 2010. Reprints and permissions: http://www.sagepub.co.uk/ Christopher J. Hoimes and W. Kevin Kelly journalsPermissions.nav Abstract: Prostate cancer relies on signaling through the androgen receptor (AR) for maintenance and progression; and androgen-deprivation therapy remains a cornerstone of treatment for advanced prostate cancer. An effective clinical classification of prostate cancer should account for the extent of the disease as well as the mechanisms that are driving the growth of the tumor. The previous terms hormone-sensitive and hormone-refractory described response to treatment. It has become clear that these terms do not reflect the mechanism of disease relapse; however over the last decade there has been a better understanding of androgen-receptor mediated signaling effects and incomplete suppression of androgens in prostate cancer. The Prostate Cancer Clinical Trials Working Group 2 (PCWG2) now recommends addressing the spectrum of clinical states based on castration status as this ligand-centered terminology can more accurately describe the patients’ disease, and ultimately provides a useful framework for patient management and drug development. Optimized use of androgen-deprivation therapy, low molecular weight inhibitors of adrenal androgen biosynthesis, and new AR antagonists are promising new therapeutics that can further define the meaning of castrate state. As hormone resistance is redefined to include patients that are refractory to treatments that ablate adrenal and in situ tumoral androgens, a meaningful new clinical state in patients will be forged. We propose a model for incorporating these patients into the current PCWG2 conceptualization of the disease. Keywords: androgen-deplete prostate cancer, androgen-deplete signaling pathways, androgen receptor signaling, castrate resistant prostate cancer, collateral androgen deplete, prostatic adenocarcinoma Correspondence to: Introduction mechanisms that are mediated by the AR — W. Kevin Kelly, DO Prostate adenocarcinoma leads to the second such as tumor in situ androgen production and Yale University School of Medicine, Yale most common cause of male cancer deaths amplification of AR protein — or those that Comprehensive Cancer [Jemal et al. 2009] and its tumorigenesis is primar- bypass it such as coactivators and transactivators. Center, 333 Cedar Street, FMP 114, New Haven, CT ily regulated by androgen binding and transcrip- In this setting, 1030% of patients will respond to 06520, USA tion signals of the androgen receptor (AR). Even secondary hormonal maneuvers such as estro- wm.kevin.kelly@yale.edu as the majority of patients are cured with definitive gens, antiandrogen therapy, or adrenal androgen Christopher J. Hoimes, DO primary treatments, those with high-risk locally targeted therapy [Small et al. 2006]. Docetaxel Yale Comprehensive advanced disease or metastatic disease are offered plus prednisone chemotherapy is considered for Cancer Center, Yale University School of medical or surgical castration which can induce castrate-resistant prostate cancer (CRPC) Medicine, New Haven, CT, durable remissions for a median of 1430 patients who progress on hormonal therapy or USA months [Singer et al. 2008]. Though nearly all have a rapid disease progression. There is no stan- respond to hormone maneuvers initially, most dard for patients who progress beyond this, and patients progress and recurrent tumors re-express new therapies on the horizon are pushing the active AR signaling as indicated by continuous envelope of attenuating and ablating resurgent target gene expression despite having castrate AR signaling in CRPC. Optimized use of andro- levels of androgens [Chen et al. 2004]. The gen deprivation therapy (ADT), low molecular return of AR signaling in the castrate patient (tes- weight inhibitors of adrenal androgen biosynthe- tosterone 50 ng/dL) can be attributed to sis, and new AR antagonists are promising new http://tam.sagepub.com 107 Therapeutic Advances in Medical Oncology 2 (2) delivery strategies and therapeutics that can disparities where African-American men are pro- account for the more common causes of hormone portionately more severely affected. Between resistance in CRPC. Achieving a depleted AR 2001 and 2005, the yearly prostate cancer inci- signal will likely forge a meaningful new clinical dence for African-American men was 249 (per state in patients previously resistant to hormone 100,000) compared with 157 for Caucasians, therapy. and 138 for Hispanics [Jemal et al. 2009]. Furthermore, during the same 4-year period, Castration-resistant disease is a fatal manifesta- the yearly mortality for African-Americans was tion of prostate cancer and significant efforts are 59 (per 100,000) exceeding twice that underway to better understand this phase of the of Caucasian (25 per 100,000) and Hispanic disease and develop treatments. At present we (21 per 100,000) patients [Jemal et al. 2009]. understand that there is a significant degree It is unclear whether this increased mortality of heterogeneity amongst CRPC patients with rate in African-American men is due to different profiles of progression from slow to unique racial, biological, and genetic factors, aggressive. There are some known biologic asso- rather than dietary influences, comorbid medical ciations with these heterogeneous populations. conditions, lifestyle differences, and/or access to Examples are prostate specific membrane antigen healthcare. (PSMA) status, loss of Phosphatase and tensin homolog (PTEN), gains of v-myc myelocytoma- Retrospective and prospective studies have tosis viral oncogene homolog (MYC), ErbB3 shown, however, that race does not play a role status, cadherin-11 status, and TMPRSS2-ERG in cause-specific survival once diagnosed with fusion gene status. Cause and effect has not been advanced CRPC [these studies are pre-PCWG2 adequately established for many of these; how- and used cohorts of patients defined as having ever, as we are beginning to understand this androgen independent prostate cancer (AIPC) phase of disease, we are likely to see these candi- which would now be considered CRPC patients], date biologic profiles become a relevant subclas- response to antiandrogens, the time to PSA sification of CRPC patients that will impact nadir, PSA doubling time, or in overall prognosis rational treatment decisions and prognosis. This [Wyatt et al. 2004; McLeod et al. 1999; Brawn more individualized approach is likely several et al. 1993]. Other studies have shown that race years away and requires further elucidation of does not correlate with extent of disease in bone, the relevant biologic pathways that most impact number of metastases, or time to CRPC [Wyatt disease course and drug development and deliv- et al. 2004]. Nonetheless; African-American and ery strategies that can perturb them. Hispanic patients were younger at diagnosis with more advanced disease than Caucasian cohorts. Currently, however, we are on the horizon of sev- There may be differences in biology that lead to eral new systemic therapies that are reinforcing difference in prevalence, and earlier onset of dis- biologic principles of ligand and AR signaling dis- ease, but those differences do not appear to be covered in the past one to two decades. These driving the cancer at a disproportionate tempo therapies are showing enough promise with toler- once patients receive therapy. ability and efficacy that our current models will need to incorporate these patients into the cur- Prostate cancer displays a range of disease tempo, rent Prostate Cancer Clinical Trials Working from tumors of no clinical impact to those that Group 2 (PCWG2) conceptualization of the are aggressive and lethal with multiple metasta- disease. ses. Between these two ends of the range are the locally advanced tumors with few metastases that Castrate-resistant prostate cancer: clinical insidiously infiltrate pelvic structures causing sig- heterogeneity nificant morbidity in the way of urinary urgency, Risk factors for prostate cancer include a male incomplete voiding with risk for urinary obstruc- with advancing age and an intact tion, constipation and hematochezia, insomnia, hypothalamic-pituitary-gonadal axis. There is a fatigue, obstructive lymphedema, sacral plexus relative risk increase of 1.4 for a brother of a neuropathy, and pain. The clinical subsets of man with prostate cancer, and having two to patients with prostate cancer become clear over three first degree relatives with the disease can time as a patient is treated or actively observed — increase the risk by 511 times, respectively, unfortunately, current wisdom of identifying the over the general population. There are race low risk patient is only in hindsight. 108 http://tam.sagepub.com CJ Hoimes and WK Kelly Even as patients progress to advanced CRPC dis- Previous to the PCWG2, disease states and clinical ease, there continues to be heterogeneity with a classification were not as clearly defined and caused spectrum of disease progression. The range difficulty interpreting outcomes. Clinical experi- amongst patients with CRPC is from advanced ence with the antiandrogen flutamide in metastatic prostate cancer patients led to the observation of pelvic disease with few metastases and relatively the flutamide withdrawal syndrome [Kelly et al. long survival of over 40 months [Assikis et al. 1993]. The initial series described approximately 2004] to those that develop neuroendocrine fea- a third of patients with a significant PSA decline tures with a rapid tempo of disease. Accurate (>50%) and clinical improvement upon disconti- staging that represents the patients’ disease nuation of flutamide therapy [Scher and Kelly, course is therefore important for prognostic and 1993]. It quickly became clear that antiandrogen treatment decisions. withdrawal is a hormone maneuver in its own right. However, this important therapy and clinical state Castrate-resistant prostate cancer: terminol- was not uniformly incorporated into clinical trial ogy and current classification use for several more years and not doing so was Clinical staging describes the profile of the extent likely responsible for false-positive results in many of the prostate tumor at one point in a time con- trials during that time [Scher et al. 1995]. There tinuum of the patient; much like the Rai clinical was confusion in interpreting trials as a staging system achieves in chronic lymphocytic hormone-sensitive patient in one trial may leukemia [Rai et al. 1975]. As the Rai system have been considered resistant in another [Scher has needed modification [Gale et al. 1987], pros- et al. 1995]. tate cancer clinical staging has needed to be updated or revised as new understanding of A classification scheme was developed for what drives castrate-resistant biology and as ther- prostate cancer based on hormone sensitivity in apeutics are discovered that are tolerable and 1995 and used categories of hormone-naı ¨ve, favorably impact prognosis. While pathologically androgen-independent and hormone-sensitive, staging based on morphologic appearance using and hormone-independent [Scher et al. 1995]. the Gleason score is useful and provides the best These clinical states correlated well with prog- indicator of patient outcome for localized disease nostic factors and treatment decisions. In prac- [Maitland and Collins, 2008], it does not help in tice, these clinical states had previously been describing patients who progress, and becomes loosely defined and were refined to achieve less clinically relevant when recommending treat- more uniform cohorts in trials that would yield ment options. relevance in the clinic [Scher et al. 1995]. Various terms have been used to describe patients To have a common language amongst clinicians who progress while on hormone therapy, includ- and investigators a vocabulary was established ing androgen-independent prostate cancer by the PCWG2 that is based on categorizing (AIPC), androgen refractory or hormone refrac- prostate cancer on a disease continuum [Scher tory prostate cancer (HRPC). However, the et al. 2008]. The clinical states address presence PCWG2 advised against using the term of metastases and whether the patient has ‘hormone-refractory disease’ as it describes a castrate levels of testosterone achieved either response to treatment that we have learned is medically [luteinizing hormone releasing hor- not absolute, as patients have had responses mone (LHRH) agonist, and/or peripheral andro- with therapies such as aminoglutethimide gen receptor blockade] or by surgical [Ahmann et al. 1987, Harnett et al. 1987], AR orchiectomy. The states are localized disease, antagonists, ketoconazole [Figg et al. 2005], rising PSA and noncastrate, metastases and adrenalectomy or hypophysectomy [Raghavan, noncastrate, rising PSA and castrate, and metas- 1988], and 5a-reductase inhibitors [Shah et al. tases and castrate. This clinical staging (Figure 1) 2009; Eisenberger et al. 2004]. The current ter- provides our most current framework to minology for clinical classification is CRPC, assess prognosis and define therapeutic which encompasses castrate or anorchid objectives along the course of disease, rather patients with a rising prostate specific antigen than based on the tumor-node-metastasis (PSA) alone; with or without metastases, radio- (TNM) (TNM: Staging system of tumor size, graphic progression or clinical progression regional lymph node involvement, and distant [Scher et al. 2008]. metastasis) stage of the tumor at diagnosis. http://tam.sagepub.com 109 Therapeutic Advances in Medical Oncology 2 (2) No disease- prevention Rising PSA Rising PSA castrate non-castrate Clinically localized Clinical metastasis Clinical metastasis castrate non-castrate Death from disease Death from other causes Figure 1. Clinical states model of prostate cancer as conceptualized by the Prostate Cancer Working Group (PCWG2). Adapted from Scher et al. [2000, 2008] with permission. Androgen-receptor signaling axis in prostate pressure leads to survival of a tumor clone that cancer enables the CRPC state, or if alterations of the Testosterone is the major circulating androgen AR and/or AR signaling occur de novo [Maitland and 9095% is synthesized in the Leydig cells and Collins, 2008]. of the testis, with 510% coming from the adre- nals [Labrie, 2004]. Testosterone, as are all ster- The AR gene is located in the X chromosome oid hormones, is poorly soluble in water and and the AR structure is similar to other steroid upon release into circulation, associates with sex receptors with a modular structure of a hormone-binding globulin (SHBG) which trans- well-conserved DNA binding domain and NH - ports the hormone through the circulatory terminal transcriptional activation domain, in system to target tissues such as the prostate and addition to a carboxyl terminal ligand binding skin. Circulating free testosterone enters prostate domain [Culig et al. 2005]. The AR is identical cells and is converted to dihydrotestosterone in all androgen-responsive sites in the body and is (DHT) by 5a-reductase within the prostate. required for normal prostate development, DHT is the primary androgen in prostatic tissues muscle hypertrophy, bone density, and cognition. as it binds the AR more stably. Prior to ligand binding, the AR is sequestered in the cytoplasm with a complex of heat-shock pro- Androgens are a requirement for growth and teins, molecular chaperones, and immunophilins avoidance of apoptosis of prostate cancer cells, which all help induce high-affinity conformation. and castration triggers programmed cell death Once bound to testosterone or DHT, the AR dis- in both normal as well as malignant prostate sociates from the complex and forms a homodi- cells [Denmeade et al. 1996]. Prostate cancer mer with exposure of the AR nuclear growth depends on androgens stimulating prolif- translocation where the bound AR engages spe- eration and inhibiting apoptosis. Castration cific chromatin regions, androgen response ele- causes a rate of cell death which is greater than ments (AREs), to control target gene the rate of cell proliferation. However, castration expression. The binding of AR with the AREs is rarely curative. It is not known if selection recruits coregulatory proteins which play an 110 http://tam.sagepub.com CJ Hoimes and WK Kelly important role in initiation and fine tuning of decrease in pain and PSA, with a decrease in transcription. PSA is the most familiar tumor bulk. Relapse, however, is nearly inevitable AR-regulated gene and is an important marker and castrate-resistant disease is incurable with a not only for screening but for disease progression time to death of approximately 2 years [Tannock including CRPC, indicating a functional AR sig- et al. 2004]. The presence of SHBG, whose con- naling axis. centration in the circulation can change in response to a variety of physiologic conditions, The AR was first noted to have an important role can complicate efforts to accurately measure the in resistant prostate cancer in 1991 [Van Der active circulating testosterone. Nonetheless, mea- Kwast et al. 1991]. AR principally acts as surement of serum testosterone is warranted in ligand-inducible transcriptional enhancer factor. patients who are progressing on ADT with a The AR signaling axis involves the physiologic goal of serum testosterone less than 50 ng/dL. ligands, testosterone and DHT, ligand regulation and transport through the bloodstream in associ- Though therapy is usually tolerated, side effects ation with SHBG, the AR, the regulation of related to testosterone deficiency include muscle unbound AR in the cytoplasm, and the regulation atrophy and weakness, erectile dysfunction, hair of dimerized and phosphorylated AR transport to loss, insulin resistance and diabetes, increased fat the nucleus for engaging the ARE, and recruit- mass and decreased lean body mass and anemia ment of coregulatory proteins for fine tuning [Hang et al. 2005]. As estrogens are derived from transcriptional output. The axis is important in aromatization of testosterone in men, estrogen many diseases including prostate cancer, deficiency commonly occurs in patients treated benign prostatic hyperplasia, alopecia, and hir- with ADT (either medically or surgically) and sutism. A secondary role of the AR may mediate leads to side effects that include hot flashes, nongenomic signaling independent of the princi- reduced bone mineral density and increased frac- pal transcription factor role and does not ture risk, mood changes, memory loss, gyneco- require DNA binding, such as through the mastia, and lipid changes [Freedland et al. 2009]. c-Src tyrosine kinase signaling cascade of mitogen-activated protein kinase (MAPK)/extra- Despite these anticipated physiologic symptoms cellular signal-regulated kinase (ERK) pathway that impact nearly every organ system, a castrate [Migliaccio et al. 2000]. serum value is not necessarily a reliable represen- tation of the androgen level at the tumor site. In The concentration of AR in the cytosol is tightly CRPC, prostate cancer cells develop a variety of controlled by a number of factors that includes aberrant pathways to survive in a castrate envi- the state of differentiation of the tissue. AR levels ronment. Failure of castration therapy was pre- usually drop dramatically immediately after tes- sumed to be solely due to low levels of circulating tosterone or DHT exposure as there is a net nongonadal production of androgens; however movement of the ligand-receptor complex to the tumor stem-cell, genetic, epigenetic, and tumor nucleus. Eventually, the ARs are repopulated by microenvironment in AR signaling are new synthesis or recycling of receptor after disso- implicated. ciation from the ligand [Dehm and Tindall, 2007]. The search for a prostate cancer stem cell (CSC) is difficult as it is complicated by the heterogene- Resistance to hormonal therapy and mechan- ity of tumors. A likely contender that retains self isms of AR signaling in CRPC renewal and tumor generating capacity has the + high + Achieving castrate or anorchid levels of testoster- CD133 /a2b1 integrin /CD44 phenotype one (50 ng/dL) with ADT remains the most [Gu et al. 2007; Collins et al. 2005]. effective therapy for metastatic disease and has Heterogeneity and multifocality, in fact, may be been long recognized as the first systemic antic- the phenotypic depiction of stem cell tumorigen- ancer maneuver for prostate cancer [Huggins and esis in the prostate as many stem cells become Hodges, 1941; Huggins et al. 1941]. Half of all activated to acquire tumor-initiating properties. men with prostate cancer are treated with ADT As the progeny cells either fail, expand and dif- during the course of their disease and many for ferentiate slowly, or expand and acquire a muta- prolonged periods of time [Cooperberg et al. tion to differentiate more rapidly; the various 2003; Meng et al. 2002]. The cancer usually clones and failures contribute to the multifocality. responds well initially, resulting in prompt The disease course, however, is determined by http://tam.sagepub.com 111 Therapeutic Advances in Medical Oncology 2 (2) the more aggressive clone and overshadows the leads to 19-carbon androgens. 18-carbon estro- others. Interestingly, the prostate CSC popula- gens are also produced, and through a peripheral tion does not express AR, and therefore inher- tissue reversible interconversion pathway, can ently resistant to hormone maneuvers. The change estradiol to testosterone. An additional CSC may be able to repopulate the tumor with source is that CRPC tumors have the biochemi- AR dependent and AR independent progeny cells cal machinery for local intratumoral synthesis of [Pienta and Bradley, 2006]. While this provides androgens. For these reasons, tumor androgen an explanation for minimal residual disease after levels may not be too far from baseline, despite hormone maneuvers, it is unclear why this impor- what is measured in the serum [Chen et al. 2004; tant gain of function selection in AR is not seen at Mohler et al. 2004]. Recent data from human the cancer stem cell level [Maitland and Collins, tissue samples show that castrate levels of 2008]. Perhaps steroid response is not conducive serum androgens do not accurately or consis- to activated CSCs maintaining an undifferen- tently represent the intratumoral androgen level tiated, or in some cases, a dedifferentiated which may be due to de novo synthesis of andro- (from a committed basal cell) state. gen within the tumor [Locke et al. 2008; Montgomery et al. 2008; Mostaghel et al. 2007; The axiom that prostate cancer is a hormone- Page et al. 2006; Mohler et al. 2004]. dependent disease because it requires androgens Intratumoral levels are often close enough to for survival is becoming eroded by better under- baseline controls where prostate cancer cell pro- standing of the castrate state and now seems to be liferation, apoptosis, and androgen-regulated only partly true. The central dependence for protein expression, including PSA, are unaffected tumor survival is on the AR signal, which may [Page et al. 2006]. or may not involve an androgen ligand. Prostate cancer cells use five mechanisms mediated AR hypersensitivity: mutations through the AR to promote tumor growth, AR-activating mutations allow AR signaling by three of which depend on ligand signaling. nongonadal androgens that would not normally They are persistence of intratumoral androgens cause AR activation. AR mutations have been as a result of in situ steroidogenesis or adrenal identified in prostate cancer cell lines such as source; AR mutations that allow promiscuous LNCaP and CWR22 as well as in patient tissue activation by otherwise nonsignaling ligands; samples where adrenal androgens such as dihy- wild-type AR gene amplification; alterations in droepiandrosterone (DHEA) or androstenedione AR coactivator to corepressor ratio that impact causes a severalfold higher transcriptional transcription; outlaw AR pathways that bypass response than wild-type AR [Koivisto et al. the need for androgens by signaling through 1998; Tan et al. 1997; Taplin et al. 1995; crosstalk with other ligand-bound receptors, Veldscholte et al. 1990]. According to one cytokines, or transactivation of activated report, approximately 20% of metastatic tumors tyrosine kinase receptors in the cytosol have an AR mutation that modulates steroid spe- [Mellado et al. 2009; Freeman et al. 2005; cificity [Marcelli et al. 2000]. Mutations can also Scher and Sawyers, 2005; Eder et al. 2001; increase sensitivity of the AR to nonandrogen Feldman and Feldman, 2001]. One or many of steroids and molecules, including antiandrogens these mechanisms may be playing a role, even [Buchanan et al. 2004; Veldscholte et al. 1990]. within the same patient, and may be an explana- tion, in part, for heterogeneous responses. AR hypersensitivity: amplification More common is the third mechanism which is Surreptitious tumor androgen exposure despite associated with increased levels of wild-type AR castrate serum levels The first ligand-dependent mechanism of contin- protein secondary to gene amplification which ued signaling through the AR can occur as pros- can impart a growth advantage without a specific tate cancer tissues continue to be exposed to mutation. This has been shown to be amplified in androgens. The source can be from extragonadal 2030% of patients with CRPC and less than 5% androgen conversion pathways. The adrenal of those with primary prostate cancer [Bubendorf gland imports cholesterol or synthesizes it et al. 1999; Koivisto et al. 1998, 1999; Visakorpi de novo from acetate to make the 21-carbon preg- et al. 1995]. Elevated AR protein expression is nenolone which serves as the substrate for the necessary and sufficient to confer resistance to multiple enzyme cascade of steroidogenesis that antiandrogen therapy in murine xenografts and 112 http://tam.sagepub.com CJ Hoimes and WK Kelly sensitizes prostate cancer cells to respond to low to corepressor ratio can direct a change in AR levels of androgen ligand [Chen et al. 2004]. function. Deregulated expression of AR coactiva- tors tends to increase with tumor dedifferentia- Alteration in coactivator to corepressor balance tion and correlate with aggressive disease and Two additional AR-centric mechanisms of poor prognosis [Need et al. 2009]. Specifically, CRPC are considered that activate the AR with the AR p160 coactivator family of steroid recep- minimal to no ligand requirement. These are tor coactivator-1, and others, can recruit HAT indirect mechanisms of continued AR signaling activity [Kang et al. 2004]. ARA proteins and involve coregulator molecules, and crosstalk enhance AR-dependent transcriptional activation with tyrosine kinases, cytokines, and other recep- and are well studied in prostate cancer [Kikuchi tors. Though indirect, these mechanisms are not et al. 2007; Mestayer et al. 2003; Li et al. 2002; less significant; and on the contrary, perhaps have Yeh et al. 1999]. For instance, ARA267a as much of a role in resistance to castration as the enhances AR-dependent transcription that is more intuitively proposed and parsimonious additive to HAT activity [Kang et al. 2004]. direct mechanisms. Interestingly, these mechan- ARA54 and ARA70 can sensitize the AR to isms have the potential to be magnified by the lower concentrations of testosterone or DHT, or other aberrant pathways, when present, such as even alternative ligands such as estradiol and AR amplification, AR mutation, and preserved hydroxyflutamide, or even allow intratumoral androgen levels. ligand-independent enhancement of cell cycle progression via induction of cyclin D1, or via Binding of AR homodimers at the AREs induces receptor tyrosine kinases such as HER2 the attraction of coregulatory molecules such as [Kikuchi et al. 2007; Scher and Sawyers, 2005]. the cointegrators c-AMP response element bind- Corepressor proteins NCoR and SMRT can ing protein (CREB)-binding protein (in total interact to form complexes with HDAC [Xu ‘CBP’) and p300, coactivators of AR-associated et al. 1999] and inhibit AR function in a (ARA) proteins and p160, and corepressors such ligand-dependent manner. as nuclear receptor corepressor (NCoR) and SMRT (silencing mediator for retinoic acid and Outlaw pathways thyroid hormone receptors). Transcription The fifth mechanism is AR transcriptional activ- depends on the recruitment of RNA polymerase ity that can be activated in the absence of andro- II to promoters of the AR target genes. The cor- gen. Signaling to a genomic (via AREs) or egulator molecules make up the preinitiation nongenomic route is possible. Signaling of the complex (PIC) and direct specific interaction of AR to the AREs is possible through crosstalk RNA polymerase II and the promoter and can with agonist occupied membrane receptors contribute to transcriptional synergy (coactiva- as described in many steroid hormone tors), or in the case of competitive binding of receptors including estrogen receptor, progester- these factors, transcriptional repression (corepres- one receptor, and AR [Scher and Sawyers, sors) [Vo and Goodman, 2001] of the AR func- 2005; Pietras et al. 1995; Zhang et al. 1994; tion. These molecules help regulate accessibility Power et al. 1991]. of gene promoters to transcription and DNA rep- lication machinery through two active pathways or AR crosstalk and transactivation can occur with classes including ATP-dependent chromatin transduction pathways for proliferation, survival, remodeling complexes that reorganize chromatin or motility. This signaling mechanism does not structure, and a class of enzymes that catalyze signal to AREs and is considered a nongenomic posttranslational modifications in histones, the pathway as opposed to the aforementioned. It best characterized are histone acetyltransferases may or may not involve ligand and can occur (HAT) and histone deacetylases (HDAC). through transactivation of kinases, or crosstalk with cytokines or growth factor receptors. AR-associated coregulators are important to the development of aberrant AR action. Not only is Ability to transactivate through nongenomic this true for prostate cancer, but is seen in other mechanisms via cholesterol-rich lipid rafts is diseases such as the link of androgenic alopecia or one way of linking AR signaling to the prolifera- hepatitis B virus to preponderance of male risk of tive and cell survival transduction pathways hepatocellular cancer [Chiu et al. 2007; Lee et al. [Baron et al. 2004; Migliaccio et al. 2000; 2005]. In each of these, changing the coactivator Peterziel et al. 1999]. Transactivation with http://tam.sagepub.com 113 Therapeutic Advances in Medical Oncology 2 (2) activated tyrosine kinase receptors has been and activator of transcription (STAT). This crosstalk shown between the AR-signaling path and acti- enhancement of AR signaling has been shown to vation of the MAPK and MAPK/extracellular confer castration resistance in preclinical models signaling-regulated kinase kinase-1 (MEKK1), [Wang et al. 2007]. and the epidermal growth factor receptor (EGFR) pathway, including HER2/neu Castrate-resistant prostate cancer: novel [Bonaccorsi et al. 2004; Abreu-Martin et al. therapies for AR-signaling depletion 1999; Peterziel et al. 1999]. As prostate cancer continues to evade hormone manipulations and rely on AR signaling, drug AR can also crosstalk with cytokines including development has focused efforts to target the path- nuclear factor kappa B (NF-kB),IL-6, IL-8,inaddi- way at many points for CRPC patients (Table 1). tion to beta-catenin [Malinowska et al. 2009; Therapies developed include novel and potent AR Robinson et al. 2008; Seaton et al. 2008]. Crosstalk antagonists which block AR nuclear translocation with other growth factor receptors such as EGFR, v- and DNA binding, addressing prostate tumor in raf murine sarcoma viral oncogene homolog B1 situ steroidogenesis with enzyme-specific adrenal (BRAF), and v-src sarcoma viral oncogene homolog androgen inhibitors, trials of 5a-reductase inhibi- (SRC) can induce activation of growth and survival tion, addressing crosstalk and transactivation path- pathways including MAPK, v-akt murine thymoma ways with small molecule tyrosine kinase inhibition viral oncogene homolog (AKT), signal transducer or mammalian target of rapamycin (mTOR) Table 1. Mechanisms of continued androgen receptor (AR) signaling axis despite castration and options for noncytotoxic chemo- therapy therapeutic intervention. AR-signaling Target Therapeutic intervention Ligand-dependent pathways Testis androgen synthesis H-P-G axis LHRH or GnRH agonists Degarelix (GnRH antagonist) Orchiectomy Adrenal androgen synthesis Androgen feedback, DHEA, ERb DES [Kitahara et al. 1999; Pravettoni et al. 2007] Non-specific CYP-17 Ketoconazole 11b-hydroxylase CYP 17A1 (17a hydroxylase & C17,20-lyase) Abiraterone* Tumor androgen synthesis 5a-R, primarily type II isozyme Finasteride 5a-R, primarily type I isozyme Dutasteride AR mutation/alternate ligands AR Bicalutamide after flutamide Nilutamide after bicalutamide AAWD BMS-641988* [Mellado et al. 2009] AR Antiandrogens Progestins Glucocorticoids AR gene amplification AR, nuclear trans and ARE binding MDV3100* [Scher et al. 2009] RD162* [Tran et al. 2009] Ligand-independent pathways Coregulator HDAC SAHA LBH589 P160, TIF2 Arsenic trioxide [Rosenblatt and Burnstein, 2009] Crosstalk/transactivation Cell surface receptors RTK inhibitors, antibodies Src pathway Dasatinib [Yu et al. 2008] PTEN loss with active mTOR pathway Temsirolimus [Wu et al. 2005] PI3K activation by HER-2 signaling Lapatinib [Whang et al. 2008] PKCb/PI3K/AKT Enzastaurin* 5a-R, 5a-reductase; AAWD, anti-androgen withdrawal; AR, androgen receptor; ARE, androgen response elements; DES, diethylstilbestrol;, dehydroepiandrosterone; diethylstilbestrol; DHEA, dehydroepiandrosterone; CYP, cytochrome; cytochrome P450; ER, estrogen receptor; GnRH, gonadotropin releasing hormone; HDAC, histone deacetylase; H-P-G, hypothalamic-pituitary-gonadal; LHRH, luteinizing hormone release hor- mone; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinases; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase; SAHA, suberoylanilide hydroxamic acid; Src, sarcoma; TIF2, transcriptional mediators/intermediary factor 2; trans, translocation. *not FDA approved, in clinical trials. 114 http://tam.sagepub.com CJ Hoimes and WK Kelly inhibition. Investigations for targeting coregulator tumor cell (CTC) counts after treatment can molecules are underway, and arsenic trioxide has in serve as a robust intermediate endpoint for overall vitro results that support a coregulator inhibition survival [Attard et al. 2009a]. It has completed that attenuates the AR signal. Histone deacetylase enrollment of over 1100 patients and results are (HDAC) inhibition may also impact coregulator maturing that will yield further information on the ability of the PIC to access the chromatin structure. population that may have a clinical benefit. [National Institutes of Health et al. 2009] Of those that are not FDA approved, perhaps abir- aterone acetate is the furthest along in clinical trials MDV3100 is a second generation small-molecule and showing tolerability and efficacy. Abiraterone antagonist of the AR that prevents nuclear trans- acetate is a prodrug low molecular weight inhibitor location and DNA binding of AR without agonist of CYP17A1, also knowninthe adrenalsteroid activity [Tran et al. 2009] that recently reported pathway as the dual role enzyme of interim results of a phase I/II trial of 140 patients 17a-hydroxylase, and 17, 20 desmolase. A different that were either chemotherapy naı ¨ve or postche- name is given to a different activity of the same motherapy with progression of CRPC. The enzyme as it adds a hydroxyl group to pregnenolone dose-escalation study of 30600 mg orally daily to form 17a-hydroxypregnenolone, and then acting was well tolerated and nearly half of the patients as 17, 20 desmolase (also called a lyase) removes a had at least a 50% PSA decline at week 12; and side-chain carbon to form DHEA. The same 38% of evaluable patients receiving 240 mg/day enzymes are involved in the parallel progesterone dosing had a radiographic partial response (PR) pathway in the conversion from progesterone to [Scher et al. 2009]. An international phase III 17a-hydroxyprogesterone to androstenedione. The placebo-controlled trial is underway using the phase I single center study of abiraterone acetate 240 mg/day dose [National Institutes of Health showed that 21 chemotherapy and ketoconazole et al. 2009]. naı ¨ve patients with metastatic CRPC tolerated the therapy well and had significant antitumor activity Systemic therapies in development that do not with over half of patients experiencing a greater than target the AR signal are also being investigated 50% PSA decline that lasted a minimum of 3 and include immunotherapy; bone targeted ther- months [Attard et al. 2008a; De Bono et al. 2008]. apy with a monoclonal antibody against receptor This trial seamlessly expanded into a two stage, activator of nuclear factor k B ligand (RANK-L), single-arm, phase II trial where abiraterone acetate oral endothelin inhibitors; Src kinase inhibitors was dosed once daily at 1000 mg for 28 day cycles such as dasatinib; altering tumor apoptotic sensi- until PSA progression at which point dexametha- tivity to chemotherapy using a clusterin inhibitor; sone 0.5 mg daily was added. In the 42 phase II monoclonal antibody to prostate specific mem- patients, 67% had a more than 50% decline in brane antigen, and an antisense oligonucleotide PSA, and declines of more than 90% were seen in against B-cell leukemia/lymphoma-2 gene eight patients [Attard et al. 2009a]. The median (BCL-2). Review of novel therapies is beyond the time to PSA progression (TTPP) was 225 days, at scope of this article and can be reviewed in recent which point dexamethasone 0.5 mg daily was added publications [Fleming et al. 2009; Lassi and and yielded an additional 151 days of median Dawson, 2009; Shah et al. 2009; Tran et al. 2009] TTPP. The additional response gained with dexa- methasone was independent of previous treatment Molecular heterogeneity in CRPC: with dexamethasone [Attard et al. 2009a]. TMPRSS2:ETS and the lethal phenotype It is clear the past decade has seen a significant While all these patients had progressive disease increase in understanding the basis of prostate despite castration and further reduction in andro- cancer progression and specifically the role of the gens were possible, this raises the question AR and the factors it cooperates with while whether we can call the responding patients truly unbound in the cytosol or during activated signaling castrate resistant. Unfortunately biomarkers have to the nucleus. The AR mechanisms of resis- nothelped us to identify this subsetof patients. tance are the survival traits prostate cancer has This will be addressed in the phase III trial of developed or acquired to flourish. Many of the abiraterone acetate which is a placebo-controlled ligand-independent crosstalk and transactivation trial in combination with prednisone. The primary mechanisms are important in enabling prostate endpoint is overall survival and also incorporates cancer to share in the ‘hallmarks’ that define the prospective evaluation of whether circulating common characteristics of cancer [Hanahan and http://tam.sagepub.com 115 Therapeutic Advances in Medical Oncology 2 (2) Weinberg, 2000] and lend to the molecular lethal and researchers have looked to correlate fusion phenotype [Loberg et al. 2007]. These AR mechan- events with histologic phenotype and prognosis. isms enable genetic instability, limitless replicative Researchers have identified a significant associa- potential, evasion of cell death, and can be rendered tion between the fusion gene and prostate cancer capable of growth factor independent growth. specific death, as well as a link between ERG perturbations and a higher Gleason score The number of AR coregulators reported is over [Demichelis et al. 2007]. The 5 to ERG Edel 150, indicating a daunting level of functional fusion is found in approximately 6070% of the diversity among these proteins [Heemers and cancers containing ERG rearrangements and has Tindall, 2007]. Also, crosstalk and transactiva- been found to correlate with a higher tumor stage tion lend AR the ability to interact with — and and pelvic lymph node metastasis [Attard et al. in many cases such as EGFR, regulate — other 2008b; Perner et al. 2006]. Further clinicopatho- growth factor receptors and signals, tyrosine logic correlation has identified a subtype with kinases, and cytokine pathways. There are also poor survival using fluorescent in situ hybridiza- many molecular pathways that are important in tion (FISH) analysis. These patients comprised the initiation and progression of prostate cancer. nearly 7% of 445 previously untreated patients Germ-line mutations of several genes have been and were found to have a 2+ Edel (two or more 0 0 found in a fairly small subset of hereditary pros- FISH copies of 3 to ERG without 5 to ERG) tate cancers. Promoter hypermethylation leads to which correlated with a poor cause-specific and loss of expression of glutathione S-transferase overall survival in a multivariate analysis. gene (GSTP1) and is seen in many prostate (and other) cancers as well as prostatic intrae- The estrogen receptor (ER) is also implicated as pithelial neoplasia (PIN) [Lee et al. 1994]. ERa stimulation results in TMPRSS2-ERG Another frequent mutation seen in prostate can- upregulation [Mertz et al. 2008; Taplin, 2007], cers (many early, localized), is allelic loss of chro- even in an AR-negative cell line [Taplin, 2007]. mosome 8p. More recently discovered is the first This suggests that an ERa antagonist may have epithelial malignancy fusion gene, and is found in activity in prostate cancer through inhibition of over 50% of prostate tumors. This now links the TMPRSS2-ERG expression. In fact, antitumor pathogenic AR in CRPC to oncogenic transcrip- activity of abiraterone acetate may be explained, tion factors, ETS (erythroblastosis virus E26 in part, by suppressing estradiol and therefore oncogene like - avian). attenuating upregulation of TMPRSS2-ERG expression via the ERa receptor [Ellem and The most common mechanism of ETS overex- Risbridger, 2007]. The abiraterone phase I pression is the fusion of the ETS gene, ETS study investigated this hypothesis as a correlative gene-related gene (ERG), with the highly and found that of six patients with the AR-regulated transmembrane protease serine 2 TMPRSS2-ERG gene fusion, five responded to (TMPRSS2) gene [Tomlins et al. 2005]. abiraterone acetate with a >50% PSA decline, a TMPRSS2 is expressed in normal and malignant response that was 30% more than the overall prostate and dependent on androgen. ERG is a group [Attard et al. 2008a]. It is not clear if the transcription factor involved in oncogenic trans- success of abiraterone acetate in this case was locations in Ewing’s sarcoma and myeloid leuke- acting by decreasing estradiol availability which mias [Saramaki et al. 2008]. Additionally, ERG could otherwise act promiscuously with the AR interacts with histone methyltransferase and may directly, abolish extragonadal tissue androgen impact silencing of target genes [Saramaki et al. production through its intended CYP17A1 inhi- 2008]. Both are close in proximity on chromo- bition, or by inhibiting the reversible interconver- some 21, and interstitial deletion (Edel) of sion pathway of estradiol to testosterone. sequences 5 to ERG has been found to be a common mechanism of TMPRSS2-ERG fusion Another treatment directed at the in prostate cancer. Moreover, in CRPC, Edel was TMPRSS2-ERG gene fusion can take advantage found to be the exclusive mechanism of rearran- of its dependence on HDAC for fusion gene acti- gement and with a particularly aggressive pheno- vation. HDAC inhibitors have been shown to type in a cohort of 30 men [Mehra et al. 2008]. directly block genes involved in the TMPRSS2:ERG fusion and warrant further clin- TMPRSS2 also can become fused to other ETS ical studies to evaluate these drugs in this setting transcription factors such as ETV1 and ETV4 [Attard et al. 2009b; Welsbie et al. 2009; 116 http://tam.sagepub.com CJ Hoimes and WK Kelly Bjorkman et al. 2008; Tomlins et al. 2008; Kelly They are responsible for much of the latitude of et al. 2002]. cancer survival and ultimately, its lethal pheno- type. Hormone-resistant tumors could perpetu- Need for a new CRPC clinical state: androgen ate solely through the ligand-independent depleted pathways. The proposed prostate CSCs do not A Medline search of keywords ‘castration resis- express AR, and may impart in progeny tumor tant’ or ‘castrate resistant’ yields its earliest rele- cells robust ‘workaround’ AR signal vant usage in 2000 and defined as prostate cancer ligand-independent pathways that could serve that has progressed despite medical or surgical to be the principal operator of progression in means of castration [Solit et al. 2003; Scher and hormone-resistant tumors. Heller, 2000]. To define a patient’s clinical state as castrate resistant gives it a basis in physiology A modification to the current PCWG2 clinical we can all understand; i.e. medical or surgical states model is needed to classify this new popu- castration levels of circulating free testosterone. lation of castrate resistant patients with clinical Reference to the clinical syndrome of ‘hormone metastasis. We propose a new category of ‘andro- resistance’ can be interpreted as a patient with a gen depleted’ which is the clinical state of prostate tumor that is resistant to endogenous patients with tumor that have predominant androgens, or, as more often used, a patient AR-signaling ligand-independent pathways driv- who no longer responds to hormone maneuvers. ing proliferation. A schematic to incorporate the We now understand that it is more complicated new clinical state is shown in Figure 2. than just what’s going on with the serum testos- Androgen-depleted patients may or may not terone level. have metastases and the state is preceded by cas- trate patients that have either rising PSA or clin- A hormone-resistant tumor is now redefined as ical metastases. Death from other causes can one that progresses in an environment of collat- occur along this continuum, though death from eral androgen depletion (CoAD) where androgen disease represents a proportionately larger frac- levels are ablated beyond castrate levels. CoAD tion of androgen-depleted castrate patients with maneuvers target the ligand-dependent pathways a rising PSA and those with clinical metastases. of gonadal and extragonadal (physiologic), and in situ tumor (pathologic) androgenesis. A com- Interest has turned to therapeutic intervention of bination of ligand-dependent directed therapeu- the AR-signal ligand-independent pathways with tic interventions (see Table 1) can achieve the familiar receptor targets such as EGFR, and CoAD state. HER2 and using antibodies and small-molecule receptor tyrosine kinase (RTK) inhibitors. Despite these interventions to ablate the ligand, Clinical trials are investigating the effect of dasa- AR signaling may persist via the tinib, gefitinib, cetuximab, mTOR inhibitors, the ligand-independent crosstalk and transactivation PKCb inhibitor, enzastaurin, in combination pathways. Early data for treatment of the AR with cytotoxic agents. Additionally, there are sev- signal ligand-dependent pathways are demon- eral AR-signal pathway inhibitors that are in pre- strating a substantial number of patients with clinical and clinical testing, and of these, the potential long remissions. Unfortunately, how- second-generation antiandrogens like MDV ever, there does appear to be a population of 3100 with ability to degrade the AR and patients that progress despite castration plus RD162 are likely the furthest along showing tol- CoAD treatments. Though the AR-signaling erability and efficacy [Tran et al. 2009]. As we ligand-dependent pathways are maximally atte- develop therapeutics for this web of AR signaling, nuated, there is likely a predominant we anticipate a learning curve for clinical trialists AR-signaling ligand-independent pathway to determine their optimal usage. Approaches responsible as the principal cause for this group being considered include sequential use in of resistant patients. advanced disease, use in earlier disease, as well as adjuvant to primary therapy. In addition, due In the androgen-depleted state, AR signal to AR-signal redundancy, clinical benefit may be ligand-independent pathways are likely a survival gained from adding AR-signal active agents trait the prostate cancer developed through rather than switching after a failed therapy. chance accumulation, or clonal expansion with Depleting the AR-signal redundancy would or without selective therapeutic pressure. require an annihilation approach where CoAD http://tam.sagepub.com 117 Therapeutic Advances in Medical Oncology 2 (2) No disease- prevention Rising PSA Rising PSA Rising PSA castrate castrate non-castrate androgen depleted Clinically localized Clinical metastasis Clinical metastasis Clinical metastasis castrate castrate non-castrate androgen depleted Death from disease Death from other causes Figure 2. Proposed clinical states model of prostate cancer to incorporate a new category of androgen-depleted clinical states which reflect tumors that are have predominant AR signaling via ligand-independent pathways. treatment is combined with ligand-independent pathologic predictor of outcome for localized dis- interventions. For example, an annihilation ease and novel biomarkers of AR-driven path- approach may include combination of an ways are desperately needed as we continue our LHRH agonist, 5a-reductase inhibitor, a development of the new generation of androgen second-generation [Tran et al. 2009] anti- and AR therapeutics. However, the current clas- androgen, a CYP17A1 inhibitor, and an AR sification schema for CRPC does not take into degrader, such as an HDACi. account these new AR therapeutics and we pro- pose the clinical state ‘androgen depleted’ to Research has shown since the 1940s that the AR reflect the AR-signal ligand-independent path- signal is crucial to attenuate in prostate cancer. ways for those patients who are refractory to cas- The AR cascade interacts with many chaperones tration plus CoAD. This clinical state is proposed and other cell machinery and signals, and can to create a common vocabulary amongst clinical become hypersensitive to ligand, use ligand that trialists and physicians so data sets can be inter- is produced in the tumor tissue or extragonadal preted accurately, and correlation with prognosis pathways, use signals from other growth recep- will be needed to qualify the new category. tors, crosstalk with cytokines, transactivate tyro- sine kinases, and can be preferentially activated by its coregulators. Now that we know an onco- Conflict of interest statement gene is a downstream target of AR in the majority None declared. of patients, namely the TMPRSS2-ETS fusion gene, depleting androgen and inhibiting the AR signal is paramount. References Abreu-Martin, M.T., Chari, A., Palladino, A.A., Craft, Conclusion N.A. and Sawyers, C.L. 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Redefining hormone resistance in prostate cancer:

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Abstract

Therapeutic Advances in Medical Oncology Review Ther Adv Med Oncol Redefining hormone resistance in (2010) 2(2) 107123 DOI: 10.1177/ prostate cancer ! The Author(s), 2010. Reprints and permissions: http://www.sagepub.co.uk/ Christopher J. Hoimes and W. Kevin Kelly journalsPermissions.nav Abstract: Prostate cancer relies on signaling through the androgen receptor (AR) for maintenance and progression; and androgen-deprivation therapy remains a cornerstone of treatment for advanced prostate cancer. An effective clinical classification of prostate cancer should account for the extent of the disease as well as the mechanisms that are driving the growth of the tumor. The previous terms hormone-sensitive and hormone-refractory described response to treatment. It has become clear that these terms do not reflect the mechanism of disease relapse; however over the last decade there has been a better understanding of androgen-receptor mediated signaling effects and incomplete suppression of androgens in prostate cancer. The Prostate Cancer Clinical Trials Working Group 2 (PCWG2) now recommends addressing the spectrum of clinical states based on castration status as this ligand-centered terminology can more accurately describe the patients’ disease, and ultimately provides a useful framework for patient management and drug development. Optimized use of androgen-deprivation therapy, low molecular weight inhibitors of adrenal androgen biosynthesis, and new AR antagonists are promising new therapeutics that can further define the meaning of castrate state. As hormone resistance is redefined to include patients that are refractory to treatments that ablate adrenal and in situ tumoral androgens, a meaningful new clinical state in patients will be forged. We propose a model for incorporating these patients into the current PCWG2 conceptualization of the disease. Keywords: androgen-deplete prostate cancer, androgen-deplete signaling pathways, androgen receptor signaling, castrate resistant prostate cancer, collateral androgen deplete, prostatic adenocarcinoma Correspondence to: Introduction mechanisms that are mediated by the AR — W. Kevin Kelly, DO Prostate adenocarcinoma leads to the second such as tumor in situ androgen production and Yale University School of Medicine, Yale most common cause of male cancer deaths amplification of AR protein — or those that Comprehensive Cancer [Jemal et al. 2009] and its tumorigenesis is primar- bypass it such as coactivators and transactivators. Center, 333 Cedar Street, FMP 114, New Haven, CT ily regulated by androgen binding and transcrip- In this setting, 1030% of patients will respond to 06520, USA tion signals of the androgen receptor (AR). Even secondary hormonal maneuvers such as estro- wm.kevin.kelly@yale.edu as the majority of patients are cured with definitive gens, antiandrogen therapy, or adrenal androgen Christopher J. Hoimes, DO primary treatments, those with high-risk locally targeted therapy [Small et al. 2006]. Docetaxel Yale Comprehensive advanced disease or metastatic disease are offered plus prednisone chemotherapy is considered for Cancer Center, Yale University School of medical or surgical castration which can induce castrate-resistant prostate cancer (CRPC) Medicine, New Haven, CT, durable remissions for a median of 1430 patients who progress on hormonal therapy or USA months [Singer et al. 2008]. Though nearly all have a rapid disease progression. There is no stan- respond to hormone maneuvers initially, most dard for patients who progress beyond this, and patients progress and recurrent tumors re-express new therapies on the horizon are pushing the active AR signaling as indicated by continuous envelope of attenuating and ablating resurgent target gene expression despite having castrate AR signaling in CRPC. Optimized use of andro- levels of androgens [Chen et al. 2004]. The gen deprivation therapy (ADT), low molecular return of AR signaling in the castrate patient (tes- weight inhibitors of adrenal androgen biosynthe- tosterone 50 ng/dL) can be attributed to sis, and new AR antagonists are promising new http://tam.sagepub.com 107 Therapeutic Advances in Medical Oncology 2 (2) delivery strategies and therapeutics that can disparities where African-American men are pro- account for the more common causes of hormone portionately more severely affected. Between resistance in CRPC. Achieving a depleted AR 2001 and 2005, the yearly prostate cancer inci- signal will likely forge a meaningful new clinical dence for African-American men was 249 (per state in patients previously resistant to hormone 100,000) compared with 157 for Caucasians, therapy. and 138 for Hispanics [Jemal et al. 2009]. Furthermore, during the same 4-year period, Castration-resistant disease is a fatal manifesta- the yearly mortality for African-Americans was tion of prostate cancer and significant efforts are 59 (per 100,000) exceeding twice that underway to better understand this phase of the of Caucasian (25 per 100,000) and Hispanic disease and develop treatments. At present we (21 per 100,000) patients [Jemal et al. 2009]. understand that there is a significant degree It is unclear whether this increased mortality of heterogeneity amongst CRPC patients with rate in African-American men is due to different profiles of progression from slow to unique racial, biological, and genetic factors, aggressive. There are some known biologic asso- rather than dietary influences, comorbid medical ciations with these heterogeneous populations. conditions, lifestyle differences, and/or access to Examples are prostate specific membrane antigen healthcare. (PSMA) status, loss of Phosphatase and tensin homolog (PTEN), gains of v-myc myelocytoma- Retrospective and prospective studies have tosis viral oncogene homolog (MYC), ErbB3 shown, however, that race does not play a role status, cadherin-11 status, and TMPRSS2-ERG in cause-specific survival once diagnosed with fusion gene status. Cause and effect has not been advanced CRPC [these studies are pre-PCWG2 adequately established for many of these; how- and used cohorts of patients defined as having ever, as we are beginning to understand this androgen independent prostate cancer (AIPC) phase of disease, we are likely to see these candi- which would now be considered CRPC patients], date biologic profiles become a relevant subclas- response to antiandrogens, the time to PSA sification of CRPC patients that will impact nadir, PSA doubling time, or in overall prognosis rational treatment decisions and prognosis. This [Wyatt et al. 2004; McLeod et al. 1999; Brawn more individualized approach is likely several et al. 1993]. Other studies have shown that race years away and requires further elucidation of does not correlate with extent of disease in bone, the relevant biologic pathways that most impact number of metastases, or time to CRPC [Wyatt disease course and drug development and deliv- et al. 2004]. Nonetheless; African-American and ery strategies that can perturb them. Hispanic patients were younger at diagnosis with more advanced disease than Caucasian cohorts. Currently, however, we are on the horizon of sev- There may be differences in biology that lead to eral new systemic therapies that are reinforcing difference in prevalence, and earlier onset of dis- biologic principles of ligand and AR signaling dis- ease, but those differences do not appear to be covered in the past one to two decades. These driving the cancer at a disproportionate tempo therapies are showing enough promise with toler- once patients receive therapy. ability and efficacy that our current models will need to incorporate these patients into the cur- Prostate cancer displays a range of disease tempo, rent Prostate Cancer Clinical Trials Working from tumors of no clinical impact to those that Group 2 (PCWG2) conceptualization of the are aggressive and lethal with multiple metasta- disease. ses. Between these two ends of the range are the locally advanced tumors with few metastases that Castrate-resistant prostate cancer: clinical insidiously infiltrate pelvic structures causing sig- heterogeneity nificant morbidity in the way of urinary urgency, Risk factors for prostate cancer include a male incomplete voiding with risk for urinary obstruc- with advancing age and an intact tion, constipation and hematochezia, insomnia, hypothalamic-pituitary-gonadal axis. There is a fatigue, obstructive lymphedema, sacral plexus relative risk increase of 1.4 for a brother of a neuropathy, and pain. The clinical subsets of man with prostate cancer, and having two to patients with prostate cancer become clear over three first degree relatives with the disease can time as a patient is treated or actively observed — increase the risk by 511 times, respectively, unfortunately, current wisdom of identifying the over the general population. There are race low risk patient is only in hindsight. 108 http://tam.sagepub.com CJ Hoimes and WK Kelly Even as patients progress to advanced CRPC dis- Previous to the PCWG2, disease states and clinical ease, there continues to be heterogeneity with a classification were not as clearly defined and caused spectrum of disease progression. The range difficulty interpreting outcomes. Clinical experi- amongst patients with CRPC is from advanced ence with the antiandrogen flutamide in metastatic prostate cancer patients led to the observation of pelvic disease with few metastases and relatively the flutamide withdrawal syndrome [Kelly et al. long survival of over 40 months [Assikis et al. 1993]. The initial series described approximately 2004] to those that develop neuroendocrine fea- a third of patients with a significant PSA decline tures with a rapid tempo of disease. Accurate (>50%) and clinical improvement upon disconti- staging that represents the patients’ disease nuation of flutamide therapy [Scher and Kelly, course is therefore important for prognostic and 1993]. It quickly became clear that antiandrogen treatment decisions. withdrawal is a hormone maneuver in its own right. However, this important therapy and clinical state Castrate-resistant prostate cancer: terminol- was not uniformly incorporated into clinical trial ogy and current classification use for several more years and not doing so was Clinical staging describes the profile of the extent likely responsible for false-positive results in many of the prostate tumor at one point in a time con- trials during that time [Scher et al. 1995]. There tinuum of the patient; much like the Rai clinical was confusion in interpreting trials as a staging system achieves in chronic lymphocytic hormone-sensitive patient in one trial may leukemia [Rai et al. 1975]. As the Rai system have been considered resistant in another [Scher has needed modification [Gale et al. 1987], pros- et al. 1995]. tate cancer clinical staging has needed to be updated or revised as new understanding of A classification scheme was developed for what drives castrate-resistant biology and as ther- prostate cancer based on hormone sensitivity in apeutics are discovered that are tolerable and 1995 and used categories of hormone-naı ¨ve, favorably impact prognosis. While pathologically androgen-independent and hormone-sensitive, staging based on morphologic appearance using and hormone-independent [Scher et al. 1995]. the Gleason score is useful and provides the best These clinical states correlated well with prog- indicator of patient outcome for localized disease nostic factors and treatment decisions. In prac- [Maitland and Collins, 2008], it does not help in tice, these clinical states had previously been describing patients who progress, and becomes loosely defined and were refined to achieve less clinically relevant when recommending treat- more uniform cohorts in trials that would yield ment options. relevance in the clinic [Scher et al. 1995]. Various terms have been used to describe patients To have a common language amongst clinicians who progress while on hormone therapy, includ- and investigators a vocabulary was established ing androgen-independent prostate cancer by the PCWG2 that is based on categorizing (AIPC), androgen refractory or hormone refrac- prostate cancer on a disease continuum [Scher tory prostate cancer (HRPC). However, the et al. 2008]. The clinical states address presence PCWG2 advised against using the term of metastases and whether the patient has ‘hormone-refractory disease’ as it describes a castrate levels of testosterone achieved either response to treatment that we have learned is medically [luteinizing hormone releasing hor- not absolute, as patients have had responses mone (LHRH) agonist, and/or peripheral andro- with therapies such as aminoglutethimide gen receptor blockade] or by surgical [Ahmann et al. 1987, Harnett et al. 1987], AR orchiectomy. The states are localized disease, antagonists, ketoconazole [Figg et al. 2005], rising PSA and noncastrate, metastases and adrenalectomy or hypophysectomy [Raghavan, noncastrate, rising PSA and castrate, and metas- 1988], and 5a-reductase inhibitors [Shah et al. tases and castrate. This clinical staging (Figure 1) 2009; Eisenberger et al. 2004]. The current ter- provides our most current framework to minology for clinical classification is CRPC, assess prognosis and define therapeutic which encompasses castrate or anorchid objectives along the course of disease, rather patients with a rising prostate specific antigen than based on the tumor-node-metastasis (PSA) alone; with or without metastases, radio- (TNM) (TNM: Staging system of tumor size, graphic progression or clinical progression regional lymph node involvement, and distant [Scher et al. 2008]. metastasis) stage of the tumor at diagnosis. http://tam.sagepub.com 109 Therapeutic Advances in Medical Oncology 2 (2) No disease- prevention Rising PSA Rising PSA castrate non-castrate Clinically localized Clinical metastasis Clinical metastasis castrate non-castrate Death from disease Death from other causes Figure 1. Clinical states model of prostate cancer as conceptualized by the Prostate Cancer Working Group (PCWG2). Adapted from Scher et al. [2000, 2008] with permission. Androgen-receptor signaling axis in prostate pressure leads to survival of a tumor clone that cancer enables the CRPC state, or if alterations of the Testosterone is the major circulating androgen AR and/or AR signaling occur de novo [Maitland and 9095% is synthesized in the Leydig cells and Collins, 2008]. of the testis, with 510% coming from the adre- nals [Labrie, 2004]. Testosterone, as are all ster- The AR gene is located in the X chromosome oid hormones, is poorly soluble in water and and the AR structure is similar to other steroid upon release into circulation, associates with sex receptors with a modular structure of a hormone-binding globulin (SHBG) which trans- well-conserved DNA binding domain and NH - ports the hormone through the circulatory terminal transcriptional activation domain, in system to target tissues such as the prostate and addition to a carboxyl terminal ligand binding skin. Circulating free testosterone enters prostate domain [Culig et al. 2005]. The AR is identical cells and is converted to dihydrotestosterone in all androgen-responsive sites in the body and is (DHT) by 5a-reductase within the prostate. required for normal prostate development, DHT is the primary androgen in prostatic tissues muscle hypertrophy, bone density, and cognition. as it binds the AR more stably. Prior to ligand binding, the AR is sequestered in the cytoplasm with a complex of heat-shock pro- Androgens are a requirement for growth and teins, molecular chaperones, and immunophilins avoidance of apoptosis of prostate cancer cells, which all help induce high-affinity conformation. and castration triggers programmed cell death Once bound to testosterone or DHT, the AR dis- in both normal as well as malignant prostate sociates from the complex and forms a homodi- cells [Denmeade et al. 1996]. Prostate cancer mer with exposure of the AR nuclear growth depends on androgens stimulating prolif- translocation where the bound AR engages spe- eration and inhibiting apoptosis. Castration cific chromatin regions, androgen response ele- causes a rate of cell death which is greater than ments (AREs), to control target gene the rate of cell proliferation. However, castration expression. The binding of AR with the AREs is rarely curative. It is not known if selection recruits coregulatory proteins which play an 110 http://tam.sagepub.com CJ Hoimes and WK Kelly important role in initiation and fine tuning of decrease in pain and PSA, with a decrease in transcription. PSA is the most familiar tumor bulk. Relapse, however, is nearly inevitable AR-regulated gene and is an important marker and castrate-resistant disease is incurable with a not only for screening but for disease progression time to death of approximately 2 years [Tannock including CRPC, indicating a functional AR sig- et al. 2004]. The presence of SHBG, whose con- naling axis. centration in the circulation can change in response to a variety of physiologic conditions, The AR was first noted to have an important role can complicate efforts to accurately measure the in resistant prostate cancer in 1991 [Van Der active circulating testosterone. Nonetheless, mea- Kwast et al. 1991]. AR principally acts as surement of serum testosterone is warranted in ligand-inducible transcriptional enhancer factor. patients who are progressing on ADT with a The AR signaling axis involves the physiologic goal of serum testosterone less than 50 ng/dL. ligands, testosterone and DHT, ligand regulation and transport through the bloodstream in associ- Though therapy is usually tolerated, side effects ation with SHBG, the AR, the regulation of related to testosterone deficiency include muscle unbound AR in the cytoplasm, and the regulation atrophy and weakness, erectile dysfunction, hair of dimerized and phosphorylated AR transport to loss, insulin resistance and diabetes, increased fat the nucleus for engaging the ARE, and recruit- mass and decreased lean body mass and anemia ment of coregulatory proteins for fine tuning [Hang et al. 2005]. As estrogens are derived from transcriptional output. The axis is important in aromatization of testosterone in men, estrogen many diseases including prostate cancer, deficiency commonly occurs in patients treated benign prostatic hyperplasia, alopecia, and hir- with ADT (either medically or surgically) and sutism. A secondary role of the AR may mediate leads to side effects that include hot flashes, nongenomic signaling independent of the princi- reduced bone mineral density and increased frac- pal transcription factor role and does not ture risk, mood changes, memory loss, gyneco- require DNA binding, such as through the mastia, and lipid changes [Freedland et al. 2009]. c-Src tyrosine kinase signaling cascade of mitogen-activated protein kinase (MAPK)/extra- Despite these anticipated physiologic symptoms cellular signal-regulated kinase (ERK) pathway that impact nearly every organ system, a castrate [Migliaccio et al. 2000]. serum value is not necessarily a reliable represen- tation of the androgen level at the tumor site. In The concentration of AR in the cytosol is tightly CRPC, prostate cancer cells develop a variety of controlled by a number of factors that includes aberrant pathways to survive in a castrate envi- the state of differentiation of the tissue. AR levels ronment. Failure of castration therapy was pre- usually drop dramatically immediately after tes- sumed to be solely due to low levels of circulating tosterone or DHT exposure as there is a net nongonadal production of androgens; however movement of the ligand-receptor complex to the tumor stem-cell, genetic, epigenetic, and tumor nucleus. Eventually, the ARs are repopulated by microenvironment in AR signaling are new synthesis or recycling of receptor after disso- implicated. ciation from the ligand [Dehm and Tindall, 2007]. The search for a prostate cancer stem cell (CSC) is difficult as it is complicated by the heterogene- Resistance to hormonal therapy and mechan- ity of tumors. A likely contender that retains self isms of AR signaling in CRPC renewal and tumor generating capacity has the + high + Achieving castrate or anorchid levels of testoster- CD133 /a2b1 integrin /CD44 phenotype one (50 ng/dL) with ADT remains the most [Gu et al. 2007; Collins et al. 2005]. effective therapy for metastatic disease and has Heterogeneity and multifocality, in fact, may be been long recognized as the first systemic antic- the phenotypic depiction of stem cell tumorigen- ancer maneuver for prostate cancer [Huggins and esis in the prostate as many stem cells become Hodges, 1941; Huggins et al. 1941]. Half of all activated to acquire tumor-initiating properties. men with prostate cancer are treated with ADT As the progeny cells either fail, expand and dif- during the course of their disease and many for ferentiate slowly, or expand and acquire a muta- prolonged periods of time [Cooperberg et al. tion to differentiate more rapidly; the various 2003; Meng et al. 2002]. The cancer usually clones and failures contribute to the multifocality. responds well initially, resulting in prompt The disease course, however, is determined by http://tam.sagepub.com 111 Therapeutic Advances in Medical Oncology 2 (2) the more aggressive clone and overshadows the leads to 19-carbon androgens. 18-carbon estro- others. Interestingly, the prostate CSC popula- gens are also produced, and through a peripheral tion does not express AR, and therefore inher- tissue reversible interconversion pathway, can ently resistant to hormone maneuvers. The change estradiol to testosterone. An additional CSC may be able to repopulate the tumor with source is that CRPC tumors have the biochemi- AR dependent and AR independent progeny cells cal machinery for local intratumoral synthesis of [Pienta and Bradley, 2006]. While this provides androgens. For these reasons, tumor androgen an explanation for minimal residual disease after levels may not be too far from baseline, despite hormone maneuvers, it is unclear why this impor- what is measured in the serum [Chen et al. 2004; tant gain of function selection in AR is not seen at Mohler et al. 2004]. Recent data from human the cancer stem cell level [Maitland and Collins, tissue samples show that castrate levels of 2008]. Perhaps steroid response is not conducive serum androgens do not accurately or consis- to activated CSCs maintaining an undifferen- tently represent the intratumoral androgen level tiated, or in some cases, a dedifferentiated which may be due to de novo synthesis of andro- (from a committed basal cell) state. gen within the tumor [Locke et al. 2008; Montgomery et al. 2008; Mostaghel et al. 2007; The axiom that prostate cancer is a hormone- Page et al. 2006; Mohler et al. 2004]. dependent disease because it requires androgens Intratumoral levels are often close enough to for survival is becoming eroded by better under- baseline controls where prostate cancer cell pro- standing of the castrate state and now seems to be liferation, apoptosis, and androgen-regulated only partly true. The central dependence for protein expression, including PSA, are unaffected tumor survival is on the AR signal, which may [Page et al. 2006]. or may not involve an androgen ligand. Prostate cancer cells use five mechanisms mediated AR hypersensitivity: mutations through the AR to promote tumor growth, AR-activating mutations allow AR signaling by three of which depend on ligand signaling. nongonadal androgens that would not normally They are persistence of intratumoral androgens cause AR activation. AR mutations have been as a result of in situ steroidogenesis or adrenal identified in prostate cancer cell lines such as source; AR mutations that allow promiscuous LNCaP and CWR22 as well as in patient tissue activation by otherwise nonsignaling ligands; samples where adrenal androgens such as dihy- wild-type AR gene amplification; alterations in droepiandrosterone (DHEA) or androstenedione AR coactivator to corepressor ratio that impact causes a severalfold higher transcriptional transcription; outlaw AR pathways that bypass response than wild-type AR [Koivisto et al. the need for androgens by signaling through 1998; Tan et al. 1997; Taplin et al. 1995; crosstalk with other ligand-bound receptors, Veldscholte et al. 1990]. According to one cytokines, or transactivation of activated report, approximately 20% of metastatic tumors tyrosine kinase receptors in the cytosol have an AR mutation that modulates steroid spe- [Mellado et al. 2009; Freeman et al. 2005; cificity [Marcelli et al. 2000]. Mutations can also Scher and Sawyers, 2005; Eder et al. 2001; increase sensitivity of the AR to nonandrogen Feldman and Feldman, 2001]. One or many of steroids and molecules, including antiandrogens these mechanisms may be playing a role, even [Buchanan et al. 2004; Veldscholte et al. 1990]. within the same patient, and may be an explana- tion, in part, for heterogeneous responses. AR hypersensitivity: amplification More common is the third mechanism which is Surreptitious tumor androgen exposure despite associated with increased levels of wild-type AR castrate serum levels The first ligand-dependent mechanism of contin- protein secondary to gene amplification which ued signaling through the AR can occur as pros- can impart a growth advantage without a specific tate cancer tissues continue to be exposed to mutation. This has been shown to be amplified in androgens. The source can be from extragonadal 2030% of patients with CRPC and less than 5% androgen conversion pathways. The adrenal of those with primary prostate cancer [Bubendorf gland imports cholesterol or synthesizes it et al. 1999; Koivisto et al. 1998, 1999; Visakorpi de novo from acetate to make the 21-carbon preg- et al. 1995]. Elevated AR protein expression is nenolone which serves as the substrate for the necessary and sufficient to confer resistance to multiple enzyme cascade of steroidogenesis that antiandrogen therapy in murine xenografts and 112 http://tam.sagepub.com CJ Hoimes and WK Kelly sensitizes prostate cancer cells to respond to low to corepressor ratio can direct a change in AR levels of androgen ligand [Chen et al. 2004]. function. Deregulated expression of AR coactiva- tors tends to increase with tumor dedifferentia- Alteration in coactivator to corepressor balance tion and correlate with aggressive disease and Two additional AR-centric mechanisms of poor prognosis [Need et al. 2009]. Specifically, CRPC are considered that activate the AR with the AR p160 coactivator family of steroid recep- minimal to no ligand requirement. These are tor coactivator-1, and others, can recruit HAT indirect mechanisms of continued AR signaling activity [Kang et al. 2004]. ARA proteins and involve coregulator molecules, and crosstalk enhance AR-dependent transcriptional activation with tyrosine kinases, cytokines, and other recep- and are well studied in prostate cancer [Kikuchi tors. Though indirect, these mechanisms are not et al. 2007; Mestayer et al. 2003; Li et al. 2002; less significant; and on the contrary, perhaps have Yeh et al. 1999]. For instance, ARA267a as much of a role in resistance to castration as the enhances AR-dependent transcription that is more intuitively proposed and parsimonious additive to HAT activity [Kang et al. 2004]. direct mechanisms. Interestingly, these mechan- ARA54 and ARA70 can sensitize the AR to isms have the potential to be magnified by the lower concentrations of testosterone or DHT, or other aberrant pathways, when present, such as even alternative ligands such as estradiol and AR amplification, AR mutation, and preserved hydroxyflutamide, or even allow intratumoral androgen levels. ligand-independent enhancement of cell cycle progression via induction of cyclin D1, or via Binding of AR homodimers at the AREs induces receptor tyrosine kinases such as HER2 the attraction of coregulatory molecules such as [Kikuchi et al. 2007; Scher and Sawyers, 2005]. the cointegrators c-AMP response element bind- Corepressor proteins NCoR and SMRT can ing protein (CREB)-binding protein (in total interact to form complexes with HDAC [Xu ‘CBP’) and p300, coactivators of AR-associated et al. 1999] and inhibit AR function in a (ARA) proteins and p160, and corepressors such ligand-dependent manner. as nuclear receptor corepressor (NCoR) and SMRT (silencing mediator for retinoic acid and Outlaw pathways thyroid hormone receptors). Transcription The fifth mechanism is AR transcriptional activ- depends on the recruitment of RNA polymerase ity that can be activated in the absence of andro- II to promoters of the AR target genes. The cor- gen. Signaling to a genomic (via AREs) or egulator molecules make up the preinitiation nongenomic route is possible. Signaling of the complex (PIC) and direct specific interaction of AR to the AREs is possible through crosstalk RNA polymerase II and the promoter and can with agonist occupied membrane receptors contribute to transcriptional synergy (coactiva- as described in many steroid hormone tors), or in the case of competitive binding of receptors including estrogen receptor, progester- these factors, transcriptional repression (corepres- one receptor, and AR [Scher and Sawyers, sors) [Vo and Goodman, 2001] of the AR func- 2005; Pietras et al. 1995; Zhang et al. 1994; tion. These molecules help regulate accessibility Power et al. 1991]. of gene promoters to transcription and DNA rep- lication machinery through two active pathways or AR crosstalk and transactivation can occur with classes including ATP-dependent chromatin transduction pathways for proliferation, survival, remodeling complexes that reorganize chromatin or motility. This signaling mechanism does not structure, and a class of enzymes that catalyze signal to AREs and is considered a nongenomic posttranslational modifications in histones, the pathway as opposed to the aforementioned. It best characterized are histone acetyltransferases may or may not involve ligand and can occur (HAT) and histone deacetylases (HDAC). through transactivation of kinases, or crosstalk with cytokines or growth factor receptors. AR-associated coregulators are important to the development of aberrant AR action. Not only is Ability to transactivate through nongenomic this true for prostate cancer, but is seen in other mechanisms via cholesterol-rich lipid rafts is diseases such as the link of androgenic alopecia or one way of linking AR signaling to the prolifera- hepatitis B virus to preponderance of male risk of tive and cell survival transduction pathways hepatocellular cancer [Chiu et al. 2007; Lee et al. [Baron et al. 2004; Migliaccio et al. 2000; 2005]. In each of these, changing the coactivator Peterziel et al. 1999]. Transactivation with http://tam.sagepub.com 113 Therapeutic Advances in Medical Oncology 2 (2) activated tyrosine kinase receptors has been and activator of transcription (STAT). This crosstalk shown between the AR-signaling path and acti- enhancement of AR signaling has been shown to vation of the MAPK and MAPK/extracellular confer castration resistance in preclinical models signaling-regulated kinase kinase-1 (MEKK1), [Wang et al. 2007]. and the epidermal growth factor receptor (EGFR) pathway, including HER2/neu Castrate-resistant prostate cancer: novel [Bonaccorsi et al. 2004; Abreu-Martin et al. therapies for AR-signaling depletion 1999; Peterziel et al. 1999]. As prostate cancer continues to evade hormone manipulations and rely on AR signaling, drug AR can also crosstalk with cytokines including development has focused efforts to target the path- nuclear factor kappa B (NF-kB),IL-6, IL-8,inaddi- way at many points for CRPC patients (Table 1). tion to beta-catenin [Malinowska et al. 2009; Therapies developed include novel and potent AR Robinson et al. 2008; Seaton et al. 2008]. Crosstalk antagonists which block AR nuclear translocation with other growth factor receptors such as EGFR, v- and DNA binding, addressing prostate tumor in raf murine sarcoma viral oncogene homolog B1 situ steroidogenesis with enzyme-specific adrenal (BRAF), and v-src sarcoma viral oncogene homolog androgen inhibitors, trials of 5a-reductase inhibi- (SRC) can induce activation of growth and survival tion, addressing crosstalk and transactivation path- pathways including MAPK, v-akt murine thymoma ways with small molecule tyrosine kinase inhibition viral oncogene homolog (AKT), signal transducer or mammalian target of rapamycin (mTOR) Table 1. Mechanisms of continued androgen receptor (AR) signaling axis despite castration and options for noncytotoxic chemo- therapy therapeutic intervention. AR-signaling Target Therapeutic intervention Ligand-dependent pathways Testis androgen synthesis H-P-G axis LHRH or GnRH agonists Degarelix (GnRH antagonist) Orchiectomy Adrenal androgen synthesis Androgen feedback, DHEA, ERb DES [Kitahara et al. 1999; Pravettoni et al. 2007] Non-specific CYP-17 Ketoconazole 11b-hydroxylase CYP 17A1 (17a hydroxylase & C17,20-lyase) Abiraterone* Tumor androgen synthesis 5a-R, primarily type II isozyme Finasteride 5a-R, primarily type I isozyme Dutasteride AR mutation/alternate ligands AR Bicalutamide after flutamide Nilutamide after bicalutamide AAWD BMS-641988* [Mellado et al. 2009] AR Antiandrogens Progestins Glucocorticoids AR gene amplification AR, nuclear trans and ARE binding MDV3100* [Scher et al. 2009] RD162* [Tran et al. 2009] Ligand-independent pathways Coregulator HDAC SAHA LBH589 P160, TIF2 Arsenic trioxide [Rosenblatt and Burnstein, 2009] Crosstalk/transactivation Cell surface receptors RTK inhibitors, antibodies Src pathway Dasatinib [Yu et al. 2008] PTEN loss with active mTOR pathway Temsirolimus [Wu et al. 2005] PI3K activation by HER-2 signaling Lapatinib [Whang et al. 2008] PKCb/PI3K/AKT Enzastaurin* 5a-R, 5a-reductase; AAWD, anti-androgen withdrawal; AR, androgen receptor; ARE, androgen response elements; DES, diethylstilbestrol;, dehydroepiandrosterone; diethylstilbestrol; DHEA, dehydroepiandrosterone; CYP, cytochrome; cytochrome P450; ER, estrogen receptor; GnRH, gonadotropin releasing hormone; HDAC, histone deacetylase; H-P-G, hypothalamic-pituitary-gonadal; LHRH, luteinizing hormone release hor- mone; mTOR, mammalian target of rapamycin; PI3K, phosphoinositide 3-kinases; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase; SAHA, suberoylanilide hydroxamic acid; Src, sarcoma; TIF2, transcriptional mediators/intermediary factor 2; trans, translocation. *not FDA approved, in clinical trials. 114 http://tam.sagepub.com CJ Hoimes and WK Kelly inhibition. Investigations for targeting coregulator tumor cell (CTC) counts after treatment can molecules are underway, and arsenic trioxide has in serve as a robust intermediate endpoint for overall vitro results that support a coregulator inhibition survival [Attard et al. 2009a]. It has completed that attenuates the AR signal. Histone deacetylase enrollment of over 1100 patients and results are (HDAC) inhibition may also impact coregulator maturing that will yield further information on the ability of the PIC to access the chromatin structure. population that may have a clinical benefit. [National Institutes of Health et al. 2009] Of those that are not FDA approved, perhaps abir- aterone acetate is the furthest along in clinical trials MDV3100 is a second generation small-molecule and showing tolerability and efficacy. Abiraterone antagonist of the AR that prevents nuclear trans- acetate is a prodrug low molecular weight inhibitor location and DNA binding of AR without agonist of CYP17A1, also knowninthe adrenalsteroid activity [Tran et al. 2009] that recently reported pathway as the dual role enzyme of interim results of a phase I/II trial of 140 patients 17a-hydroxylase, and 17, 20 desmolase. A different that were either chemotherapy naı ¨ve or postche- name is given to a different activity of the same motherapy with progression of CRPC. The enzyme as it adds a hydroxyl group to pregnenolone dose-escalation study of 30600 mg orally daily to form 17a-hydroxypregnenolone, and then acting was well tolerated and nearly half of the patients as 17, 20 desmolase (also called a lyase) removes a had at least a 50% PSA decline at week 12; and side-chain carbon to form DHEA. The same 38% of evaluable patients receiving 240 mg/day enzymes are involved in the parallel progesterone dosing had a radiographic partial response (PR) pathway in the conversion from progesterone to [Scher et al. 2009]. An international phase III 17a-hydroxyprogesterone to androstenedione. The placebo-controlled trial is underway using the phase I single center study of abiraterone acetate 240 mg/day dose [National Institutes of Health showed that 21 chemotherapy and ketoconazole et al. 2009]. naı ¨ve patients with metastatic CRPC tolerated the therapy well and had significant antitumor activity Systemic therapies in development that do not with over half of patients experiencing a greater than target the AR signal are also being investigated 50% PSA decline that lasted a minimum of 3 and include immunotherapy; bone targeted ther- months [Attard et al. 2008a; De Bono et al. 2008]. apy with a monoclonal antibody against receptor This trial seamlessly expanded into a two stage, activator of nuclear factor k B ligand (RANK-L), single-arm, phase II trial where abiraterone acetate oral endothelin inhibitors; Src kinase inhibitors was dosed once daily at 1000 mg for 28 day cycles such as dasatinib; altering tumor apoptotic sensi- until PSA progression at which point dexametha- tivity to chemotherapy using a clusterin inhibitor; sone 0.5 mg daily was added. In the 42 phase II monoclonal antibody to prostate specific mem- patients, 67% had a more than 50% decline in brane antigen, and an antisense oligonucleotide PSA, and declines of more than 90% were seen in against B-cell leukemia/lymphoma-2 gene eight patients [Attard et al. 2009a]. The median (BCL-2). Review of novel therapies is beyond the time to PSA progression (TTPP) was 225 days, at scope of this article and can be reviewed in recent which point dexamethasone 0.5 mg daily was added publications [Fleming et al. 2009; Lassi and and yielded an additional 151 days of median Dawson, 2009; Shah et al. 2009; Tran et al. 2009] TTPP. The additional response gained with dexa- methasone was independent of previous treatment Molecular heterogeneity in CRPC: with dexamethasone [Attard et al. 2009a]. TMPRSS2:ETS and the lethal phenotype It is clear the past decade has seen a significant While all these patients had progressive disease increase in understanding the basis of prostate despite castration and further reduction in andro- cancer progression and specifically the role of the gens were possible, this raises the question AR and the factors it cooperates with while whether we can call the responding patients truly unbound in the cytosol or during activated signaling castrate resistant. Unfortunately biomarkers have to the nucleus. The AR mechanisms of resis- nothelped us to identify this subsetof patients. tance are the survival traits prostate cancer has This will be addressed in the phase III trial of developed or acquired to flourish. Many of the abiraterone acetate which is a placebo-controlled ligand-independent crosstalk and transactivation trial in combination with prednisone. The primary mechanisms are important in enabling prostate endpoint is overall survival and also incorporates cancer to share in the ‘hallmarks’ that define the prospective evaluation of whether circulating common characteristics of cancer [Hanahan and http://tam.sagepub.com 115 Therapeutic Advances in Medical Oncology 2 (2) Weinberg, 2000] and lend to the molecular lethal and researchers have looked to correlate fusion phenotype [Loberg et al. 2007]. These AR mechan- events with histologic phenotype and prognosis. isms enable genetic instability, limitless replicative Researchers have identified a significant associa- potential, evasion of cell death, and can be rendered tion between the fusion gene and prostate cancer capable of growth factor independent growth. specific death, as well as a link between ERG perturbations and a higher Gleason score The number of AR coregulators reported is over [Demichelis et al. 2007]. The 5 to ERG Edel 150, indicating a daunting level of functional fusion is found in approximately 6070% of the diversity among these proteins [Heemers and cancers containing ERG rearrangements and has Tindall, 2007]. Also, crosstalk and transactiva- been found to correlate with a higher tumor stage tion lend AR the ability to interact with — and and pelvic lymph node metastasis [Attard et al. in many cases such as EGFR, regulate — other 2008b; Perner et al. 2006]. Further clinicopatho- growth factor receptors and signals, tyrosine logic correlation has identified a subtype with kinases, and cytokine pathways. There are also poor survival using fluorescent in situ hybridiza- many molecular pathways that are important in tion (FISH) analysis. These patients comprised the initiation and progression of prostate cancer. nearly 7% of 445 previously untreated patients Germ-line mutations of several genes have been and were found to have a 2+ Edel (two or more 0 0 found in a fairly small subset of hereditary pros- FISH copies of 3 to ERG without 5 to ERG) tate cancers. Promoter hypermethylation leads to which correlated with a poor cause-specific and loss of expression of glutathione S-transferase overall survival in a multivariate analysis. gene (GSTP1) and is seen in many prostate (and other) cancers as well as prostatic intrae- The estrogen receptor (ER) is also implicated as pithelial neoplasia (PIN) [Lee et al. 1994]. ERa stimulation results in TMPRSS2-ERG Another frequent mutation seen in prostate can- upregulation [Mertz et al. 2008; Taplin, 2007], cers (many early, localized), is allelic loss of chro- even in an AR-negative cell line [Taplin, 2007]. mosome 8p. More recently discovered is the first This suggests that an ERa antagonist may have epithelial malignancy fusion gene, and is found in activity in prostate cancer through inhibition of over 50% of prostate tumors. This now links the TMPRSS2-ERG expression. In fact, antitumor pathogenic AR in CRPC to oncogenic transcrip- activity of abiraterone acetate may be explained, tion factors, ETS (erythroblastosis virus E26 in part, by suppressing estradiol and therefore oncogene like - avian). attenuating upregulation of TMPRSS2-ERG expression via the ERa receptor [Ellem and The most common mechanism of ETS overex- Risbridger, 2007]. The abiraterone phase I pression is the fusion of the ETS gene, ETS study investigated this hypothesis as a correlative gene-related gene (ERG), with the highly and found that of six patients with the AR-regulated transmembrane protease serine 2 TMPRSS2-ERG gene fusion, five responded to (TMPRSS2) gene [Tomlins et al. 2005]. abiraterone acetate with a >50% PSA decline, a TMPRSS2 is expressed in normal and malignant response that was 30% more than the overall prostate and dependent on androgen. ERG is a group [Attard et al. 2008a]. It is not clear if the transcription factor involved in oncogenic trans- success of abiraterone acetate in this case was locations in Ewing’s sarcoma and myeloid leuke- acting by decreasing estradiol availability which mias [Saramaki et al. 2008]. Additionally, ERG could otherwise act promiscuously with the AR interacts with histone methyltransferase and may directly, abolish extragonadal tissue androgen impact silencing of target genes [Saramaki et al. production through its intended CYP17A1 inhi- 2008]. Both are close in proximity on chromo- bition, or by inhibiting the reversible interconver- some 21, and interstitial deletion (Edel) of sion pathway of estradiol to testosterone. sequences 5 to ERG has been found to be a common mechanism of TMPRSS2-ERG fusion Another treatment directed at the in prostate cancer. Moreover, in CRPC, Edel was TMPRSS2-ERG gene fusion can take advantage found to be the exclusive mechanism of rearran- of its dependence on HDAC for fusion gene acti- gement and with a particularly aggressive pheno- vation. HDAC inhibitors have been shown to type in a cohort of 30 men [Mehra et al. 2008]. directly block genes involved in the TMPRSS2:ERG fusion and warrant further clin- TMPRSS2 also can become fused to other ETS ical studies to evaluate these drugs in this setting transcription factors such as ETV1 and ETV4 [Attard et al. 2009b; Welsbie et al. 2009; 116 http://tam.sagepub.com CJ Hoimes and WK Kelly Bjorkman et al. 2008; Tomlins et al. 2008; Kelly They are responsible for much of the latitude of et al. 2002]. cancer survival and ultimately, its lethal pheno- type. Hormone-resistant tumors could perpetu- Need for a new CRPC clinical state: androgen ate solely through the ligand-independent depleted pathways. The proposed prostate CSCs do not A Medline search of keywords ‘castration resis- express AR, and may impart in progeny tumor tant’ or ‘castrate resistant’ yields its earliest rele- cells robust ‘workaround’ AR signal vant usage in 2000 and defined as prostate cancer ligand-independent pathways that could serve that has progressed despite medical or surgical to be the principal operator of progression in means of castration [Solit et al. 2003; Scher and hormone-resistant tumors. Heller, 2000]. To define a patient’s clinical state as castrate resistant gives it a basis in physiology A modification to the current PCWG2 clinical we can all understand; i.e. medical or surgical states model is needed to classify this new popu- castration levels of circulating free testosterone. lation of castrate resistant patients with clinical Reference to the clinical syndrome of ‘hormone metastasis. We propose a new category of ‘andro- resistance’ can be interpreted as a patient with a gen depleted’ which is the clinical state of prostate tumor that is resistant to endogenous patients with tumor that have predominant androgens, or, as more often used, a patient AR-signaling ligand-independent pathways driv- who no longer responds to hormone maneuvers. ing proliferation. A schematic to incorporate the We now understand that it is more complicated new clinical state is shown in Figure 2. than just what’s going on with the serum testos- Androgen-depleted patients may or may not terone level. have metastases and the state is preceded by cas- trate patients that have either rising PSA or clin- A hormone-resistant tumor is now redefined as ical metastases. Death from other causes can one that progresses in an environment of collat- occur along this continuum, though death from eral androgen depletion (CoAD) where androgen disease represents a proportionately larger frac- levels are ablated beyond castrate levels. CoAD tion of androgen-depleted castrate patients with maneuvers target the ligand-dependent pathways a rising PSA and those with clinical metastases. of gonadal and extragonadal (physiologic), and in situ tumor (pathologic) androgenesis. A com- Interest has turned to therapeutic intervention of bination of ligand-dependent directed therapeu- the AR-signal ligand-independent pathways with tic interventions (see Table 1) can achieve the familiar receptor targets such as EGFR, and CoAD state. HER2 and using antibodies and small-molecule receptor tyrosine kinase (RTK) inhibitors. Despite these interventions to ablate the ligand, Clinical trials are investigating the effect of dasa- AR signaling may persist via the tinib, gefitinib, cetuximab, mTOR inhibitors, the ligand-independent crosstalk and transactivation PKCb inhibitor, enzastaurin, in combination pathways. Early data for treatment of the AR with cytotoxic agents. Additionally, there are sev- signal ligand-dependent pathways are demon- eral AR-signal pathway inhibitors that are in pre- strating a substantial number of patients with clinical and clinical testing, and of these, the potential long remissions. Unfortunately, how- second-generation antiandrogens like MDV ever, there does appear to be a population of 3100 with ability to degrade the AR and patients that progress despite castration plus RD162 are likely the furthest along showing tol- CoAD treatments. Though the AR-signaling erability and efficacy [Tran et al. 2009]. As we ligand-dependent pathways are maximally atte- develop therapeutics for this web of AR signaling, nuated, there is likely a predominant we anticipate a learning curve for clinical trialists AR-signaling ligand-independent pathway to determine their optimal usage. Approaches responsible as the principal cause for this group being considered include sequential use in of resistant patients. advanced disease, use in earlier disease, as well as adjuvant to primary therapy. In addition, due In the androgen-depleted state, AR signal to AR-signal redundancy, clinical benefit may be ligand-independent pathways are likely a survival gained from adding AR-signal active agents trait the prostate cancer developed through rather than switching after a failed therapy. chance accumulation, or clonal expansion with Depleting the AR-signal redundancy would or without selective therapeutic pressure. require an annihilation approach where CoAD http://tam.sagepub.com 117 Therapeutic Advances in Medical Oncology 2 (2) No disease- prevention Rising PSA Rising PSA Rising PSA castrate castrate non-castrate androgen depleted Clinically localized Clinical metastasis Clinical metastasis Clinical metastasis castrate castrate non-castrate androgen depleted Death from disease Death from other causes Figure 2. Proposed clinical states model of prostate cancer to incorporate a new category of androgen-depleted clinical states which reflect tumors that are have predominant AR signaling via ligand-independent pathways. treatment is combined with ligand-independent pathologic predictor of outcome for localized dis- interventions. For example, an annihilation ease and novel biomarkers of AR-driven path- approach may include combination of an ways are desperately needed as we continue our LHRH agonist, 5a-reductase inhibitor, a development of the new generation of androgen second-generation [Tran et al. 2009] anti- and AR therapeutics. However, the current clas- androgen, a CYP17A1 inhibitor, and an AR sification schema for CRPC does not take into degrader, such as an HDACi. account these new AR therapeutics and we pro- pose the clinical state ‘androgen depleted’ to Research has shown since the 1940s that the AR reflect the AR-signal ligand-independent path- signal is crucial to attenuate in prostate cancer. ways for those patients who are refractory to cas- The AR cascade interacts with many chaperones tration plus CoAD. This clinical state is proposed and other cell machinery and signals, and can to create a common vocabulary amongst clinical become hypersensitive to ligand, use ligand that trialists and physicians so data sets can be inter- is produced in the tumor tissue or extragonadal preted accurately, and correlation with prognosis pathways, use signals from other growth recep- will be needed to qualify the new category. tors, crosstalk with cytokines, transactivate tyro- sine kinases, and can be preferentially activated by its coregulators. Now that we know an onco- Conflict of interest statement gene is a downstream target of AR in the majority None declared. of patients, namely the TMPRSS2-ETS fusion gene, depleting androgen and inhibiting the AR signal is paramount. References Abreu-Martin, M.T., Chari, A., Palladino, A.A., Craft, Conclusion N.A. and Sawyers, C.L. 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Journal

Therapeutic Advances in Medical OncologySAGE

Published: Dec 8, 2009

Keywords: androgen-deplete prostate cancer; androgen-deplete signaling pathways; androgen receptor signaling; castrate resistant prostate cancer; collateral androgen deplete; prostatic adenocarcinoma

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