`
`J OURNAL OF CLINICAL O NCOLOGY
`
`REVIEW ART I CLE
`
`From the GenitOurinary Oncology
`Service, Department ol Med1c1ne.
`Sidney K1mmel Center for Prostate
`and UrologiC Cancers. Memonal
`Sloa~>-Kettenng Cancer Center,
`Joan and Sanford E Weift eonege of
`Med>One of Cornell UnrverSity,
`New York, NY, Howard Hughes
`Med1cal lnsutute, University of
`Calilorn1a, Los Angeles/Hematology(cid:173)
`Oncology, Los Angeles. CA
`
`Subm1tted July 14. 2005; accepted
`August 1, 2005.
`
`Authors' d1sdosures of potent.al
`confliCts of Interest are found at the
`end ol th1s art1cle.
`
`Address repnnt requests to Howard
`I. Scher, MD, Gemtourmary Oncology
`Servrce, Department of Med1c1ne.
`S1dney K1mmel Center for Prostate
`and Urolog•c Cancers, Memonal
`Sloa~>-Kettenng Cancer Center1275
`Yorlc Ave. New Yorlc, NY 10021;
`e-ma1l' ScherhOmsl<cc.org
`c 200!> by Amencan Soc1ety of Clin1cal
`Oncology
`
`0732·183X/05/2332·825:y$20.00
`
`DOl 1 0.1200fJC0 .2005.03 4777
`
`Biology of Progressive, Castration-Resistant Prostate
`Cancer: Directed Therapies Targeting the
`Androgen-Receptor Signaling Axis
`Howard I. Scher and Charles L. Sawyers
`
`A B S T R A C T
`
`Prostate cancers that are progressing on medical and surgical therapies designed to ablate the
`action of androgens continue to express androgen receptor (AR) and to depend on signaling
`through the receptor for growth. A more clinically relevant classification of castration-resistant
`disease focuses on the mechanisms of receptor activation. which include (1) changes in the
`level of ligand(s) in tumor tissue; (2) increased levels of the protein due to gene amplification
`or altered mRNA expression; (3) activating mutations in the receptor that affect structure and
`function; (4) changes in coregulatory molecules including coactivators and corepressors; and
`(5) factors that lead to act~ation of the receptor independent of the level of ligand or receptor
`allowing kinase cross talk. From an AR perspective, the term "hormone refractory" is inap(cid:173)
`propriate. On the basis of this schema. we discuss strategies that are focused on the AR either
`directly or indirectly, as single agents or in combination. that are in clinical development.
`
`J Clin Otlcol 23:8253-8261. © 2005 by American Society of Clinical Oncology
`
`The spectrum of prostate cancers that are
`progrrssing despite castrate levels of testos(cid:173)
`terone includes tumors that have shown
`varying degrees ;and durations of response
`to primary hormf>ne treatment, and clinical
`manifestations that range from a rising
`prostate-specific antigen (PSA) alone, a
`rising PSA with osseous and/or soft-tissue
`spread, or a predominantly visceral disease
`pattern. This evolution, from the clini(cid:173)
`cally localized hormone-na'ive state to a
`castration-resistant metastatic state (Fig 1), 1
`involves the complex interplay of a network
`of signaling molecules that collectively pro(cid:173)
`mote net cell proliferation relative to cell
`death. This range of clinical phenotypes is
`associated with different genotypes that
`are also influenced by both the microenvi(cid:173)
`ronment of the tumor in the location to
`which it has spread. That prostate cancers
`that have spread to lymph nodes often
`regress completely and rarely recur in this
`location while tumors in bone are rarely
`
`eliminated and are often the first site of
`clinical progression is consistent with this
`view. 2 Further support is provided by a
`study showing that prostate cancer metas(cid:173)
`tases in different sites from an individual
`who as a result of the disease are bio(cid:173)
`logically distinct.3 The biology of the pro(cid:173)
`gressing tumor is also influenced by the
`specific therapy to which it has been ex(cid:173)
`posed. This concept, which we have termed
`"therapy-mediated
`selection pressure,
`must also be considered when considering
`treatment options.4
`In 2004, the combination of docetaxel
`and prednisone was established as the new
`standard of care for patients who have
`progressed on androgen deprivation based
`on
`two prospective
`randomized
`trials
`showing a prolongation of life relative to
`mitoxantrone and prednisone, the previous
`standard.5•6 However, docetaxel and pred(cid:173)
`nisone are not curative, and optimal timing
`of administration remains controversial.
`Consequently, many groups are focused
`
`8253
`
`WCK1029
`Page 1
`
`
`
`Scher and Sawyers
`
`Use of Androgen Ablation
`
`Clinical
`Metastases· • •
`/ Noncastrate
`
`Clinically
`localited -+ Rising
`Disease
`PSA
`
`Death From
`..... Other Causes
`...
`,•
`
`..
`
`Clinical
`Metastase$:
`Castrate
`lsi Line
`
`············· ...•
`
`t
`Death As a
`Result of Disease
`
`Fig 1. Prostate cancer clinical states illustrating points rn the illness at which
`androgen depnvation can be apphed, separated on the basrs of castration
`status. Note chnical metastases castrate drsease rs drvrded into first and
`second hne based on the demonstration of a survrval benefrt wrth docetaxel.
`PSA. prostate-specific antigen. Modifred from Scher et al. 125
`
`on developing new approaches, and are focused in partic(cid:173)
`ular on the identification and targeting of critical signaling
`molecu les and pathways that contribute to tumor growth
`in the different clinical states (Fig I).
`Androgens are the primary regulators of prostate can(cid:173)
`cer cell growth and proliferation. When androgens are ab(cid:173)
`lated or withdrawn, apoptosis is observed in a proportion of
`cells, while those that survive arrest in the G I phase of the cell
`cycle.7 Clinical progression is the result of the regrowth of
`cells that were primarily resistant to androgen ablation, or
`which, after a period of growth arrest, adapted to the low(cid:173)
`androgen environment and resumed proliferation.8 It is
`possible, but not proven, that cells primarily resistant to
`androgen-deprivation therapy are those with stem-cell prop(cid:173)
`erties that never required androgens for survival and growth.
`Studies in xenografts in which androgen ablation(cid:173)
`na'ive tumors were propagated sequentially in male mice
`with low levels of testosterone and once established, prop(cid:173)
`agated again in female mice with testosterone levels that are
`below the level of detection, showed a sequentially increas(cid:173)
`ing degree of gene dysregulation.9 From a mechanistic and
`clinical point of view, it is critical to recognize that progres(cid:173)
`sion despite androgen deprivation is associated with an ac(cid:173)
`tive androgen receptor (AR) -signaling pathway. This is
`shown by the fact that progression is accompanied by
`a rise in PSA in virtually all cases, and that many of these tu(cid:173)
`mors are sensitive to secondary and tertiary hormonal ma(cid:173)
`nipulations such as the discontinuation of steroidal and
`nonsteroidal hormones, or to the addition of antiandro(cid:173)
`gens, estrogens, progestational agents, glucocorticoids, or
`enzymatic inhibitors of the adrenal androgen synthetic
`pathway. 10' 12 As it is difficult to determine a priori which
`tumors will respond to these hormonal therapies, the tem1s
`" hormone refractory," ''hormone resistant," "androgen resis(cid:173)
`tant," or "androgen refractory," widely used to describe these
`tumors, illustrate a fundamental misunderstanding of the
`mechanism of disease relapse. More appropriate is to focus
`efforts on the development of clinical descriptions that
`reflect the mechanisms that are contributing to continued
`
`signaling through the receptor or the action of ligand on
`the receptor, rather than on the ligand itself.13
`To date, the targeted approaches that have been the
`most successful approaches have been those directed against
`specific oncogenic alterations in tumors, such as the Bcr-Abl
`fusion protein in CML,14 point mutations inc-Kit, platelet(cid:173)
`derived growth factor-alpha kinascs in gastrointestinal
`stromal tumors, 15 or point mutations in the epidermal
`growth factor receptor tyrosine kinase domain in lung can(cid:173)
`cer.1 6 Although analogous genetic alterations in kinases
`have not been reported in prostate cancer, profiling studies
`of prostate cancers representing different clinical states have
`shown that a range of receptor tyrosine kinases, including
`members of the HER kinase family (epidermal growth factor
`18 platelet-derived growth fac(cid:173)
`receptor [EGFR], HER2), 17
`'
`tor19·20 and c-met,21 are expressed in a proportion of these
`tumors. Perhaps the most frequent genetic alteration is
`loss of the phosphatase and tensin homolog (PTEN) tumor
`suppres~or,22•23 which can lead to increased activity of Akt
`and mammalian target of rapamycin (mTOR).24 But, de(cid:173)
`spite the presence of the target on or in tumor cells, clinical
`results with single agents directed at these targets have been
`disappointihg at best.
`\
`AR Signaling
`There is a growing literature showing that the AR
`itself, a protein required for prostate development but
`not traditionally considered to play a causative role in can(cid:173)
`cer progression, rnay in fact be oncogen ic under certain
`circumstances.25
`' 30 This underscores the importance of
`developing therapies that affect AR signaling even in the
`setting of resistance to conventional antiandrogens, or
`to, the medical and surgical approaches used to lower se(cid:173)
`rum testosterone levels in the blood. In this section, we will
`focus on alterations in AR signaling, and how alterations
`in one pathway may affect response to agents targeting
`a second pathway.
`Using published reports and clinical outcomes, a clas(cid:173)
`sifi.cation scheme of alterations in AR signaling can be de(cid:173)
`veloped on the basis of (1) changes in the level of ligand(s)
`in turrfor tissue; (2) increased levels of the protein due to
`gene amplification or altered mRNA expression; (3) acti(cid:173)
`vating mutations in the receptor that affect structure and
`function; (4) changes in coregulatory molecules including
`coactivators and corepressors; and (5) factors that lead to
`activation of the receptor independent of the level of li(cid:173)
`gand or receptor allowing kinase cross talk.13'25
`26·31 These
`'
`are illustrated schematically in Figure 2.
`
`Direct M echanisms of AR Activation
`Incomplete blockade of AR-Iigand production.
`It has
`long been recognized that the medical and surgical thera(cid:173)
`pies designed to ablate production or androgen action do
`not result in undetectable androgen levels in tumor tissue.
`This is based on the direct measurement of androgens in
`
`8254
`
`J OllRJ'IAL OP CUN'ICAL O NCOLOGY
`
`WCK1029
`Page 2
`
`
`
`Castration-Resistant Prostate Cancers
`
`BG C -
`
`C
`
`LIGAND DEPENDENT
`
`LIGAND INDEPENDENT
`
`Receptor tyrosine kinases,
`
`.. ~-=---~~~ .. ~~ ............ -.~~:::r.:::=============~~~~~~~:=~=::=~~::o:kin~es~ncogenes
`
`Testosterone
`
`RECE~OR
`
`0
`ucocorticoids
`Q
`........_Anti-androgens
`D Estrogens 8;
`V'
`Progostins 0 Metabolites
`Adrenal
`androgens
`;;,:,O~.'i,~'" 0
`
`SYNTHESIS
`~e
`,86~ ADRENAL
`MATURA~ON
`1
`y
`ANDROGENS ~
`/LYASEAND
`1
`ADRENAL
`ANDROGEN
`
`Q
`DIHYDROTESTOSTERONE
`
`/
`
`R
`
`' ~1
`
`' J~jR~~ "'"ro""""""'
`
`/
`
`~
`
`p
`
`3. ACTIVATING MUTATIONS
`
`2. LEVEL OF AR ~ROTEIN
`
`...........
`Nuclear localization
`& DNA binding
`
`~
`
`TRANSCRIPTIONrL REGULATION -------,~
`
`IGROWTHIIDfFFERENTIAnDij lsuRvrvAIJ
`
`5. LIGAND INDEPENDENT AC~VA~ON
`
`I
`
`Nuclear lo~ti:
`/
`
`& DNA binding
`
`Cofactor recruitment
`
`4. CHANGES IN COREGULATORY
`MOLECULES
`(coactivators +co repressors)
`
`Fig 2. A classification of mechanisms associateqwith continued signaling through the androgen-signaling axis despite castration. SHBG, sex hormone-binding
`globulins; Hsp. heat shock protein; TPR. tncopepude repeat; AR, androgen receptor; MAPK, mrtogen-acuvated protein kinase; mut, mutated; wt, wild-type; COR,
`corepressors. Modified from Scher et al. 13
`
`and squalene epoxidase, rate-limiting enzymes involved in
`sterol synthesis, are increased relative to noncastrate tu(cid:173)
`mors.39 Overall the results suggest that prostate tumors
`rarely encounter a completely androgen-depleted environ(cid:173)
`ment.36 They also question whether defining progressive
`disease after castration on the basis of a measured testoster(cid:173)
`one level in the blood below 50 nglmL is appropriate.40
`i11Creased
`levels of AR protein without muta(cid:173)
`tion. Amplification of the AR gene, detected as an increased
`gene copy mtmber by flu orescence in situ hybridization or
`array-based comparative genome hybridization (CGH)
`methods has been documented in 20% to 25% of both
`castration-resistant metastatic41 and recurrent primary tu(cid:173)
`mors.42'43 In addition, an increase in the level of AR and/
`or AR-reguJated genes has been shown to be increased in
`prostate cancer xenografts that have progressed postcastra(cid:173)
`tion relative to tumors growing in intact male hosts, in
`the absence increased AR gene copy number.9.28'44
`5 In seven
`matched androgen ablation-naive and - resistant ceU lines,
`the only consistent change in mRNA expression was an in(cid:173)
`crease in AR mRNA levels, the significance of which was
`shown in transfection studies that demonstrated that both
`the onset and rapidity of tumor onset varied directly with
`
`•4
`
`the prostates of patients who have undergone castra(cid:173)
`33 That inhibitors of adre~al androgen synthesis
`tion. 32
`•
`such as ketoconazole34 and aminoglutethimide35 have
`anti-prostate cancer effects in some patients ill, this clinical
`setting suggests that the levels of androgen thft remain in
`the tumor despite castrate levels of testosterone in the blood
`are sufficient to produce tumor growth. This has been con(cid:173)
`firmed in a more recent report that showed that the intra(cid:173)
`tumoral testosterone levels in patients with castration
`resistant disease were similar to untreated benign prostatic
`disease, and that the level of dihydrotestosterone (1.45
`nM) was sufficient to maintain AR signaling and expres(cid:173)
`sion of PSA.36 In a foUow-up study, altho ugh dihydrotes(cid:173)
`tosterone (DHT) levels in recurrent primary prostate
`tumors were decreased by 97o/o relative to non-androgen
`suppressed benign prostatic tissue, the levels in the range
`of 1.25 nM, were sufficient to transactivate the receptor
`based on in vitro ceU line studies.37
`The intratumoral androgens may come from an adre(cid:173)
`nal source, or result from direct synthesis within the tumor
`by an intracrine mechanism. 38 Molecular profiling of
`castration-resistant prostate tumors showed that the expres(cid:173)
`sion of3-hydroxy-3-methylglutaryl-coenzyme A synthase l
`
`ovww.jco.org
`
`WCK1029
`Page 3
`
`
`
`Scher and Sawy ers
`
`AR level.28 The increase in AR protein sensitizes prostate
`cancer cells to respond to low levels of Iigand?s,46
`In human prostate cancer, AR protein is expressed in
`prostate cancers of all clinical states, and at higher levels i11
`50
`castration-resistant as opposed to noncastrate tumors.39.47
`-
`This increase in AR protein levels, coupled with the in(cid:173)
`creased levels of androgenic steroids in the tumor, further
`sensitizes the tumor to low levels of ligand.
`AR mutations. Reported AR mutation rates in hu(cid:173)
`man prostate range fTom 5% to 50% depending in part of
`the tumor material studied (primary v metastatic, pre- v
`post-androgen ablation), the prior therapy received, and
`whether all eight code on exons of the receptor-including
`the amino-terminus exon 1, which contains the activation
`factor l (AF-1) and AF-5 sites (http://www.androgendb.
`mcgill.ca/). 13
`31 The majority of mutations reported are in
`'
`1 and most of the mutations
`the ligand-binding domain, 5
`that have been identified are associated with gains as op(cid:173)
`posed to a loss of function and produce a receptor that is
`more sensitive to native ligand, or that can be activated
`by other steroid hormones and/or by the specific antiandro(cid:173)
`52
`gen used in clinical management of the disease. 13
`53 In one
`•
`•
`report, the mutations identified in patients progressing on
`flutamide were shown in vitro to be activated by flutamide
`55 This lack of
`and inactivated by other antiandrogens.54
`•
`cross resistance was subsequently shown in the clinic by
`the demonstration that patients who progress on one anti(cid:173)
`58
`androgen often respond to another.56
`-
`
`Indirect Mechanisms of AR Activation
`The transcriptio nal activity of the AR is mediated, in
`part., by coactivators that enhance or corepressors that re(cid:173)
`duce receptor fun ctio n.59 Coactivator proteins such as
`ARA54 and ARA70 can selectively enhance the activity
`of the receptor to alternative ligands such as estradiol
`and hydroxyflutamide, sensitize the receptor to lower
`concentrations of native and nonnative Ligands, or allow
`ligand-independent activa tion by receptor tyrosine kinases
`62 Decreased expression of core(cid:173)
`(RTKs) such as HER2.60
`-
`pressors such as nuclear receptor corepressor (N-CoR)
`and silencing mediator of retinoid and thyroid receptors
`(SMRT), which mediate, in part, the antagonist action
`ofbicalutamide, flutamide and mifepristone, may contrib(cid:173)
`ute to the agonist activity that can be observed with these
`64 A change in the coactivator-to-corepressor
`agents.63
`'
`ratio can alter AR transactivation activity in the presence
`of low concentrations of DHT. Conversely, the core(cid:173)
`pressors SMRT and NCoR can inhibit AR function in a
`ligand-dependent manner. Experimental models show
`that alterations in the coactivator-to-corepressor ratio
`can also explain the paradoxical agonist effects of anti(cid:173)
`androgens and other steroid hormones on prostate cru1cer
`65 Unclear, however, is whether this serves as tile
`growth.59
`•
`mechanistic basis for clinical antiandrogen resistance or
`
`the occasional clinical responses seen in patients upon
`-.\Tithdrawal of antiandrogens. More recently, p300 was
`shown to activate expression of the PSA gene in the ab(cid:173)
`sence of or in the presence of androgens or antiandrogens.
`The effect was independent of the level of receptor. The
`findings suggest a role for coactivators in castration-resis(cid:173)
`tant disease.30
`HER-2/neu, a member of the EGFR family of RTKs,
`is consistently overexpressed in some castrate prostate
`cancer celllines,66 and in the human disease, at a higher
`frequency in castration resistant as opposed to hormone(cid:173)
`18 In one report evaluating nine
`na'ive primary tumo rs. 17
`'
`primary prostate and metastatic samples from tile same
`patient, three patients \\Tith HER2-negative primary tu(cid:173)
`mors had metastatic tumors that were HER2 positive.67
`It is now known that HER2, and other growth factors
`such as keratinocyte growth factor, insulin-like growth
`factor- 1, and epidermal growth factor; HER-2; and cyto(cid:173)
`kines su.ch as interleukin-6, can activate the AR and min(cid:173)
`imize or possibly even negate
`the requirement for
`ligand.25·66c68
`71 HER-2/neu is thought to promote DNA
`-
`binding and AR stability through activation of mitogen(cid:173)
`activated protein kinase (MAPK) and Akt, which can
`73 This provides a ratio(cid:173)
`also bind directly tot~ receptor.72
`•
`nale for targeting HER kinase signaling (Fig 3).
`
`HER2/3
`
`\
`
`AKT
`
`PI3K
`PIP3 ~ PIP2
`~~ \
`PTEN
`
`PKC
`
`Other
`AR1 ki nases?
`
`Enhanced AR stability
`optimal transactivation
`
`Fig 3. Schema of k1nase s1gnahng cross talk with androgen receptor (ARJ.
`The illustration dep1cts a postulated signaling pathway involving Her-2/Her-3
`heterodimers and P13K that leads to activation of the androgen receptor
`function through enhanced stability and transcnpuonal actiVation. Increased
`PIP3 levels. generated e1ther by Her-2/Her-3 and P13K activation or by
`phosphatase and tensin homolog (PTEN) loss. actiVate downstream kinase
`pathways including Akt. protein kinase C and others. Although Akt and
`protein kinase C can phosphorylate AR directly, the physiologic relevance
`rema1ns to be fully def1ned. Alternatively. PIP3-activated kinases may
`enhance AR function Indirectly by phosphorylating accessory molecules
`(coactivators) involved 1n AR function (not shown).
`
`8256
`
`JO\!lt'IAI. 01' CWIICAI. Ol<OOLOCY
`
`WCK1029
`Page 4
`
`
`
`Castration-Resistant Prostate Cancers
`
`Therapeutic Considerations
`The characterization of prostate cancers representing
`different clinical states is a rapidly evolving work in progress.
`The results reported to date clearly show the significance of
`directing therapies toward the various mechanisms that
`contribute to conti nued signaling through the androgen/
`AR pathway(Fig 2). Until AR function can be completely ab(cid:173)
`rogated, it will not be possible to say conclusively whether
`regrowth of prostate tumors after failure of androgen abla(cid:173)
`tion depends on AR signaling or other regulatory pathways.
`The approaches include those directed at the ligand, there(cid:173)
`ceptor, or factors that may function to activate the receptor
`independent ofligand. A number of strategies are illustrated
`schematically in Figure 2 and listed in Table l. It must be
`recognized, however, that each of these approaches will
`likely to have multiple effects on AR signaling.
`Reduce ligand concentration and competitively block
`AR function. The first issue in the management of a pa(cid:173)
`tient with progression of disease on hormones is to ensure
`that testosterone levels are in fact in the castrate range. Pa(cid:173)
`tients who are receiving antiandrogen monotherapy or an
`antiandrogen in combination with the 5-alpha-reductase
`inhibitor finasteride will typically have measured testos(cid:173)
`terone levels that are increased from their pretreatlnfnt
`baselines,74
`75 and may respond to the administration of
`'
`a gonadotropin-releasing hormone (GnRH) analog or sur(cid:173)
`gical orchiectomy. Patients being managed with a formal
`on-and-off or intermittent therapy76•7~ approach may also
`have testosterone levels in the noncastrate range and
`respond again to testosterone lowering agents.
`For those with testosterone concentrations that areal(cid:173)
`ready in the castrate range and who are progressing on the
`combination of a GnRH hormone ·~nalog in combination
`with an antiandrogen as part of a combined androgen or
`maximal androgen blockade approach, a proportion will
`show declines in PSA, regression of measuroble tumor
`masses and relief of cancer-related symptoms after discon(cid:173)
`tinuation of the antiandrogen while the GnRJi: analog
`
`therapy is continued. The phenomenon of withdrawal
`responses was first observed after the selective discontinu(cid:173)
`ation of flutamide. 10 Subsequently, they were reported
`with other non-steroidal antiandrogens (ie, nilutamide
`and bicalutamide), estrogens (diethylstilbestrol) and pro(cid:173)
`
`gestational agents (megestrol acetate).78"84 The overall fre(cid:173)
`quency of response is difficu lt to ascertain because of the
`differences in outcome measures used. In many series, re(cid:173)
`sponse proportions ranges from as low as 10% to as high
`as 60% depending on the agent(s) used. The median du(cid:173)
`rations are typically 3 to 4 months, recognizing that in cer(cid:173)
`tain cases, the duration of benefit exceeds 1 year. Clinical
`benefit has also been observed with second-line hormonal
`agents such as diethylstilbesterol,85 and to inhibitors of ad(cid:173)
`renal androgen synthesis aminoglutethimide86 or ketoco(cid:173)
`nazole and hydrocortisone.87 In one series, ketoconazole
`400 mg tid yielded a PSA decline from basel ine of over
`SOo/o in 62.5% (30 of 48) of the patients treated 12
`• Recently,
`the 17alpha-hydroxylase/C( 17,20)-lyase inhibitor abira(cid:173)
`terone acetate was shown to reduce testosterone levels
`in both noncastrate and castrate patients.88 17alpha(cid:173)
`hydroxylase-C 17,20-lyase (P450 17, CYP 17) is a critical
`enzyme in androgen biosynthesis.89
`Lower AR protein levels. Another approach is to
`target the receptor itself in addition to targeting the
`ligand. A number of strategies are under development.
`Preclinical strategies include double-stranded RNA inter(cid:173)
`ference,90 microinjection of anti-AR antibodies,91•92 and
`antisense oligonucleotides.93"95
`Ansamycin antibiotics are natural products that in(cid:173)
`duce the degradation of steroid hormone receptors and
`a number of mutated oncogenes by interfering with heat
`shock protein (Hsp) 90 binding and preventing protein re(cid:173)
`folding.96"98 These agents, now in clinical testing, reduce
`the level of AR and inhibit prostate cancer cell growth
`in vivo in a dose dependent manner.98 Other Hsp90 sub(cid:173)
`strates affected by this agent include HER2/neu, c-met, and
`phosphor-Akt, all of which are expressed at a higher
`
`Mechanism
`
`Adrenal androgen synthesis
`17.20 lyase inhibitors
`5-a reductase tnhibttor
`
`Hsp90 chaperone mhtbttors that tnduce
`protein degradatton
`Histone deactylase tnhibitors
`New antiandrogens based on crystal
`structure of the AR
`Antt·sense AR therapy
`Non-<:ross-reststant anttandrogens
`
`Coregulatory molecules
`
`Table 1. Strategtes Directed at Continued AR Signaltng
`
`Agent
`
`Effect(s) on AR Signaling
`
`Status
`
`Ketoconazole
`Abtraterone
`Finastende
`Otlutamtde
`Ansamycms-17AAG. DMAG
`
`Histone deacetylase inhibttors-SAHA
`
`Btcalutamtde aher flutamtde
`Nilutamtde aher bicalutamtde
`Mifepnstone
`
`1. 2. 3. 5
`
`2,4
`2
`
`2
`3
`
`4
`
`Phase II
`Phase II
`
`Phase II
`
`Phase II
`Preclinical
`
`Preclinical
`
`Phase II planned
`
`NOTE. Effects on androgen-receptor (AR) stgnaling mclude (1) changes in the level of ligand; (2) normal or increased levels of wild· type receptor; (3)
`activating mutations; (4) changes in coregulatory molecules; and (5) ligand-independent activation.
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`frequency in castration-resistant as opposed to castration(cid:173)
`na·ive
`tumors.
`Indeed,
`the AR-lowering effects of
`ansamycins may occur, in part, through degradation of
`Her-2 and/or Akt, both of which positively influence AR
`stability. In phase I trials we and others have demonstrated
`that the effects of 17 -allylamino-geldanamycin were both
`dose and schedule dependent, and that concentrations
`known to affect key client proteins associated with prostate
`cancer progression including the AR, HER-2 and Akt
`could be achieved safely.99"102
`It should also be possible to target AR directly for deg(cid:173)
`radation using novel antiandrogens, analogous to the ef(cid:173)
`fects of faslodex on estrogen receptors. The identification
`of such compounds may become more tractable due to re(cid:173)
`cent progress in solving the x-ray crystal structure of AR
`bound to bicalutamide (which does not alter AR protein
`levels) 103 and to dihydrotestosterone as well as through
`a better molecular tmderstanding of post-translational
`AR modifications that affect stability.
`Histone deacetylase inhibitors (HDAC!s) such as
`suberoylanilide hydroxamic acid (SAHA) and phenylbuty(cid:173)
`rate are now known to affect the binding of Hsp90 client
`proteins such as AR and HER-2
`to this molecular
`•104' 107 Both have anti- prostate cancer effects
`chaperone.92
`in vitro and in vivo. 105•108 These and other HDACis are
`currently under study against a range of solid tumors in(cid:173)
`cluding prostate cancer.109' 110 A phase II trial of SAHA in
`castration-resistant prostate cancer will begin shortly at the
`University of Michigan (Ann Arbor, MI) and Memorial
`Sloan-Kettering Cancer Institute (MSKCC; New York, NY).
`Targeting cooperative alterations i11 sig11nling path(cid:173)
`ways.
`In unselected patients in whom the receptor status
`of the twnor is unknown, inhibitors of the HER kinase
`signaling axis using monoclonal antibodies such as
`cetuximab directed at the EGFR, 111
`trastuzumab at
`HER-2,67 or 2C4 (Agus D et al, abstract submitted for
`publication) which blocks HER-2/HER-3 dimerization, 112
`or small-molecule inhibitors of RTKs such as gefitinib, 113
`or imatinib, or downstream pathways such as mTOR have
`shown limited activity as single agents. 11'1 For example, a
`phase II trial of 51 patients with castration-resistant disease
`treated with gefitinib, only one PSA response occurred and
`eight patients had stable disease, 113 whereas no PSA declines
`were observed using imatinib as monotherapy.20
`These findings led us and others to explore the ques(cid:173)
`tion whether other molecular alterations that might be
`present in the tumor would affect sensitivity to HER
`kinase in hibitors. Upwards of 80% of prostate cancers
`have red uced levels of PTEN, which leads to increased ac(cid:173)
`tivation of AKT and subsequent activation of a down(cid:173)
`stream protein important for cell growth, mTOR, which
`serves as a molecular sensor that regulates protein synthe(cid:173)
`sis. Increased PI3K can lead also lead to AR phosphoryla(cid:173)
`tion which results in a receptor that is more stable and
`
`8258
`
`with increased transactivation activity (Fig 3). In preclin(cid:173)
`ical models, we have shown that PTEN-deficient tumor
`cells do not require HER-kinase signaling for growth or
`survival. ll5 Cell lines that are deficient in PTEN are resis(cid:173)
`tant to treatment with EGFR inhibitors, whereas induction
`of PTEN expression or pharmacologic inhibition of PI3
`116
`kinase sensitizes tl1ese cells to EGFR inhibitors. 115
`'
`The impl ications of these findings are that constitutive
`activation of PI3kinase/ AKT signaling relieves the cells
`of dependence on kinase signaling, by activating down(cid:173)
`stream targets. Normal epithelial cells require RTK(cid:173)
`dependent MAPK signaling to regulate growth and
`apoptosis. In hibition of PI-3 kinase makes the cell depen(cid:173)
`dent on the normal default pathway, which when inhibited
`pharmacologically, induces death of the cell This concept
`is currently under study at MSKCC using a combination of
`gefitinib and RAD-001. An additional area of controversy
`is whether a single high dose of the signaling inhibitor
`might be superior to low-dose chronic administration,
`which is currently practiced in most settings. 117 The anti(cid:173)
`tumor effects of chronic low-dose therapy may produce
`cellular dormancy or nonproliferation, whereas higher(cid:173)
`dose therapy may result in an apoptotic response. This,
`too, is under clinica\ evaluation.
`The modest activity observed to date using signaling
`pathway-targeting agents as monotherapy, coupled with
`the recent approval of docetaxel as a standard first-line
`treatment has mandated a change in developmental strat(cid:173)
`egies. For many, Tailure to observe significant antitumor
`effects as a single agent does not necessarily mean that
`the drug will have no role in management. An alternative
`approach is to study these drugs in chemoresistant pa(cid:173)
`t~nts, or to study them in combination with docetaxel
`as first -line therapy. At MSKCC, we are nearing comple(cid:173)
`tion of a phase I trial of 17 -AAG and docetaxel, 118 based
`on a preclinical study showing synergistic antitumor ef(cid:173)
`fects against prostate cancer cell lines and xenografts. 119
`The combinat1on of docetaxel and imatinib is under eval(cid:173)
`uation as an lnterSPORE Prostate Cancer Trial,20 docetaxel
`and bevacizumab under evaluation by the Cancer and
`Leukemia Group B (CALGB 11570)} 20 and the combina(cid:173)
`tion of docetaxel plus RAD-001 by investigators at Dana(cid:173)
`Farber Cancer Institute (Boston, MA). Perhaps the greatest
`challenge is to design trials in which clinical responses can
`be correlated with the molecular phenotype of the tumor,
`either directly through tissue acquisition or indirectly
`through novel in1aging probes or serum biomarkers that
`read out molecular pathway status. Characterization of
`circulating tumor cells121 may provide the necessary infor(cid:173)
`mation. Recently, positron emission tomography imaging
`tracers specific for HER-2 122 and fluoro-DHT have been de(cid:173)
`veloped. 123 These may be useful both to determine tumors
`express a particular determinant, and to assess pharmacody(cid:173)
`namic effects.
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`Castration-Resistant Prostate Cancers
`
`More important is the finding that the specific bio(cid:173)
`logic determinants that conu·ibute to the growth of pros(cid:173)
`tate cancers change over time as a result of tumor, host,
`and treatment factors. This argues for a paradigm of early
`intervention, in theory, before the tumor has changed sig(cid:173)
`nificantly,9 and eliminating it once and for all. For patients
`wbo have not received androgen deprivation, tumor bur(cid:173)
`den alone as assessed by the level of PSA and the presence
`or absence of metastatic