Novel targets and approaches in advanced prostate cancer
`Boris A. Hadaschika, Richard D. Sowerya,b and Martin E. Gleavea,b
`
`Purpose of review
`The development of therapeutic resistance is the underlying
`cause for most cancer deaths. By understanding the
`molecular basis of resistance to androgen withdrawal and
`chemotherapy in prostate cancer, the rational design of
`targeted therapeutics is possible. We review new treatment
`options for men with advanced prostate cancer.
`Recent findings
`Although the taxanes currently represent the most active
`chemotherapeutic agents and standard of care for first-line
`treatment of metastatic hormone-refractory prostate
`cancer, most patients eventually progress because of
`intrinsic or acquired drug resistance. In recent years,
`increased knowledge of cancer progression and
`therapeutic resistance has identified many gene targets that
`regulate apoptosis, proliferation, and cell signalling. To
`date, numerous novel compounds have entered clinical
`trials as either single agents or in combination with cytotoxic
`chemotherapy.
`Summary
`Even though hormone-refractory prostate cancer is still
`incurable, it is not untreatable. As cancer cells are proficient
`at adapting to therapeutic stressors, a combination regimen
`with drugs that target crucial cellular networks like the
`apoptotic rheostat may be more promising than treatment
`with highly selective single-target agents. Recent findings
`are very hopeful, but challenges remain to demonstrate
`effective antitumour activity in phase III trials with survival as
`the principal endpoint.
`
`Keywords
`advanced prostate cancer, antisense oligonucleotides,
`novel agents, targeted therapy
`
`Curr Opin Urol 17:182–187. ß 2007 Lippincott Williams & Wilkins.
`
`aThe Prostate Centre at Vancouver General Hospital and bDepartment of Urologic
`Sciences, University of British Columbia, Vancouver, British Columbia, Canada
`
`Correspondence to Martin E. Gleave, MD, 2775 Laurel Street, Level 6, Vancouver,
`BC, V5Z 1M9, Canada
`Tel: +1 604 875 5006; fax: +1 604 875 5654; e-mail: m.gleave@ubc.ca
`
`Current Opinion in Urology 2007, 17:182–187
`
`Abbreviations
`
`ASO
`HRPC
`HSP27
`PSA
`
`antisense oligonucleotide
`hormone-refractory prostate cancer
`heat-shock protein 27
`prostate-specific antigen
`
`ß 2007 Lippincott Williams & Wilkins
`0963-0643
`
`182
`
`Introduction
`Treatment options for men with advanced prostate can-
`cer have changed dramatically over the last decade. With
`a 9% response rate, chemotherapy was once thought to
`play a clinically insignificant role in metastatic hormone-
`refractory prostate cancer (HRPC) [1]. This led many
`clinicians at that time to treat patients with HRPC with a
`degree of therapeutic nihilism. More recently, however, a
`role has emerged for systemic chemotherapy after the
`demonstration of a small but significant survival benefit
`for taxane-based chemotherapy in the two landmark
`studies TAX327 and SWOG9916 [2,3]. Since median
`survival for patients with HRPC is still only around
`18 months, current chemotherapy leaves plenty of room
`for further improvement.
`
`There is a substantial number of novel agents that have
`been developed that show promise in the management of
`patients with advanced prostate cancer, both alone and
`especially in a combination regimen. Whereas hormonal
`therapy as well as conventional chemo- and immunother-
`apy are reviewed elsewhere in this issue, novel agents
`like nucleotide-based targeted therapies, small-molecule
`inhibitors, antiangiogenic agents, novel cytotoxic thera-
`peutics, and calcitriol will be discussed here. Due to the
`rapid progress of this field it is beyond the scope of this
`review to cover all compounds under investigation.
`Therefore, we focus on several broad therapeutic
`categories and selected targets with significant biologic
`rationale and a reasonable likelihood of success.
`
`Nucleotide-based targeted therapy
`Therapeutic resistance results from multiple, stepwise
`changes in DNA structure and gene expression: a
`Darwinian interplay of genetic and epigenetic factors,
`ironically arising in part from selective pressures of treat-
`ment. This highly dynamic process cannot be attributed
`to singular events, involving instead cumulative genetic
`changes that facilitate escape from normal regulatory
`control of cell growth. In prostate cancer, changes in
`the hormonal environment precipitate a cascade of events
`in gene expression and signalling networks that provide a
`selective survival and growth advantage for subpopu-
`lations of tumour cells, thereby accelerating androgen-
`independent progression and rendering cells more resist-
`ant to chemotherapy [4,5]. Advances in tumour biology
`research have identified a plethora of attractive molecular
`targets for new drug discovery. The most promising
`candidates are those targets that become upregulated
`during and are causally related to cancer progression
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`JANSSEN EXHIBIT 2009
`Amerigen v. Janssen IPR2016-00286
`
`

`
`and therapeutic resistance. Moreover, the targets should
`be selectively overexpressed in tumour cells to minimize
`the side effects of knockdown. Although potential gene-
`target
`libraries developed by microarray technology
`are valuable, their information must be balanced by
`the inherent limitations of gene-array analyses. These
`include the inability to examine translational and post-
`translational regulatory mechanisms that
`impact
`the
`activity of various cellular proteins.
`
`Antisense oligonucleotides (ASOs) offer one approach to
`regulate genes involved in cancer progression, especially
`those that are not amenable to small-molecule or anti-
`body inhibition [6]. ASOs are single-stranded, chemically
`modified DNA-like molecules that are 17–22 nucleotides
`in length. They are designed to be complementary to a
`selected gene’s mRNA and thereby specifically inhibit
`expression of that gene. It is estimated that any sequence
`of at least 13 bases in RNA and 17 bases in DNA is
`represented only once within the human genome. Thus,
`the specificity implicit in the design of ASOs theoretically
`leads to decreased toxicity. ASO technology has quickly
`moved from preclinical models to testing in the clinic.
`Challenges remain to optimize tissue exposure, cellular
`uptake and demonstration of mechanism and antitumour
`activity. The lack of success of the first-generation
`ASOs G3139 and ISIS3521 in recent
`randomized
`phase III trials in lung cancer, leukaemia, myeloma,
`and melanoma has dampened enthusiasm for ASO thera-
`peutics [7,8,9,10,11]. However, next-generation ASO
`chemistry holds significant potential advantages for
`patient-friendly dosing and routes of administration,
`enhanced activity, and improved toxicity profile. A survey
`of a number of ASO drugs in clinical development against
`HRPC is given in Table 1 and three compounds are
`discussed below.
`
`The clusterin gene encodes a cytoprotective chaperone
`protein which has been implicated in a number of physio-
`logic processes [12]. During times of stress it is thought
`to act as a survival protein and stabilizes conformations of
`
`Novel targets and approaches Hadaschik et al. 183
`
`proteins, thereby inhibiting their precipitation and mem-
`brane damage [13]. In prostate cancer, increased clusterin
`levels are closely correlated with the Gleason score
`[14,15,16]. Although clusterin expression is low in most
`untreated hormone-naı¨ve tissues, levels increase signifi-
`cantly within weeks after neoadjuvant hormone therapy
`[17]. Preclinical studies have indicated that clusterin
`suppresses apoptotic cell death in response to andro-
`gen withdrawal, chemotherapy, and radiation [18–21].
`OGX-011 (OncoGeneX Technologies, Vancouver, British
`Columbia, Canada) is a second-generation ASO against
`the human clusterin mRNA. OGX-011 incorporates 20-O-
`methoxyethyl modifications to the four bases on either
`end of the 21-mer phosphorothioate backbone [22]. Such
`‘gapmer’ modifications maintain the improved tissue
`pharmacokinetic profile and relaxed dosing regimen of
`second-generation chemistry but preserve the high
`affinity for target mRNA and the recruitment of RNase
`H necessary for target degradation. Indeed, weekly
`OGX-011 was recently reported to potently suppress
`clusterin expression in prostate cancer tissues in com-
`bination with androgen-deprivation therapy [23]. This
`phase I trial had a unique design, where men with loca-
`lized prostate cancer were administered OGX-011 prior
`to radical prostatectomy, allowing for dose-dependent
`correlations between clusterin expression and drug
`concentrations in tissues. Thus, in addition to the usual
`parameters of
`toxicity the presurgery study design
`allowed determination of an optimal biologically effec-
`tive dose based on a >90% knockdown of clusterin. A
`second phase I trial combined increasing doses of OGX-
`011 with docetaxel in patients with metastatic breast
`cancer, nonsmall cell lung cancer, and HRPC and con-
`firmed the phase II dose for OGX-011 of 640 mg for use in
`a combination regimen with docetaxel [24]. Two random-
`ized phase II trials of OGX-011 in combination with both
`first- and second-line chemotherapy are now underway
`in HRPC patients (NCIC IND.165, CUOG P-06B).
`Moreover, a phase III registration trial of OGX-011 with
`mitoxantrone as second-line chemotherapy in men
`with docetaxel-resistant HRPC will begin by mid-2007.
`
`Table 1 Antisense therapeutics targeting hormone-refractory prostate cancer in late-stage preclinical or clinical development
`
`Target
`
`Compound
`
`Company
`
`Phase of development
`
`BCL2
`PKCa
`Clusterin
`RAF1
`PKA
`RNR (R1 and R2 component)
`Survivin
`XIAP
`HSP27
`eIF4E
`IGFBPs 2 and 5
`
`G3139 (Oblimersen, Genasense)
`ISIS3521 (Affinitak, Aprinocarsen)
`OGX-011
`ISIS5132
`GEM231
`GTI-2501, GTI-2040
`LY2181308, ISIS23722
`AEG35156, GEM640
`OGX-427
`LY2275796
`OGX-225
`
`Genta
`Lilly/Isis
`OncoGeneX
`Isis
`Hybridon/Idera
`Lorus
`Lilly/Isis
`Aegera
`OncoGeneX
`Lilly/Isis
`OncoGeneX
`
`II–III
`II–III
`II
`II
`II
`I–II
`I
`I
`I
`Preclinical–phase I
`Preclinical
`
`BCL2, B-cell lymphoma 2; eIF4E, eukaryotic translation-initiation factor 4E; HSP27, heat-shock protein 27; IGFBP, insulin-like growth factor-binding
`protein; PKA, protein kinase A; PKC, protein kinase C; RAF1, v-raf-1 murine leukaemia viral oncogene homologue 1; RNR, ribonucleotide reductase;
`XIAP, X-linked inhibitor of apoptosis protein.
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`
`184 Prostate cancer
`
`The rationale behind the second-line approach is that
`OGX-011 has been shown to reverse docetaxel resistance
`and enhance the antitumour activity of mitoxantrone
`and docetaxel in vitro and in vivo (R.D. Sowery and
`M.E. Gleave, unpublished data).
`
`Ribonucleotide reductase is an important enzyme for cell
`division and tumour growth that is required for the
`reductive conversion of ribonucleotides to deoxyribonu-
`cleotides, which is a crucial step in the synthesis and
`repair of DNA [25]. GTI-2040 (Lorus Therapeutics,
`Toronto, Ontario, Canada) is a first-generation phosphor-
`othioate antisense molecule that inhibits the expression
`of the R2 subunit of ribonucleotide reductase [26]. In a
`dose-finding phase I study four out of 36 patients with
`advanced tumours had a stabilization of their disease [27].
`Preliminary results of a following phase II trial of GTI-
`2040 in combination with docetaxel and prednisone in
`patients with chemotherapy-naı¨ve HRPC have recently
`been reported, with nine patients out of 22 having a
`response in prostate-specific antigen (PSA) [28].
`
`Heat-shock protein 27 (HSP27) is one of the most
`strongly induced chaperones at times of cellular stress.
`Similar to clusterin, HSP27 binds to a wide variety of
`client proteins and prevents the aggregation of damaged
`proteins [29]. HSP27 is abundantly expressed in malig-
`nant cells and participates in conferring chemoresistance
`[30,31]. Accumulating evidence links rising HSP27 levels
`with HRPC [32–36]. HSP27 may eventually serve as a
`therapeutic hyper-node, a target situated at the centre
`of many pathways involved in regulating the response of
`a cell to treatment-induced stress. Thus, HSP27 is a
`rational target for drug development as its inhibition
`would silence multiple survival pathways at once. Several
`phase I/II clinical trials using a second-generation ASO
`against HSP27 (OGX-427; OncoGeneX Technologies)
`are set to begin in 2007.
`
`Small-molecule inhibitors
`Small-molecule inhibitors herald considerable promise as
`they can specifically block cellular signalling pathways
`involved in growth and apoptosis. Endothelin-1 and its
`ET-A receptor have been demonstrated to generate
`multiple effects on cellular physiology and paracrine
`signalling in prostate cancer. Endothelin-1 is implicated
`in the regulation of cell growth and higher levels correlate
`with progressive disease [37]. Endothelin-1 has also been
`shown to be involved in osteoblastic activity and may
`influence the development of bony metastasis and bone-
`related pain in prostate cancer [38]. Atrasentan (Xinlay,
`Abbott Labs, Abbott Park, Illinois, USA) is a selective
`ET-A receptor antagonist under investigation for use in
`HRPC. In a phase II trial, patients with metastatic HRPC
`treated with an oral 10 mg dose of atrasentan had a trend
`toward prolongation in median time to progression
`
`compared with placebo (183 compared with 137 days,
`P¼ 0.13) [39]. In addition, a statistically significant delay
`in median time to PSA progression was demonstrated
`(155 days for atrasentan compared with 71 days for
`placebo, P¼ 0.002). In the following phase III trial,
`809 men with metastatic prostate cancer were random-
`ized to atrasentan or placebo [40]. However, this study
`was closed early on review of the unexpectedly large
`number of early events that suggested the trial results
`would not be different from control outcomes. The
`significance of the radiographic markers of progression
`used in the study without clinical symptoms remains
`controversial. Although the primary endpoint, time to
`progression, was not statistically different
`from the
`placebo group,
`secondary endpoints demonstrated
`clinical activity. These included improvement in quality
`of life and pain scores, and reductions in the rise of
`laboratory markers, including alkaline phosphatase and
`PSA. A meta-analysis of pooled phase II and III data was
`able to show a significant increase in time to progression,
`as well as a prolongation in the pain-free duration by
`3 months for patients taking atrasentan [41]. In all trials,
`atrasentan was well tolerated with mild adverse events
`such as headache, rhinitis, and peripheral oedema. These
`data suggest biological activity and identify the endothe-
`lin axis as a potential target in advanced prostate cancer.
`Atrasentan has not yet obtained US Food and Drug
`Administration approval because of a failure to demon-
`strate a perceived clinically relevant benefit. A phase III
`study of docetaxel and prednisone with or without
`atrasentan is currently recruiting HRPC patients with
`bone metastases (SWOG-S0421).
`
`Imatinib (Gleevec; Novartis Pharmaceuticals, East
`Hanover, New Jersey, USA) is an agent that inhibits
`the tyrosine kinase activity of the platelet-derived growth
`factor receptor, which is abundant in metastatic prostate
`cancer and has therefore been evaluated in the treatment
`]. A phase II trial
`in
`of patients with HRPC [42,43
`men with biochemical relapse of prostate cancer after
`definitive local therapy was recently conducted [44].
`Unfortunately, a lack of effect on PSA-doubling time,
`and pronounced toxicity at the dose given in the trial
`(400 mg orally, twice daily) led to early closure of this
`trial. The role of imatinib in combination therapy, how-
`ever, may be promising, and phase II clinical trials
`combining imatinib and docetaxel
`in the metastatic
`setting are underway (NCT00080678, NCT00251225).
`
`Angiogenesis inhibitors
`Angiogenesis is a complex and tightly regulated process
`that is necessary for tumour growth and metastasis [45].
`Vascular endothelial growth factor is a key mediator in
`promoting tumour angiogenesis
`[46]. Bevacizumab
`(Avastin; Genentech, San Francisco, California, USA)
`is a humanized monoclonal antibody that neutralizes
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

`
`activity of vascular endothelial growth factor and has
`shown promise in HRPC. The role of bevacizumab in
`combination with estramustine and docetaxel was inves-
`tigated in the CALGB 90006 trial in 79 patients with
`metastatic HRPC [47]. Early results showed that 53%
`of patients had a partial response and 65% had a greater
`than 50% decrease in PSA. The regimen was fairly well
`tolerated, although there was some increase in thrombo-
`sis. When compared with another CALGB triplet trial in
`which carboplatin was added to estramustine and doc-
`etaxel (CALGB 99813) [48], the use of bevacizumab
`resulted in a posttherapy PSA decline in 81% of patients
`compared with 68% of the patients treated with the
`carboplatin regimen, and an overall median survival of
`21 months compared with 19 months, respectively. These
`results are encouraging and safety would be enhanced
`with the elimination of estramustine, especially in light of
`the evolving data suggesting that estramustine adds little
`to the overall survival of patients. Another ongoing phase
`II trial as first-line treatment in combination with doc-
`etaxel, prednisone, and thalidomide in metastatic HRPC
`patients showed until now no thrombosis and a high
`durable 86% response in PSA (NCT00091364) [49]. A
`phase III trial comparing docetaxel and prednisone with
`or without bevacizumab in men with metastatic HRPC is
`currently enrolling patients (CALGB 90401).
`
`Thalidomide and its analogues are additional agents with
`antiangiogenic properties under investigation in HRPC.
`Thalidomide has multiple mechanisms of action includ-
`ing immunomodulatory effects on the tumour microen-
`vironment [50]. As single agent thalidomide demon-
`strated a greater then 50% PSA response rate of only
`18% of patients [51]. In combination with docetaxel
`however, the median time to progression of chemother-
`apy-naı¨ve metastatic HRPC patients was delayed notably
`by adding thalidomide (5.9 compared with 3.7 months,
`P¼ 0.32) [52]. Moreover, as a second-line regimen a
`triplet combination of thalidomide, paclitaxel, and estra-
`mustine warrants further investigation, due to a recently
`].
`reported PSA response rate of 76% [53
`
`Novel cytotoxic therapeutics
`Satraplatin (Spectrum Pharmaceuticals, Irvine, Califor-
`nia, USA/GPC Biotech, Martinsried, Germany) is an
`orally bioavailable third-generation platinum-based com-
`pound [54]. A first phase III study of satraplatin with or
`without prednisone as first-line chemotherapy in HRPC
`patients was closed prematurely because of sponsorship
`difficulties. An ad-hoc analysis with only 50 of the anticip-
`ated 380 patients enrolled and randomized reported a
`statistically significant increase in progression-free survi-
`val with satraplatin and prednisone compared to predni-
`sone alone (5.2 compared with 2.5 months, P¼ 0.023)
`[55]. Another phase III
`registration trial
`(SPARC;
`Satraplatin and Prednisone against Refractory Cancer)
`
`Novel targets and approaches Hadaschik et al. 185
`
`is now evaluating satraplatin plus prednisone as a second-
`line therapy in patients with HRPC [56]. At the time of
`submission of this review, GPC Biotech reported a sig-
`nificant improvement in median progression-free survival
`of these second-line patients (11 weeks in the satraplatin
`plus prednisone arm compared with 9.7 weeks in the
`placebo plus prednisone arm, P < 0.00001). Nonetheless,
`the more important survival data will not be available
`until late 2007.
`
`Epothilones are a new class of tubulin-polymerizing
`agents that suppress microtubule dynamics similar to
`the taxanes, but are less susceptible to P-glycoprotein-
`induced drug efflux [57]. Phase II trials of BMS-247550
`(Ixabepilone; Bristol-Myers Squibb, New York, USA) in
`chemotherapy-naı¨ve HRPC have shown PSA responses
`in single-agent therapy (33–48%) and in combination
`with estramustine (69%) [58,59]. Since BMS-247550
`showed potent cytotoxic effects in phase I studies on
`advanced tumours in patients previously treated with
`taxanes, there might be a possible role in second-line
`therapy [60]. To evaluate this hypothesis in HRPC
`there is currently a phase I/II combination trial with
`BMS-247550, mitoxantrone, and prednisone underway
`(NCT00331344). However,
`results of a second-line
`therapy study of taxane-resistant HRPC with BMS-
`247550 as a single agent showed only modest activity
`[61].
`
`Calcitriol
`Calcitriol, the principal active metabolite of vitamin D,
`has been shown to enhance many commonly used che-
`motherapeutic agents, producing antitumour activity in
`several prostate cancer models [62]. DN-101 (Asentar;
`Novacea, San Francisco, California, USA) is a proprietary
`high-dose formulation of calcitriol which has entered
`phase III trials. A previous phase II/III trial of 250
`metastatic HRPC patients (ASCENT; Androgen inde-
`pendent prostate cancer Study of Calcitriol Enhancing
`Taxotere) showed a trend that favoured DN-101 over
`placebo when used in combination with docetaxel but did
`not reach statistical significance (63% compared with
`52% PSA response rate, P¼ 0.073). The estimated sur-
`vival for patients treated with DN-101 and docetaxel
`was 23.5 months compared with 16.4 months for patients
`treated with placebo and docetaxel [63]. Since this study
`was underpowered to detect a significant difference in
`survival, a second phase III study (ASCENT-2) investi-
`gating DN-101 in combination with docetaxel compared
`with docetaxel and prednisone is currently enrolling
`patients, with a target enrolment of 900 patients.
`
`Conclusion
`Currently, the combination of docetaxel every 3 weeks
`plus low-dose prednisone represents the standard of care
`for patients with metastatic HRPC. This chemotherapy
`
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

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`186 Prostate cancer
`
`can provide durable palliation and a modest but real
`improvement in overall survival. Nonetheless, with a
`median survival of 18–20 months rationally designed
`therapeutic approaches continue to be needed urgently.
`The development of novel therapeutics, some of which
`were discussed in this review, is essential to provide
`clinicians multiple avenues through which prostate can-
`cer can be treated more effectively. The biggest impact
`on mortality is likely to come from a multimodal com-
`bination regimen. To provide patients with the most
`appropriate treatment strategy, an integrated multidisci-
`plinary approach with urologists and oncologists working
`closely together must be further encouraged. However, it
`is imperative that we as urologists are involved in the
`assessment and implementation of these novel thera-
`peutics as we have a close interaction with the patient
`from early-stage, localized disease to HRPC. With several
`promising agents on the horizon, well-designed clinical
`trials are needed to establish the role of these agents in
`treatment regimens. The clinical experience to date
`should still be considered part of the beginning of the
`era of targeted treatment for prostate cancer.
`
`Acknowledgements
`M.E.G.
`is founder and Chief Scientific Officer of OncoGeneX
`Technologies, Vancouver, British Columbia, Canada. B.A.H. is funded
`by the German Research Foundation (DFG). R.D.S. is funded by the
`AFUD/AUAER Research Scholar Program.
`
`References and recommended reading
`Papers of particular interest, published within the annual period of review, have
`been highlighted as:
`
`of special interest
` of outstanding interest
`Additional references related to this topic can also be found in the Current
`World Literature section in this issue (pp. 208–209).
`
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`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`
`

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