Progress of Molecular Targeted Therapies For Prostatecancers

Biochimica et Biophysica Acta 1825 (2012) 140–152
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Biochimica et Biophysica Acta

journal homepage: www.elsevier.com/locate/bbacan
Review
Progress of molecular targeted therapies for prostate cancers

Weihua Fu a, b, Elena Madan a, Marla Yee a, Hongtao Zhang a,⁎
a
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
b
Institute of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
a r t i c l e i n f o a b s t r a c t
Article history: Prostate cancer remains the most commonly diagnosed malignancy and the second leading cause of cancer-
Received 5 October 2011 related deaths in men in the United States. The current standard of care consists of prostatectomy and radiation
Received in revised form 18 November 2011 therapy, which may often be supplemented with hormonal therapies. Recurrence is common, and many develop
Accepted 19 November 2011
metastatic prostate cancer for which chemotherapy is only moderately effective. It is clear that novel therapies
Available online 29 November 2011
are needed for the treatment of the malignant forms of prostate cancer that recur after initial therapies, such
Keywords:
as hormone refractory (HRPC) or castration resistant prostate cancer (CRPC). With advances in understanding
Prostate cancer of the molecular mechanisms of cancer, we have witnessed unprecedented progress in developing new forms
EGFR of targeted therapy. Several targeted therapeutic agents have been developed and clinically used for the treat-
IGF-1R ment of solid tumors such as breast cancer, non-small cell lung cancer, and renal cancer. Some of these reagents
VEGFR modulate growth factors and/or their receptors, which are abundant in cancer cells. Other reagents target the
Androgen downstream signal transduction, survival pathways, and angiogenesis pathways that are abnormally activated
Hormone resistant in transformed cells or metastatic tumors. We will review current developments in this field, focusing specifically
on treatments that can be applied to prostate cancers. Finally we will describe aspects of the future direction of
the field with respect to discovering biomarkers to aid in identifying responsive prostate cancer patients.
© 2011 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
2. Inhibitors of androgens and androgen receptor signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
3. Growth factors and growth factor receptors inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
3.1. ErbB inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
3.1.1. Monoclonal antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
3.1.2. Small tyrosine kinase inhibitors (TKI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
3.2. Inhibitors for insulin-like growth factor (IGF) receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
3.3. Platelet-derived growth factor inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
4. Anti-angiogenesis targeting therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
5. Other molecular targets for prostate cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
5.1. Prostate-specific membrane antigen (PSMA) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
5.2. Heat shock protein (Hsp) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
5.3. mTOR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
5.4. Histone deacetylase (HDAC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
6. New targets and biomarkers for prostate cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
6.1. The F77 antigen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
6.2. Serine peptidase inhibitor Kazal type 1 (SPINK1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
6.3. Survivin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
⁎ Corresponding author at: 252 John Morgan Building, 3620 Hamilton Walk, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA 19104-6082, USA. Tel.: +1 215 573 9256; fax: +1 215 898 2401.
E-mail address: [email protected] (H. Zhang).
0304-419X/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.bbcan.2011.11.003
W. Fu et al. / Biochimica et Biophysica Acta 1825 (2012) 140–152 141
1. Introduction cells or metastatic tumors. We review current developments in this

field with the focus on treatments that can be applied to prostate can-
Currently, prostate cancer is the most commonly diagnosed malig- cers (Fig. 2). These targeted therapies in development are for HRPC
nancy and the second leading cause of cancer-related deaths in men and CRPC, which are more malignant than localized lesions that can
in the United States. Based on 2010 estimates, over 200,000 new be effectively managed by surgery or radiation therapy.
cases of prostate cancer will be diagnosed and more than 30,000
men will die from this disease annually. The mortality due to prostate 2. Inhibitors of androgens and androgen receptor signaling
cancer has steadily declined for a decade, with a 4% decrease per year
between 1999 and 2003, which among several factors, may be attrib- Androgens play a major role in the development, growth, and
utable to earlier detection and improved treatment of cancer. maintenance of the prostate. As with normal prostate development,
Treatment of localized prostate cancer usually includes prostatec- primary prostate cancers are largely dependent on androgens for
tomy and radiation therapy, sometimes supplemented with hormon- growth and survival [6]. Androgens exert their effects via the intracel-
al therapies (either pharmacological anti-androgens and luteinizing lular androgen receptor (AR), a ligand-dependent transcriptional ac-
hormone–releasing hormone (LH–RH) agonists that prevent testos- tivator. In fact, androgens and AR represent the very first class of
terone production, or orchiectomy, the surgical removal of testicles) unique targets for therapies tailored for prostate cancers [7]. Despite
(Fig. 1). Recurrence, usually defined by the observation of surging the standard hormone therapy, the majority of androgen-
prostate specific antigen (PSA) levels, occurs in about 15% patients independent or hormone refractory prostate cancers still express AR
within 5 years after prostatectomy and in about 40% patients within [8], and intratumoral androgen levels remain high along with persis-
10 years [1]. Following recurrence, more than 70% of patients can tent AR activation in CRPC [9]. As a result, novel therapies targeting
still expect to survive for more than 10 years [2]. androgen and AR are needed for prostate cancer patients who suffer
In general, localized prostate cancer patients with intermediate or relapse after androgen ablation and anti-androgen therapies.
high risk (e.g. higher pathological CAPRA (Cancer of Prostate Risk As- MDV3100 (Fig. 3) is an oral androgen receptor antagonist in de-
sessment) scores have higher mortality rate even after prostatectomy, velopment for the treatment of early-stage and advanced prostate
radiation or hormone therapy [3]. Although only a small percentage of cancer [10]. It directly inhibits AR by binding the receptor irreversibly.
patients who undergo radical prostatectomy are expected to develop This interaction impairs AR nuclear translocation, DNA binding, and
metastasis (b3% in 5 years) [4], the mortality rate for metastatic pros- recruitment of co-activators [11]. Preclinical studies have demon-
tate cancer is extremely high. Current treatment options for metastat- strated that MDV3100 binds to the AR receptor with substantially
ic prostate cancer are chemotherapies, but metastatic prostate higher affinity compared to Bicalutamide (a clinical AR modulator),
patients can only expect to have a median survival of 12–15 months resulting in more complete suppression of the androgen receptor
even with chemotherapies [5]. Thus, novel therapies are on demand pathway [12]. In a Phase I/II study, MDV3100 showed anti-tumor ac-
for the treatment of the malignant forms of prostate cancer that tivity in patients with metastatic CRPC [13]. 56% of 140 patients in the
recur after initial therapies, including hormone refractory (HRPC) or trial demonstrated decreases in serum PSA of 50% or more. 61 out of
castration resistant prostate cancer (CRPC). 109 patients had stabilized bone disease after treatment. Currently,
Several targeted therapeutic agents have been developed and clin- MDV3100 is in Phase 3 trials to evaluate activity in advanced prostate
ically used for the treatment of solid tumors such as breast cancer, cancer patients with or without chemotherapy history [10].
non-small cell lung cancer, and renal cancer. These reagents modulate Abiraterone (Fig. 3) inhibits 17-α-hydroxylase/C17-20-lyase
growth factors and their receptors that are abundant in cancer cells, (CYP17), an enzyme expressed in testicular, adrenal, and prostate
or the downstream signal transduction, survival pathways, and an- tumor tissues that catalyzes the sequential reactions of the conversion
giogenesis pathways that are abnormally activated in transformed of pregnenolone and progesterone to their 17-α-hydroxy derivatives
Fig. 1. Prostate cancer's progression and treatment. Prostate cancer patients with high risk are recommended to have surgery, radiation, and/or hormone therapies. Although these
treatments are efficient in general, some patients have recurrent diseases, at which stage current treatment options, mostly chemotherapy, are limited in terms of clinical outcome.
It is hoped that development in targeted therapies can provide more options for the recurrent and metastatic prostate cancers.
142 W. Fu et al. / Biochimica et Biophysica Acta 1825 (2012) 140–152
Fig. 2. Molecular targets and designed intervention in targeted therapies for prostate cancer. In addition to androgen/androgen receptor (AR) pathways, many growth receptors
(EGFR/HER2, IGFR, PDGFR, and VEGFR), and their downstream molecules, have been explored as the targets to block growth signaling of tumor cells or the angiogenesis process
that provides nutrients to cancer cells. Antibodies to some prostate cancer specific antigens (e.g. PSMA and the F77 antigen) have also been developed.
and the subsequent formation of dehydroepiandrosterone (DHEA) Biotechnology) in combination with prednisone for the treatment
and androstenedione [14]. As DHEA and androstenedione are andro- of metastatic CRPC in men who have received prior docetaxel
gens and precursors of testosterone, inhibition of CYP17 activity by chemotherapy.
abiraterone decreases circulating levels of testosterone. After i.p. in-
jection of 0.5 mmol/kg abiraterone acetate (the pro-drug), the plasma
3. Growth factors and growth factor receptors inhibitors
concentration of abiraterone reached more than 1 μM and remained at
about 0.4 μM after 24 h [15]. Potter et al. reported that the inhibitory
Multiple growth factors and growth factor receptors have been
activity (e.g. IC50) of abiraterone for hydroxylase and lyase activity
identified as critical regulatory proteins in signaling networks that
were both at 3–4 nM [16]. The IC50 is within the range of in vivo abir-
are common to many cancer cells. Novel agents currently in clinical
aterone pharmacological concentration and therefore sufficient to ob-
treatment are designed to targeted specific protein families such as
tain clinical activity.
the epidermal growth factor receptor (EGFR) family and the
Activity of abiraterone acetate as a single agent was apparent even
platelet-derived growth factor receptor (PDGFR) family.
in Phase I trials, resulting in significant decreases of serum PSA levels
(50% or more) in 55% CRPC patients with or without prior ketocona-
zole therapy [17], and in 57% of chemotherapy free but hormone ther- 3.1. ErbB inhibitors
apy resistant prostate cancer patients [18]. Ketoconazole was initially
developed as an antimycotic agent but later found to be a nonspecific The human EGFR family (HER/ErbB) receptors have been recog-
inhibitor of steroidogenic enzymes. This study has suggested that nized as a very important family of receptor tyrosine kinases, which
abiraterone is superior to ketoconazole in clinically activity. In Phase are frequently reported to have significant impacts on the cellular sig-
II trials, when combined with low-dose glucocorticoids such as pred- naling networks within many different solid tumors, including breast
nisone, abiraterone acetate caused significant PSA drop (50% or more) cancer, colon cancer, lung cancer and prostate cancer [23]. This family
in 36% patients with progressive metastatic CRPC who failed comprises four closely related receptors: EGFR (HER-1/ErbB1), HER2
docetaxel-based chemotherapy [19], and in 67% of chemotherapy (Neu/ErbB2), HER3 (ErbB3), and HER4 (ErbB4). These transmem-
free CRPC patients [20]. In Phase III studies that involved a total of brane glycoproteins contain an extracellular ligand binding domain
1195 patients, abiraterone acetate plus prednisone (797 patients), and an intracellular receptor tyrosine kinase (RTK) domain. It has
compared to placebo plus prednisone (398 patients), prolonged over- been reported that EGFR is overexpressed in 18–37% prostate cancers
all survival among patients with metastatic CRPC who had disease [24–26]. Recently, Neto et al. also reported a significant direct correla-
progression after docetaxel-based chemotherapy [21]. The median tion of HER2/neu over-expression with the risk of death and recur-
overall survival was 14.8 months in the abiraterone acetate plus pred- rence in prostate cancer [27]. HER2 is also associated with the
nisone group vs 10.9 months in the control groups [22]. As a result of activation of androgen receptor and androgen-induced PSA expres-
the successful phase III trial, the US Food and Drug Administration sion [28]. These studies indicate that targeted agents for ErbB recep-
(FDA) has recently approved abiraterone acetate (Zytiga, Cougar tors, including monoclonal antibodies and small molecule tyrosine
Fig. 3. Structure of small molecule agents in targeted therapies for prostate cancer.
kinase inhibitors, can potentially provide treatment options for pros- cells. Trastuzumab is the first FDA approved therapeutic drug targeting
tate cancer. ErbB receptors to treat metastatic breast and stomach cancer. As HER2
overexpression has been observed in prostate cancer patients, ranging
3.1.1. Monoclonal antibodies from 25% of untreated primary tumors to 78% of castrate metastatic tu-
Cetuximab (C225/Erbitux), a monoclonal antibody initially ap- mors, it is believed Trastuzumab could be effective to treat prostate can-
proved by the Food and Drug Administration (FDA) for colorectal cancer [35]. An early study indicated that Trastuzumab might have activity
cer in 2004, directly binds to the extracellular domain of EGFR and on androgen-dependent but not androgen-independent tumor, and
blocks ligand (EGF) binding. In preclinical research, Karashima et al. combination of Trastuzumab with Paclitaxel leads to inhibition of both
reported that Cetuximab had significant anti-tumor effect in a murine type of tumors in xenografted animal models [36].
prostate cancer model, interfering with cell proliferation/angiogenesis Docetaxel may induce expression of HER2 in a human prostate
and enhancing apoptosis [29]. Cetuximab is effective for some but not cancer model, especially in hormone independent tumor cells [37],
all prostate cancer model systems. For example, Cetuximab caused a suggesting a mechanism for acquired resistance to chemotherapies.
significant growth inhibition by inducing cell apoptosis in Du145 Thus, HER2 targeted therapies may provide an approach to overcome
cells, but not in PC3 cells [30]. The activity of Cetuximab is associated the chemo-resistance. However, it has to be investigated if the doce-
with its effective inhibition of phosphorylation of EGFR at sites Tyr- taxel effect is only limited to prostate cancer. Nevertheless, it seems
845 and Tyr-1173 in Du145 but not in PC3 cells. This result might plausible that a docetaxel/trastuzumab combination may become an
be related to higher EGFR expression level in Du145 than PC3. A effective therapeutic approach for hormone refractory prostate can-
fully humanized EGFR mAb, Panitumumab (Vectibix), demonstrates cer. In fact, a phase I study has already demonstrated the safety of ad-
higher affinity to EGFR than Cetuximab does and shows significant ministration of docetaxel, estramustine, and trastuzumab in patients
growth inhibition of PC3 cells in vitro [31]. In a phase I clinical with metastatic androgen-independent prostate cancer [38].
study, 3 out of 21 prostate cancer patients showed stable disease
after Panitumumab treatment [32]. 3.1.2. Small tyrosine kinase inhibitors (TKI)
Wagener et al. showed that Cetuximab increased the treatment ef- A class of tyrosine kinase inhibitors has been developed to damp-
fects of radiation for prostate cancer in vitro and in vivo [33]. In a en the activity of ErbB receptors [39]. Clinical development of small
phase Ib/IIa trial, Cetuximab in combination with doxorubicin were molecule inhibitors of ErbB receptors, including gifitinib (IRESSA/
administered weekly for 6 times in patients with metastatic CRPC. ZD1839), erlotinib, and lapatinib (Fig. 3), has also been explored in
The median survival of patients under the combination therapy was the treatment of patients with prostate cancer. Bonaccorsi et al.
longer compared to historical control groups, although minimal PSA reported that gefitinib, which affects EGF-stimulated activation of
declines were observed [34]. PI3K/Akt pathway, suppressed invasion and proliferation of
Trastuzumab (Herceptin) is a recombinant humanized monoclonal androgen-independent prostate cancer cell lines PC3 and DU145
antibody that targets HER2, another member of the ErbB family thought [40]. Vicentini and coworkers showed that gefitinib caused cell cycle
to play a role in regulating cell proliferation and differentiation of cancer arrest and initiation of apoptosis in both androgen-sensitive cells
(ND1, LNCaP and ALVA-31) and androgen-independent cells [41]. Ef- that regulate and propagate IGF activity in various tissues [57]. Epide-
fects of gefitinib on LNCaP, PC3 and DU145 cell lines was investigated miological studies indicate that circulating IGF-I levels are positively
by Sgambato [42], who found that the anti-proliferative effect of gefi- correlated with increased risk of prostate cancer [58]. Cardillo et al.
tinib was mainly cytostatic and associated with a block in the G0/G1 analyzed 43 paraffin-embeded prostate cancer samples and found ki-
phase of the cell cycle. In DU145 cells, this block was associated netic changing of IGF system as prostate tissue progressed from a nor-
with an increase in expression of the CDK inhibitor p27kip1 that mal to malignant state, suggesting that differential expression of IGF
was not evident in the LNCaP and PC3 cells. may be associated with the malignancy of tumor phenotype [59].
Little evidence exists suggesting that gefitinib as a single-agent Given the substantial evidence that the IGF pathway plays a role in
has activity in CRPC. Although phase I studies reported improved prostate cancer, interference with this pathway appears to be a po-
pain control, an open-label, single-arm phase II trial of gefitinib in pa- tential approach for targeted therapies. Cixutumumab (IMC-A12),
tients with advanced CRPC showed that single-agent gefitinib had no which is currently in Phase II for prostate cancer [60], is a monoclonal
clinical efficacy assessed by PSA response rate [43]. This outcome is in antibody directed against IGF-1R. The antibody selectively binds to
agreement with results from two other phase II trials with HRPC pa- the membrane-bound IGF-I receptor, thereby down-regulating the
tients, one involving 40 patients who had not received prior chemo- PI3K/AKT survival pathway. In human tumor xenograft models,
therapy and the other involving 58 patients in the US [44, 45]. Both blocking of IGF-IR by IMC-A12 resulted in rapid and profound growth
trials showed no response to gefitinib treatments by monitoring PSA inhibition of cancers of the breast, lung, colon and pancreas [61]. Wu
levels. Another EGFR TKI, Erlotinib, shows moderate activity in et al. found that IMC-A12 was effective in both androgen-dependent
CRPC, leading to reduction of PSA levels in some patients [46] or (AD) and androgen-independent (AI) variant human prostate cancer
delay of PSA rise in others [47]. Lapatinib, an inhibitor for both EGFR xenografts [62]. Interestingly, IMC-A12 treatment induces both G1 ar-
and HER2, also showed single agent activity in CRPC [48]. Unexpect- rest and apoptosis in the AD tumors, whereas G2-M arrest was the
edly, lapatinib showed no activity in early stage prostate cancer pa- predominant cell cycle effect seen in AI tumors. These studies indicate
tients [49, 50]. that IGF-IR may play distinct roles in the growth and maintenance of
The conflicting results of TKIs in prostate cancer might be traced to AD and AI prostate cancers [56].
the lack of sensitive forms of kinases in the patient population. In As IGF-IR signaling is known to mediate resistance to cytotoxic
non-small cell lung cancer (NSCLC), the response rate to EGFR tyro- chemotherapy and radiation, targeted disruption of the IGF-IR axis
sine kinase inhibitors was significantly increased when treatment combined with conventional cancer treatments may be more effec-
was administered to patients with tumors containing somatic EGFR tive in the inhibition of tumor growth. This idea is supported by the
mutations [51]. It is worth noting that in all the prostate cancer trials finding that IMC-A12 enhances the therapeutic effect of docetaxel
as discussed above, patients were not examined for inhibitor sensitive on advanced prostate cancer in animal models [62].
EGFR mutations. One study examined prostate cancer patients who Alternatively, IGF signaling can be intercepted by using kinase in-
were unresponsive to gefitinib based therapy and revealed no such hibitors targeting IGFRs. Unfortunately, the tyrosine kinase domain of
sensitizing mutations in any patients [52]. In addition, in vitro studies IGF-IR and the Insulin Receptor (IR) are highly conserved, with a ho-
indicate that a low EGFR/HER2 ratio and PTEN absence are also main mology of 84% [63]. This poses a major challenge to identifying IGF-IR
factors responsible for resistance to erlotinib and gefitinib [53]. De- specific therapeutic inhibitors, as cross-activity against IR would carry
spite the lack of effectiveness of gefitinib as a monotherapy in HRPC, a great risk of diabetogenesis. INSM-18 (nordihydroguaiaretic acid,
combination of gefitinib with radio- or chemo-therapies have demon- NDGA, Fig. 3) is a TKI that selectively inhibits IGF-1R and currently
strated some positive results. Joensuu et al. reported that the combi- in phase II trial for prostate cancer [64]. In an animal model of pros-
nation of gefitinib and radiation has promising activity against tate cancer, INSM-18 demonstrated anti-tumor activity but had no ef-
nonmetastatic prostate cancer in a phase I/II trial [54]. fect on blood glucose levels, indicating that it has minimal off-target
Although the EGFR/HER2 signaling pathways are attractive targets activity for IR. Interestingly, INSM-18 can also inhibit HER2, another
for prostate cancer therapy, there remain several issues that need to kinase that plays a role in prostate cancer. INSM-18 has an IC50 of
be resolved before prostate cancer patients can fully benefit from in- 31 μM for the inhibition of IGF-1 induced autophosphorylation of
hibitors for these targets. The first question relates to the ErbB recep- IGF-IR, and its activity to inhibit ligand-independent tyrosine phos-
tor expression in prostate cancer. It has become clear that tumors phorylation of HER2 is determined to be 15 μM [65]. This characteris-
need to over-express EGFR or HER2 receptors to be effectively tar- tic of INSM-18 renders it more appealing as a therapy for prostate
geted by these inhibitors. However, clinical tests for HER2 and espe- cancer.
cially EGFR (including identification of drug sensitive mutants) need
to be developed to efficiently identify patients for therapies. Secondly,
recent understanding of the effect of downstream molecules, such as 3.3. Platelet-derived growth factor inhibitors
the k-ras mutation, on the resistance to EGFR targeted therapies has
to be incorporated into the screening of prostate patients. This will Platelet-derived growth factors (PDGFs) contain four members of
help to identify patients that are less likely to be benefited from the different polypeptides: PDGF-A, PDGF-B, PDGF-C and PDGF-D [66].
treatment. Meanwhile, simultaneously targeting ErbB receptors and PDGFs can form homodimers or heterodimers via disulfide bonds,
downstream molecules, such as Src [55], might provide an option five of which have so far been described: PDGF-AA, PDGF-AB, PDGF-
for patients who are resistant to the antibody-based therapies. BB, PDGF-CC and PDGF-DD. These factors exert their cellular effects
through receptors PDGFR-α and PDGFR-β. PDGFR-α can be activated
3.2. Inhibitors for insulin-like growth factor (IGF) receptors by PDGF-AA, PDGF-AB, PDGF-BB and PDGF-CC, whilst PDGFR-β is
only bound and activated by PDGF-BB and PDGF-DD. There is an in-
The insulin-like-growth factor (IGF)–IGF receptor (IGF-R) signal- creasing body of evidence implicating PDGFs in the development of
ing pathway plays a crucial role in the cell growth and development solid tumors. Govindarajan demonstrated that SV7tert cells overex-
of both normal and tumor cells [56]. From an evolutionary standpoint, pressing PDGF-BB induce tumor formation when transplanted into
this highly conserved pathway arose to regulate cellular proliferation nude mice [67], documenting that constitutive PDGF signaling can
in response to nutrient availability. The IGF signaling pathway con- act as a critical factor in the malignant transformation of human
sists of two ligands (IGF-I and IGF-II), two cell surface receptors cells. In prostate cancer, overexpression of PDGFRα has been detected
(IGF-IR and IGF-IIR), six specific high affinity binding proteins in epithelial and stromal cells of prostate adenocarcinomas as well
(IGFBP-1 to IGFBP-6), and several other IGFBP-interacting molecules as in bone marrow of metastatic androgen-independent disease,
indicating a role for this receptor in both primary and progression of in treating patients with progressive prostate cancer and bone metas-
prostate cancer [68, 69]. tases. Unfortunately, worsened disease progression was observed in
Expression of PDGFR in prostate tumor-associated endothelial patients treated with Tandutinib, although PDGFR inhibition was ob-
cells was much higher than prostate tumor cells [68]. Tumor cells ap- served [78]. It is suspected that PDGF may play multiple roles in pros-
pear to interact with host factors in the microenvironment to induce tate cancer, including the regulation of physiologic equilibrium
growth and the expansion of vasculature. PDGFR inhibitors can, (homeostasis) of bone metastases associated with advanced prostate
therefore, be considered as a class of antivascular therapies that de- cancer. Meanwhile, Tandutinib needs to be improved to have more
stroy tumor cells by blocking the required oxygen and nutrients for selective activity targeting only PDGFR before it can be further tested
survival. We will discuss anti-angiogenesis inhibitors in a later in prostate cancer.
section.
A study by Dolloff et al. found that PC3-ML cells, which possess 4. Anti-angiogenesis targeting therapy
high bone-metastatic potential, express significantly higher levels of
PDGFR compared to malignant but nonmetastatic PC3-N cells [70]. Angiogenesis, the process of new blood vessel formation, is a cru-
When cells were exposed to PDGF, the Akt pathway was activated cial step in the propagation of malignant tumor growth and metasta-
more profoundly in PC3-ML cells. In contrast, there was no difference sis. Tumor growth is highly dependent on diffusion of nutrients and
in EGFR expression and signaling between these two types of cells, wastes, so a steady blood supply is critical to tumor development
suggesting a determinant role for PDGF, but not EGF, in regulating [79]. Among the multiple pro-angiogenic factors that promote the
survival of bone-metastatic prostate cells. The study also postulates process of vessel formation, vascular endothelial growth factor
that the expression of PDGFR can identify cells within the primitive (VEGF) is one of the most important. Clinical trials have demonstrat-
tumor with the highest propensity to metastasize to the skeleton. ed the efficacy of anti-VEGF therapy as a treatment for many types of
Imatinib (Fig. 3) was initially found to block the kinase activity of cancers. The VEGF family of polypeptide growth factors, of which at
the Bcr-Abl fusion oncoprotein that is involved in chronic myeloid least 7 members have been described, activates VEGFR receptor tyro-
leukemia. Later Imatinib was found to be a potent inhibitor of sine kinases resulting in multiple downstream effects [80]. VEGF-A
PDGFR kinase as well [71]. Imatinib showed profound activity for has been shown to associate with key events in tumor angiogenesis.
prostate cancer in animal models. Bone lesions of xenografted mice VEGF-A binds two major receptor VEGF tyrosine receptor kinases,
carrying PC-3MM2-MDR tumors responded to systemic administra- namely VEGFR-1 that is expressed mainly in vascular endothelial
tion of imatinib and paclitaxel (but not to paclitaxel alone), raising cells, and VEGFR-2, which is important in cell trafficking [81, 82].
the possibility that imatinib could have sensitized the tumor cells to The third VEGF receptor, VEGFR3, is primarily associated with lym-
paclitaxel [72]. Meanwhile, after the co-treatment, extensive apopto- phangiogenesis [83].
sis was observed in both tumor cells and tumor associated endotheli- Angiogenesis plays a critical role in prostate cancer and is associat-
al cells [73]. A phase I study of 28 androgen-independent patients ed with higher Gleason grade, metastasis, and worse clinical out-
further confirmed the activity of imatinib in combination with doce- comes. Weidner and colleagues demonstrated that microvessel
taxel [74]. When imatinib was administered alone, only 2 out 28 pa- density (MVD) was significantly higher in prostate cancer samples
tients showed PSA decline (both b50%). After the patients were for those patients with metastatic disease when compared with
treated by the combination of imatinib and docetaxel, decline in those without metastatic disease [84]. A study by Borre et al. in 221
PSA levels were seen in 59% of patients. However, in a follow-up prostate cancer patients followed for a median of 15 years revealed
trial with metastatic CRPC patients, no difference in progression- that MVD of tumor samples at diagnosis was statistically significantly
free survival was observed for the Imatinib plus docetaxel interven- correlated with stage, grade, and disease survival [85]. Furthermore,
tion [75]. Additional investigation is required to determine the activ- serum levels of the ligand VEGF were found to be significantly higher
ity of imatinib for prostate cancer. The unexpected outcomes of the in those prostate cancer patients with metastatic disease [86]. Plasma
clinical trial might be explained by the preferential activity of imati- VEGF levels have also been shown to be an independent prognostic
nib against the osteoclastic response, which is dominant in the PC3- factor in men with metastatic prostate cancer [87, 88]. Based on
MM2 orthotopic model, over the osteoblastic response, which is these findings, angiogenesis has been targeted as a strategy to treat
much more commonly seen in human prostate cancer bone metasta- prostate cancer.
ses [75]. Bevacizumab (Avastin) is a humanized murine monoclonal anti-
SU101 (ARAVA, leflunomide, Fig. 3) is a small organic molecule body against the VEGF receptor and has been shown to have activity
that selectively inhibits PDGFRα and PDGFRβ in vitro [76]. SU101 in multiple cancer cell lines. Bevacizumab is currently FDA-approved
was first developed as a dihydroorotate dehydrogenase inhibitor for the treatment of several malignancies including colorectal carci-
to prevent pyrimidine synthesis. Clinically SU101 exhibits significant noma, NSCLC, recurrent glioblastoma and, most recently, metastatic
anti-inflammatory effects and is currently used as a disease- renal cell carcinoma. Initial preclinical studies showed that VEGF
modulating agent in the treatment of rheumatoid arthritis. In 1997, inhibition by Bevacizumab prevented further tumor growth of the
Shawver and co-workers reported that SU101 mediated inhibition prostate cancer cell line DU145 implanted in nude mice [89]. Unfor-
of mitogenesis induced by PDGF, but not by EGF [76]. In a phase II tunately, use of Bevacizumab as a single agent in prostate cancer
trial with SU101 in hormone refractory prostate cancer, PDGFR ex- was disappointing.
pression was detected in the majority of patients (80% of metastases In a phase II trial, in which 15 patients were treated with 10 mg/kg
and 88% of primary prostate cancers). For patients treated with Bevacizumab every 14 days for six infusions, objective responses or
SU101 as a single agent, 3 out of 39 demonstrated PSA reduction of meaningful PSA level declines were not observed [90]. However, in
more than 50%, one out of 19 patients had partial response for mea- 2010, two phase II clinical trials involving the use of bevacizumab in
surable disease, and 9 out of 35 people reported significant improve- combination with standard chemotherapy had positive results. 60 pa-
ment of pain [77]. SU101 has recently completed a phase II/III trial tients with progressive metastatic CRPC were enrolled and received
with mitixantrone and prednisone for stage IV prostate cancers. intravenous docetaxel and bevacizumab plus oral thalidomide and
Tandutinib (MLN518, Fig. 3), previously known as CT53518, is a prednisone. 90% of the patients had a PSA decline of greater than
small-molecule inhibitor of the type III receptor tyrosine kinases, in- 50%. Progression free survival was estimated to be 18.2 months,
cluding the Fms-like tyrosine kinase 3 receptor (FLT3), platelet- with median overall survival reported as 28.2 months [91].
derived growth factor receptor (PDGFR), and c-Kit receptor tyrosine In another phase II study, 79 patients were enrolled, and 77 of
kinase. Matthew et al. conducted a phase II trial studying Tandutinib those patients were eligible and assessable. Therapy was based on
21-day cycles. Patients received oral estramustine phosphate 3 times 5. Other molecular targets for prostate cancer therapy
daily for 5 days, decadron twice daily for 3 days and intravenous doc-
etaxel (70 mg/m 2) and bevacizumab (15 mg/kg). A 50% PSA decline 5.1. Prostate-specific membrane antigen (PSMA)
was observed in 58 patients (75%). Twenty-three of 39 patients
(59%) with measurable disease had a partial response [92]. More re- PSMA is a type II transmembrane glycoprotein predominantly
cently, a randomized phase III trial has been conducted comparing expressed in the prostate epithelium. Significantly increased expres-
the combined use of docetaxel, prednisone, and bevacizumab with sion of PSMA is observed in prostate cancer, particularly in poorly dif-
docetaxel. This study randomized 1050 chemotherapy-naïve meta- ferentiated, metastatic, and hormone refractory carcinomas [107].
static CRPC patients into each treatment group using overall survival The first PSMA mAb, 7E11-C5.3, recognizes intracellular domain of
as a primary endpoint. Despite an improvement in progression-free PSMA. As a result, 7E11-C5.3 (or the antibody conjugate Capromab
survival, disease response and PSA decline, adding bevacizumab to pendetide or CYT-365) only binds to late stage tumors or soft tissue
docetaxel and prednisone did not improve overall survival in patients metastases when cell membrane becomes permeable due to tumor
with metastatic CRPC, and was associated with greater morbidity and necrosis [108].
mortality [93]. An antibody named J591 was developed to target the external do-
Inhibition of tyrosine kinase activity of VEGF receptors is another main of PSMA [146]. Radiolabeled J591 has been shown to accurately
approach to inhibit angiogenesis. Two VEGFR tyrosine kinase inhibi- target bone and soft tissue metastatic prostate cancer sites and may
tors, Sorafenib and Sunitinib (Fig. 3), have been studied for the treat- be useful as therapeutic and diagnostic imaging agents [147]. This an-
ment of prostate cancer. Sorafenib was initially developed to inhibit tibody is currently under evaluation for prostate and non-prostate
Raf-1/BRAF but was subsequently discovered to inhibit some radio-immunotherapies. MLN2704 (Millennium Pharmaceuticals,
receptor tyrosine kinase receptors, including human VEGFR-2, with Inc., Cambridge, MA) is the humanized J591 conjugated with the mi-
IC50 in the nanomolar range [94]. In prostate cancer cells, Sorafenib crotubule-depolymerizing drug maytansinoid 1 (DM1, Immunogen,
has been shown to block the MAPK pathway and induce apoptosis Cambridge, MA) [109]. Phase I/II trials using MLN2704 have revealed
and autophagy [95]. It is expected that Sorafenib, with anti-angiogen- acceptable safety of the compound and the non-immunogenicity of
esis capability, can have more profound in vivo activity. Interestingly, the antibody. In addition, two patients showed sustained PSA decline
in a transgenic mouse adenocarcinoma prostate model, Sorafenib, of more than 50% and six patients had stable PSA levels for up to
mainly through its anti-angiogenesis effect, reduced progression of 86 days [110]. In other trials, huJ591 was radio-labeled with 111indi-
90
high grade prostate intraepithelial neoplasia to adenocarcinoma um (for imaging), yttrium (for therapy), or 177lutetium (for both im-
[96]. In clinical studies, the activity of Sorafenib was initially unclear aging and therapy) [111]. The labeled antibody was shown to target
when PSA was used as the biomarker to measure response. In one bone and/or soft tissue lesions. Kuroda et al. reported the conjugation
open-label phase II study using Sorafenib as the single agent therapy, of saporin toxin with huJ591 and demonstrated anti-tumor activity in
two patients appeared to have worsening PSA scores after treatment animal models [112].
but both had dramatic reduction of bone metastatic lesions as deter-
mined by bone scan [97]. In another phase II trial with CRPC, the PSA 5.2. Heat shock protein (Hsp)
response rate was only 3.6% during the trial, but 10 out of 16 Sorafe-
nib treated patients had PSA declines of 7%–52% after the trial is fin- Hsp is a family of chaperones that assist in the posttranslational
ished [98]. It is suspected that Sorafenib treatment might cause PSA folding of proteins. They play roles in a variety of cellular process in-
release. Thus, response to treatment should be evaluated indepen- cluding proliferation, differentiation, and survival by maintaining the
dent of PSA. A further study concluded that Sorafenib has moderate stability of regulatory proteins [113]. One such Hsp is Hsp90. Inhibi-
activity as a second-line treatment for metastatic CRPC, with one par- tion of Hsp90 function has been shown to cause degradation of client
tial response, 10 stable disease and median survival of 18.3 months proteins via the ubiquitin–proteasome pathway, resulting in the de-
for a total of 46 patients [99]. In comparison, treatment with cytotoxic pletion of multiple cancer-related proteins, including HER2. 17-(ally-
agents in CRPC after docetaxel led to median overall survival in the lamino)-17-demethoxygeldanamycin (17-AAG, Fig. 3), an Hsp90
range of 9.8 months to 17 months. inhibitor derived from geldanamycin, binds to the ATP-binding pock-
Sunitinib is another multi-specific tyrosine kinase inhibitor that et in the N-terminal domain of Hsp90 and blocks the binding of the
targets VEGFR1-3, PDGFRα/β, CSF-1R, and Flt-3 [100]. It is FDA- adenine nucleotides to Hsp90. Interestingly, 17-AAG has much higher
approved for gastrointestinal stromal tumor (as a second line treat- affinity to Hsp90 from tumor than that from normal cells[114]. How-
ment after imatinib), metastatic renal cell carcinoma, and recently ever, in a phase II clinical study 17-AGG did not show any activity in
pancreatic neuroendocrine tumors. In vivo studies showed additive metastatic androgen independent prostate cancer patients with re-
anti-tumor effect of Sunitinib in combination with docetaxel and/or gard to PSA response [115]. F4, a novobiocin analogue designed to in-
anti-EGFR antibody Cetuximab in the prostate cancer PC3 and hibit the C-terminal portion of Hsp90, demonstrated improved
DU145 xenografts [101, 102]. cytotoxicity in prostate cancer cell lines as compared to 17-AAG
In a phase II clinical study, 17 patients with no prior chemotherapy [116]. Recently, a class of small molecule Hsp90 inhibitor gamitrinibs
and 17 patients with docetaxel-resistant prostate cancer were treated showed preclinical activity and favorable safety in the PC3 xenograft
with sunitinib [103]. One patient in each group showed PSA reduction model for drug-resistant and bone metastatic prostate cancer [117].
of more than 50% from the base line. About half of patients in each Gamitrinibs are ATPase antagonists but only accumulate in the mito-
group also reported stable PSA levels at week 12. In addition, improve- chondria of tumor cells, and thus has much less toxicity to normal
ment of radiological imaging was seen in some people even without cells [118].
PSA decline. The activity of sunitinib was also confirmed in other
phase II studies in CRPC [104, 105]. In a very recent phase III trial of suni- 5.3. mTOR
tinib in combination with prednisone as compared to prednisone alone
in metastatic CRPC, treated patients had significant improvement of The phosphoinositide-3 kinase pathway (PI3K) is another critical
progression-free survival, and higher overall response rate were docu- signal transduction pathway that is involved in cancer development.
mented. Overall survival was also longer for sunitinib treated patients This pathway may be activated by growth factors such as EGF, and it
but the difference was not significant (13.1 vs 11.7 months) [106]. Be- leads to the activation of a number of important downstream cellu-
cause of the lack of significant improvement of overall survival in the lar signaling components. One such component is the mammalian
treatment regimen, Pfizer has discontinued the trial. target of rapamycin (mTOR) protein. Activation of mTOR results in
sequential activation of downstream molecules, which ultimately several molecules have recently emerged to be potential “targeted”
leads to cell division. Current mTOR Inhibitors in clinical trials are biomarkers that can be used to guide therapies.
mainly rapamycin and temsirolimus (CCI-779) (Fig. 3). The response
of prostate cancer cell lines to a combination of rapamycin and the 6.1. The F77 antigen
nonsteroidal androgen receptor (AR) antagonist bicalutamide has
been documented [119]. In a clinical study involving HRPC patients, Recently, F77, a monoclonal antibody developed by immunizing
two patients treated with Rapamycin experienced a response with mice with prostate cancer cells PC3, was shown to recognize small mo-
PSA reduction, and 4 patients were reported to have stable disease lecular species with glycolipid properties [130]. The F77 antigen,
after the treatment [120]. Wu et al. studied the effects of temsiroli- termed prostate cancer lipid antigen (PCLA), is concentrated in the
mus on hormone resistant PC3 cells, which are PTEN-negative and lipid raft microdomains that serve as platforms in the assembly of asso-
have higher Akt and mTOR activity, and DU145 cells, which are ciating protein complexes. Due to its glycolipid properties, PCLA holds
PTEN positive. Temsirolimus inhibited the growth of xenografts de- significant value as a cancer biomarker. It is expressed on both andro-
rived from both cell lines but better activity was observed with PC3 gen dependent and androgen independent prostate cancer, making it
tumors [121]. a target for early diagnosis and treatment of advanced diseases. Tissue
microarray studies show that F77 stained 112 of 166 primary and 29
5.4. Histone deacetylase (HDAC) of 34 metastatic prostate cancer specimens [130]. By eliciting ADCC/
ACD activity towards the cancer cells, the F77 antibody was useful as a
Epigenetic modifications play a key role in the patho-physiology therapeutic reagent to limit the growth of prostate cancer growth in
of cancer. Histone deacetylases (HDACs), whose substrates are not xenografted mice [130]. Currently the antibody is subjected to human-
limited to histone, are involved in cancer progression. HDACs are ization. The humanized antibody will be tested if F77 provides a novel
part of a transcriptional co-repressor complex that influences various treatment for human prostate cancer.
tumor suppressor genes. Because of the significant roles played by
HDACs in various human cancers, HDAC inhibitors are emerging as 6.2. Serine peptidase inhibitor Kazal type 1 (SPINK1)
a new class of chemotherapeutic agents. HDAC inhibitors have been
shown to induce growth arrest, differentiation, and/or apoptosis of SPINK1 is a biomarker specific to a subset of aggressive prostate can-
prostate cancer cells. Up to now, more than 100 clinical trials are on- cer that does not carry genetic rearrangement of the ETS (E26 transfor-
going with HDAC inhibitors (HDACi) either as monotherapy or in var- mation specific) transcription factors into the TMPRSS2 promoter
ious combination therapies. In one report on a phase II clinical trial region. In 2008, Tomlins et al. demonstrated that high levels of SPINK1
with the HDAC inhibitor romidepsin (Fig. 3), two of 35 HRPC patients in this subset were correlated with a greater rate of cancer recurrence
achieved a confirmed radiological response along with a PSA decline [131]. Recent in vivo data suggests that SPINK1 promotes prostate
of >50% [122]. However, 11 people experienced toxicity and were re- tumor growth through EGFR [132]. SPINK1 has structural similarities
moved from the trial, which raises safety concerns. HDAC inhibitors with EGF and binds to EGFR, inducing the dimerization and sustained
have to be improved for specificity, and combination therapies should phosphorylation of the receptor. Inhibiting SPINK1 attenuates key
be considered. downstream mediators of the EGFR pathway, including MEK, ERK, and
AKT. These results support the potential of EGFR inhibitors to treat
6. New targets and biomarkers for prostate cancer therapy SPINK1 positive prostate cancer. In fact, the anti-EGFR mAb Cetuximab
specifically decreased SPINK1+ tumor growth in mice [132].
One of the validated and widely accepted prostate cancer bio-
markers is PSA. Although the measurement of PSA is clinically prac- 6.3. Survivin
ticed to provide a way to predict response to therapy, this test fails
for some patients. While PSA is elevated in the presence of prostate Survivin is a member of the Inhibitor of Apoptosis (IAP) family that
cancer, it is also present in small amounts in the serum of healthy functions to inhibit caspase activation, leading to the prevention of ap-
males. The effectiveness is thus limited with a positive predictive optosis [133]. As this protein is highly expressed during fetal develop-
value of 28–35% [123]. A recent study also revealed that the change ment and in many human tumors, but also absent in normal
of the PSA levels (PSA velocity) was a poor biomarker for prostate terminally differentiated tissues, it is useful as both a cancer diagnostic
cancer diagnosis and unable to predict the grade (e.g. Gleason marker and therapeutic target [134]. Survivin is overexpressed in mul-
score) of the disease [124]. For some experimental therapies as we tiple types of adenocarcinomas, including prostate [135]. Zhang et al.
mentioned above, reduction of PSA levels is not observed in patients demonstrated Survivin's contribution to the development of hormonal
showing radiological responses. In some cases, the PSA levels can therapy resistance in prostate cancer cells by studying its expression
even rise in patients showing response to therapies by other mea- in LNCaP, an androgen-dependent cell line [136]. It was shown that
surements [97]. inhibiting Survivin could enhance the therapeutic effect of Flutamide,
A great effort in the field of prostate cancer has been made to dis- an anti-androgen agent. However, it was reported that in locally ad-
cover novel prostate markers. This includes extensive effort at the vanced prostate cancer cytoplasmic overexpression of Survivin pre-
proteomic scale [125] and the expansion of biomarker candidates dicted local progression but nuclear expression was associated with
from protein to DNA/RNA [126] and circulating tumor cells [127]. Re- improved survival [137]. Recent studies have revealed that acetylation
views of prostate biomarkers and recent developments are presented promotes the translocation of Survivin into the nucleus, where it func-
in other articles [128, 129]. tions as a repressor of STAT3 oncogenic activity [138]. These data indi-
In many cases, the molecular target for a targeted therapy can be cate that Survivin may have multiple roles in the cell.
used as a biomarker for prostate cancer. Whether or not these bio- Several small-molecule inhibitors and natural compounds that sup-
markers are specific to prostate, their existence in the tumor provides press Survivin expression have been developed and proven effective in
guidance to targeted therapies to obtain higher response in a sub- suppressing prostate cancer tumor growth and enhancing docetaxel-in-
category of prostate cancer. In fact, the unique linkage between the duced apoptosis. One such agent is YM155 (Fig. 3), a small molecule sup-
target and the therapy differentiates targeted therapies from the con- pressant of Survivin expression, promoting apoptosis in vitro and in a
ventional cytotoxic chemotherapeutic therapies for cancers. In addi- xenograft mouse model in vivo [139]. YM155 has completed various
tion to targeted proteins such as the PSMA we mentioned above, phase I and II trials for its safety and efficacy in several types of cancers
Table 1
Therapeutic agents and their targets in prostate cancer. mAb: monoclonal antibody; SMI: small molecule inhibitor; TKI: tyrosine kinase inhibitor; doxo: doxorubicin; DCT: doce-
taxel; RTK: receptor tyrosine kinase; PFS: progression free survival; OS: overall survival.
Drugs Targets Class of agent/mechanism Stage of development Ref
MDV3100 AR SMI/AR antagonist Phase III [10]

Abiraterone CYP17 SMI/androgen inhibitor FDA approved in 2011 [22]
Panitumumab EGFR mAb Phase I [32]
Cetuximab EGFR mAb/ligand blocking Phase Ia/IIb (with doxo) [34]
Trastuzumab HER2 mAb Phase I (with DCT) [38]
Gifinitib EGFR SMI/Tyrosine kinase inhibitor Phase I/II (with radiation) [54]
Erolotinib EGFR SMI/Tyrosine kinase inhibitor Phase II [46,47]
Lapatinib EGFR/HER2 SMI/Tyrosine kinase inhibitor Phase II [48]
Cixutumumab IGF-1R mAb Phase II [60]
INSM-18 IGF-1R/HER2 SMI/Tyrosine kinase inhibitor Phase II [64]
Imatinib PDGFR SMI/Tyrosine kinase inhibitor Phase I and II [74,75]
SU101 PDGFR SMI/Tyrosine kinase inhibitor Phase II [77]
Tandutinib Type III RTK (PDGFR) SMI/Tyrosine kinase inhibitor Failed in phase II [78]
Bevacizumab VEGF receptor mAb Phase III (with DCT; PFS observed but no OS benefit) [146]
Sorafenib VEGFR2 (Raf-1/BRAF) SMI/Tyrosine kinase inhibitor Phase II [97,98]
Sunitinib Type III RTK (PDGFR, VEGFR) SMI/Tyrosine kinase inhibitor Phase III (discontinued, no significant OS benefit) [106]
Thalidomide Angiogenesis Phase II (with bevacizumab, DCT) [91]
huJ591 PSMA mAb Phase I/II (lDM1 or radio-labeled) [110,111]
17-AAG Hsp90 SMI/blocking ATP binding Phase II (failed) [115]
F4 Hsp90 SMI/allosteric modulator Preclinical [116]
Rapamycin SMI/mTOR inhibitor Phase I [120]
F77 PCLA mAb Preclinical [130]
YM155 Survivin SMI/expression repressor Phase II [142]
Sanguinarine Survivin Natural product/promoting Survivin degradation Preclinical [143]
S12 Survivin SMI/allosteric modulator Preclinical [144]
EGFR inhibitors SPINK1 Preclinical [132]
[140, 141]. As a single-agent, YM155 induced decline in PSA concentra- CYP17 17-α-hydroxylase/C17-20-lyase
tions in two out of nine advanced prostate cancer patients [142]. DC dendritic cell
Sun et al. have identified Sanguinarine (Fig. 3), a benzophenanthri- DHEA dehydroepiandrosterone
dine alkaloid primarily derived from the bloodroot plant, as a novel in- EGF epidermal growth factor
hibitor of Survivin [143]. Sanguinarine selectively kills prostate cancer EGFR EGF receptor
cells over “normal” prostate epithelial cells. By promoting Survivin deg- FDA Food and Drug Administration
radation via the ubiquitin–proteasome system, Sanguinarine was found HDAC histone deacetylases
to induce apoptosis and inhibit in vivo tumor formation. HER human EGFR family (HER/ErbB) receptors
Recently, an allosteric modulator S12 (Fig. 3) was developed to bind HRPC hormone refractory prostate cancer
to a cavity near the dimerization domain of Survivin [144]. S12 was able HSP heat shock protein
to change spindle formation and halt mitosis, leading to cell death. It IAP inhibitor of apoptosis
showed anti-tumor activity in several animal models [144]. IGF insulin-like-growth factor
IGF-R IGF receptor
7. Summary IR insulin receptor
LH–RH luteinizing hormone
The rapid expansion of targeted therapies in the past decade has LH–RH luteinizing hormone-releasing hormone
provided new strategies for the treatment of prostate cancer, espe- NSCLC non-small cell lung cancer
cially the most malignant hormone independent and castration resis- PDGF platelet-derived growth factor
tant forms. However, the most advanced therapies in this category PDGFR PDGF receptor
(Table 1), except androgen inhibitors, are still under clinical trials. PSA prostate specific antigen
Further studies will determine the clinical use of those agents that PSMA prostate-specific membrane antigen
show promises in early stage trials. Extensive studies will also be RTK receptor tyrosine kinase
needed to optimize some lead compounds for better specificity and SPINK1 serine peptidase inhibitor Kazal type 1
higher efficacy. Although some of the initial excitements, including VEGF vascular endothelial growth factor
the endothelin A receptor antagonist, zibotentan, failed to be materi-
alized, the extensive research activities in this field have generated
insights for the development of future therapies that could be more
Acknowledgment
efficient to control this disease. In addition to these antibody or
small molecule based approaches, dendritic cell (DC) based therapies
This work was supported by grants from the National Institutes
have also been explored [145], leading to the FDA approved Provenge
of Health (1R01CA157766-01 (A.T.) and R01 CA055306 (M.I.G.))
(sipuleucel-T). The hope is that, with targeted therapies, prostate
and the Abramson Family Cancer Research Institute (to M.I.G.). We
cancer will be divided into sub-categories and treated in a more tar-
thank Dr. Mark I. Greene for his comments on this manuscript.
geted manner in the future.
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Progress of Molecular Targeted Therapies For Prostatecancers

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Biochimica et Biophysica Acta 1825 (2012) 140–152

Contents lists available at SciVerse ScienceDirect

Biochimica et Biophysica Acta

Progress of molecular targeted therapies for prostate cancers

1. Introduction cells or metastatic tumors. We review current developments in this

Drugs Targets Class of agent/mechanism Stage of development Ref

MDV3100 AR SMI/AR antagonist Phase III [10]

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