World J Urol (2009) 27:9–20 DOI 10.1007/s00345-008-0357-x
TOPIC PAPER
Molecular targets and targeted therapies in bladder cancer management Ramy F. Youssef · Anirban P. Mitra · Georg Bartsch Jr · Peter A. Jones · Donald G. Skinner · Richard J. Cote
Received: 8 October 2008 / Accepted: 4 November 2008 / Published online: 28 November 2008 © Springer-Verlag 2008
Abstract Bladder cancer remains a signiWcant health problem. Currently, conventional histopathologic evaluation criteria (tumor grade and stage) are limited in their ability to accurately predict tumor behavior. A signiWcant number of patients with muscle-invasive or extravesical disease treated by radical cystectomy alone die of metastasis. Intense research eVorts are being made to better identify and categorize tumors by their molecular alterations and biological characteristics. A majority of the aggressive, invasive bladder carcinomas have alterations in the p53 and retinoblastoma pathways that regulate the cell cycle by R. F. Youssef, A. P. Mitra, G. Bartsch Jr have contributed equally to this work. R. F. Youssef · A. P. Mitra · G. Bartsch Jr · R. J. Cote (&) Departments of Pathology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA e-mail:
[email protected] R. F. Youssef · G. Bartsch Jr · P. A. Jones · D. G. Skinner · R. J. Cote Departments of Urology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, 1441 Eastlake Avenue, Los Angeles, CA 90033, USA P. A. Jones Departments of Biochemistry and Molecular Biology, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA R. F. Youssef Department of Urology, Urology and Nephrology Center, Mansoura University, Mansoura, Egypt G. Bartsch Jr Department of Urology, Ulm University, Ulm, Germany
interacting with signal transduction pathways. Angiogenesis further contributes to the neoplastic growth by providing a constant supply of oxygen and nutrients. It is becoming apparent that the accumulation of genetic and molecular changes ultimately determines a tumor’s phenotype and subsequent clinical behavior. We provide a contemporary outline of our current understanding of the molecular and genetic events associated with tumorigenesis and progression. We emphasize the ways by which molecular biology is likely to aVect the development of future therapies that will be able to target molecular alterations in individual tumors based on their respective proWles. The current status of targeted therapies for bladder cancer is also presented as well as the ongoing clinical trials. Keywords Urothelial carcinoma · Signal transduction · p53 · Angiogenesis · Targeted therapeutics · Clinical trial
Introduction Bladder cancer is estimated to be the ninth most common cause of cancer worldwide and the 13th most numerous cause of death from cancer [1]. It is the fourth most common malignancy in men and the ninth most common in women in the US, with an estimated 68,810 new cases and 14,070 deaths predicted for the year 2008 [2]. Although frequent recurrences in non-invasive (Ta) urothelial carcinoma (UC) pose a therapeutic challenge, invasive (T1-4) tumors represent the major cause of morbidity and mortality. So far, radical cystectomy remains the mainstay of treatment for muscle-invasive (T2-4) UC. The choice and usefulness of neoadjuvant and adjuvant chemotherapy has been the subject of many investigations. An important reason for the relatively poor patient selection for
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administration of routine therapeutics is the dependence on conventional histopathologic variables, including determination of tumor grade and stage, which provide limited insight into the biology of the tumor. IdentiWcation of molecular alterations that are functionally critical for tumorgenesis and progression will lead to more reliable patient stratiWcation, outcome prediction and treatment selection. Over the last decade, scientists have demonstrated the presence of multiple interacting molecular pathways in the genesis of UC. Alterations in the receptor tyrosine kinase– Ras pathway, speciWcally mutations in the HRAS and Wbroblast growth factor receptor 3 (FGFR3) genes are more common in low-grade non-invasive UC [3]. Alterations in the p53 and retinoblastoma (Rb) pathways are more prevalent in invasive tumors [4]. The p53 and Rb pathways control the cell cycle, with the cells receiving extracellular growth signals via the Ras–mitogen activated protein kinase (MAPK) pathway. Tumor angiogenesis also contributes to the tumor-promoting extracellular milieu by providing oxygen, nutrients, and growth factors to the neoplastic cells. IdentiWcation of these molecular alterations are now creating possibilities for synthesizing novel therapeutic agents that can speciWcally target these alterations, thereby killing the tumor cells while having little eVect on normal tissues. In this review we highlight some of the major molecular pathways of bladder tumorigenesis, which also serve as markers for progression and target identiWcation. Some of the major targeted therapeutics and the ongoing trials using these agents for UC are also presented.
Signal transduction in bladder cancer Several peptide growth factors and their associated tyrosine kinase receptors (TKRs) are responsible for modulating growth signals from external cues and transmitting them via signal transduction pathways to transcription factors in the nuclei of urothelial cells. Aberrations in these growth factor receptors and/or deregulations of the signals transmitted by the pathways can result in an abnormal increase in the rate of transduction of growth signals, thereby leading to uncontrolled cellular proliferation and tumor formation. In UC, important signaling pathways include the Ras– MAPK pathway, and the phospholipase C (PLC)–protein kinase C (PKC) signaling cascade. The epidermal growth factor receptor (EGFR) family consists of four closely related receptors that can, following ligand activation, transmit signals via the Ras–MAPK pathway, regulating cell cycle progression that directly impacts cancer progression (Fig. 1). Activation of EGFR promotes processes responsible for tumor growth and progression,
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including proliferation and maturation, angiogenesis, invasion, metastasis, and inhibition of apoptosis. Among the best-studied receptors in this family are EGFR (ErbB1) and ErbB2 (Her2/neu). These receptors are generally overexpressed in invasive UC [5–7]. Increased EGFR expression has been associated with increased probability of progression and death [8–10]. Similarly, increased ErbB2 expression has been associated with worse disease-speciWc survival [6, 11, 12]. While the combined expression proWle of EGFR and ErbB2 has been suggested to be a better predictor of outcome than each individual marker alone [13], this Wnding is controversial [14]. Vascular endothelial growth factor (VEGF), an important protein family regulating angiogenesis, eVects cellular responses by binding to VEGF receptors (VEGFRs) on the cell surface. VEGFR2 (KDR/Flk-1) mediates most of the known cellular responses to VEGF. VEGFR2 expression has been correlated with increasing disease stage and tumor invasion into the muscle [15]. Our studies have also shown that VEGFR2 may be an important determinant for prediction of nodal metastasis in UC patients [16]. Constitutive activation of the Ras–MAPK pathway is a dominant alteration in most non-invasive, low-grade papillary UCs [17]. HRAS mutations have been observed in exfoliated cells in the urine of patients with low-grade bladder tumors [18]. Recent studies from our group show that HRAS is signiWcantly overexpressed in non-progressing Ta tumors compared with those that progress to an invasive phenotype [19]. Binding of a ligand such as the epidermal growth factor (EGF) causes activation of the already overexpressed EGFR, leading to receptor dimerization and autophosphorylation [4]. The activated receptor then recruits proteins that convert Ras to its activated state. This activated Ras protein can then transduce a mitogenic signal through the Ras–MAPK pathway by acting through the MAPK/extracellular-signal regulated kinase (ERK) system (Fig. 1). Translocation of ERK into the nucleus activates the mitogen- and stress-activated protein kinase 1 (MSK1), a histone H3 kinase that can relax chromatin, thus making it more transcriptionally accessible [20]. This leads to the induction of MYC [21] that encodes the c-Myc protein, a transcription factor that controls the cell cycle. To date, however, c-Myc has not proven to be a good prognostic indicator for UC [22, 23]. c-Myc signals downstream, regulating cyclin expression by inhibiting cyclin-dependent kinase inhibitor (CDKI) activity, thereby controlling the cell cycle [24–26]. PKC, a ubiquitous, phospholipid-dependent enzyme, is also involved in signal transduction associated with cell proliferation, diVerentiation, and apoptosis. The binding of a ligand to TKR activates PLC and diacylglycerol, subsequently leading to PKC activation [27]. Signaling through PKC promotes Raf, a molecule upstream in the Ras–MAPK
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Fig. 1 Prognostic markers, targets, and novel therapeutics in bladder cancer. a The signal transduction, cell cycle regulation and angiogenesis pathways can harbor several alterations in bladder tumors that can be speciWcally exploited for targeted therapy. b Several novel therapeutics are currently available for these targets and are being studied in clinical trials for bladder cancer. EGFR epidermal growth factor recep-
tor, VEGFR2 vascular endothelial growth factor receptor 2, PLC phospholipase C, PKC protein kinase C, ERK extracellular signal-regulated kinase-1, MEK mitogen-activated protein kinase/ERK kinase, MSK1 mitogen- and stress-activated kinase 1, CDK cyclin-dependent kinase, pRb phosphorylated retinoblastoma protein, TSP-1 thrombospondin-1
pathway (Fig. 1). Studies have reported that the expressions of PKC isozymes and decrease with increasing UC grade and that the levels of isozymes , , and show the opposite pattern [28, 29]. The ratio of PKC expression in the membrane to that in cytosol has been reported to be greater in UC tissues and higher-grade tumors than in normal urothelium, and patients with superWcial UC with a greater membrane/cytosol PKC ratio have a higher risk of recurrence after chemotherapy [30].
[33, 34], although this is not always the case. While p53 nuclear accumulation is predictive of outcome, particularly for patients with invasive, organ-conWned, node-negative (T1-2bN0) UC [35–37], we have shown that signiWcant discordance exists between mutations in the TP53 gene and detection of p53 nuclear accumulation by IHC [38]. Our results suggest that both nuclear accumulation and gene mutations play a role in progression, and that determining the status of both the gene and the protein provides additional synergistic information regarding prognosis. The p21WAF1/CIP1 gene encodes the p21 protein, a CDKI that is transcriptionally regulated by p53 [39]. Along with other CDKIs such as p16 and p27, p21 inactivates cyclin/ cyclin-dependent kinase (CDK) complexes that prevent release of the transcription factor E2F from the unphosphorylated Rb protein (Fig. 1). Loss of p21 expression is a signiWcant and independent predictor of UC progression, whereas the maintenance of p21 expression appears to abrogate the deleterious eVects of p53 alterations [40]. Patients with p21-negative, p53-altered tumors have a greater recurrence and lower survival rate than those with p21-positive tumors, irrespective of the tumor grade or pathologic stage. The Mdm2 protein is involved in an autoregulatory feedback loop with p53, thus controlling its activity [41]. Increased p53 levels transactivate the MDM2 promoter causing its upregulation. The translated protein then binds
Aberrations in cell cycle regulation Aberrations in cell cycle regulation are perhaps the most exhaustively investigated molecular aspects of UC. The cell cycle is primarily controlled by the p53 and Rb pathways (Fig. 1). p53 is the central molecule regulating the cell cycle and is also involved in several other important cellular processes related to cancer development, progression, and response to therapy, including angiogenesis, apoptosis, and DNA repair [31]. p53 inhibits cell cycle progression at G1S transition and mediates its control through the transcriptional activation of p21WAF1/CIP1 [32]. TP53 gene mutations are commonly seen in invasive UC [4]. Presence of such mutations are highly correlated with the nuclear accumulation of p53 as detected by immunohistochemistry (IHC)
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to p53 and transports it to the proteasome for ubiquitinmediated degradation. The resultant lowered p53 levels then reduce the levels of Mdm2. The MDM2 gene is, in turn, transcriptionally inhibited by p14 [42], providing another Wne level of control for p53 activity (Fig. 1). Altered p53 protein expression in the presence of wild-type TP53 may be caused in part by alteration in the p14/Mdm2 regulatory pathway. We and others have also shown that when alterations in several proteins involved in cell cycle regulation were accounted for in combination in UC, their prognostic capability was far better than that of the alterations individually [43]. This demonstrates a “synergism” between these markers spanning multiple molecular pathways in bladder tumorigenesis and progression, and suggests that such alterations may provide lucrative targets for therapy in UC.
Angiogenesis in bladder cancer Angiogenesis is an essential process in normal physiological functions and is an important factor in disease states such as chronic inXammation, arthritis, cancer, and macular degeneration. Angiogenesis is required for tumor growth and metastasis [44]. Blood vessels are built to supply the tumor with nutrients and oxygen, failing which central necrosis occurs in tumor implants bigger than 3 mm3 in vitro [45]. If hypoxia ensues, the cellular response to low oxygen tension involves stabilization of the hypoxia-inducible factor-1 (HIF-1) transcriptional complex that promotes cell survival and tumor invasion. This induces the formation of new blood vessels. Angiogenesis is either directly promoted by induction of angiogenic growth factors during tumorigenesis or is indirectly induced by the secretion of angiogenic mediators from recruited immune cells [46]. Such angiogenic mediators include VEGF, angiopoietins, Wbroblast growth factors, endothelins, platelet derived growth factor (PDGF), carbonic anhydrase IX, EGF and transforming growth factor [47]. Microvessel density (MVD), a surrogate marker for angiogenesis [48], has been demonstrated to be a predictive marker of progression and prognosis in invasive UC [49– 53]. Our studies have also shown an association between p53 phenotype and the extent of angiogenesis as measured by MVD; MVD provides additional prognostic information in patients with tumors that have an altered p53 phenotype [54]. The central molecule in tumor angiogenesis is VEGF. Five diVerent families of VEGFs have been identiWed, of which VEGF-A is the most important [55]. VEGF can bind to four diVerent receptor subtypes, majority of which are TKRs. Activation of these receptors on endo-
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thelial cells result in their proliferation, diVerentiation, and migration [56]. VEGF mRNA levels have been shown to predict earlier recurrence and a higher likelihood for progression in T1 UCs [57]. Higher VEGF production, as demonstrated by IHC, has been associated with increasing tumor stage [58]. Furthermore, a VEGF serum level of >400 pg/ml is highly predictive of metastatic disease [59]. In addition to its role in cell cycle regulation, p53 also plays an important role in angiogenesis. p53 upregulates thrombospondin-1 (TSP-1), a potent angiogenesis inhibitor (Fig. 1) [60]. We have shown that tumors with p53 alterations are associated with low TSP-1 expression, and these tumors are more likely to demonstrate high MVD counts [61]. Decreased TSP-1 levels are associated with increased recurrence and reduced overall survival rates in UC. Given the critical role that angiogenesis plays in UC sustenance, it is not surprising that this process is as an attractive target for novel therapeutics.
Targeting molecular alterations in bladder cancer using conventional chemotherapy In addition to surgical therapy of invasive UC, there have been several international trials focusing on preventive, adjuvant and neoadjuvant chemotherapeutic regimens [62]. Cisplatin-based combination therapies have been shown to yield only modest beneWts when used in the neoadjuvant setting [63–65] and mixed results in the adjuvant setting in UC [66]. Interestingly, there is evidence to suggest that patients with locally advanced UC who harbor p53 alterations respond beneWcially to adjuvant chemotherapy that contains DNA-damaging agents such as cisplatin [67]. The plausible explanation is that DNA damage to p53-altered urothelial cells may “uncouple” the S and M phases of the cell cycle resulting in apoptosis [68]. An international multicenter clinical trial in UC was thus designed with the aim of identifying UC patients with the greatest risk of progression, and those who would respond best to chemotherapy on the basis of the tumor’s molecular proWle. The hypothesis of the study was that p53 alteration in the primary tumor is associated with worse prognosis, and these patients with organ-conWned invasive UC would beneWt from cisplatin-containing chemotherapy [39]. Accrual for this trial is now closed and the results are currently being analyzed. This was the Wrst clinical trial in UC that targeted a molecular lesion, and is considered a prototype for molecular therapeutic targeting, where an established biomarker of risk for untoward clinical outcome was used to select patients for additional aggressive therapy, as opposed to the generally empiric criteria traditionally employed [69].
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Novel targeted therapeutics in bladder cancer While UC remains primarily a surgical disease, the high failure rate in both superWcial and invasive disease has led to increased interest in multimodal combination therapy in various clinical scenarios to improve outcomes. Recent introduction of novel pathway-speciWc therapies for UC represents a scientiWcally driven leap wherein clinical medicine is now translating bench-level research to bedside. Prompt evaluation of logical and promising therapies in preclinical models and clinical trials is now required. Interrupting critical pathway checkpoints at multiple levels in the genesis of UC through employment of therapeutic regimens that target multiple molecular pathways holds the key to successful treatment of this disease. In recent years there has been substantial interest in developing novel therapeutic agents that speciWcally target growth factor pathways that are deregulated in tumor cells (Table 1). Such targeted agents might oVer alternative treatment options for patients besides standard chemotherapy. Also, with unique mechanisms of action and toxicity proWles that generally do not overlap [70], targeted agents and standard therapies can be used in combination to enhance overall treatment eYcacy. The EGFR family represents such a rational target in UC. The most clinically advanced EGFR inhibition strategies include monoclonal antibodymediated blockade of the extracellular ligand-binding domain (cetuximab and trastuzumab) and small-molecule inhibition of the intracellular tyrosine kinase domain (geWtinib, erlotinib and lapatinib) [71]. Restoring activity of transcription factors that can suppress tumor growth and promote apoptosis also represents a unique strategy for targeted treatment using gene therapy approach. AdCMVTP53 uses this approach by delivering functional TP53 genes into urothelial cells that have the mutated gene (Table 1). Blockade of VEGF signaling has been shown to have a direct and rapid anti-vascular eVect in UCs through deprivation of tumor vascular supply and inhibition of endothelial cell proliferation. Novel therapeutics that inhibit VEGF signaling include sunitinib, sorafenib, pazopanib, aXibercept, and bevacizumab (Table 1) [72]. Many of these agents are already in clinical trials for UC (Table 2). GeWtinib GeWtinib (Iressa; AstraZeneca, London, UK) is an orally bioavailable small-molecule reversible EFGR tyrosine kinase inhibitor (TKI) that selectively inhibits EGFR by competitively blocking the intracellular ATP-binding domain. It can inhibit EGFR tyrosine kinase activity with a potency 100-fold greater than other TKIs [73]. GeWtinib’s anti-proliferative eVect on UC has been demonstrated in vitro and in vivo [74–79]. When combined with platinum-
13
derived agents, taxanes and topoisomerase inhibitors, geWtinib shows enhanced growth inhibition [80]. However, when geWtinib was combined with gemcitabine and cisplatin (GC) in 55 chemotherapy-naive patients with locally advanced or metastatic UC, the combination achieved a response rate of 51% and a median overall survival of 14.4 months, which were very similar to those obtained with GC alone, suggesting that geWtinib did not substantially add to the eYcacy of GC [81]. GeWtinib is now in phase II–III clinical trials for locally advanced or metastatic UC in combination with diVerent chemotherapy agents [82, 83]. Erlotinib Erlotininb (Tarceva; Genentech, South San Francisco, CA) is another oral small molecule EGFR TKI. It reversibly inhibits the tyrosine kinase function of wild-type EGFR and mutant EGFRvIII without decreasing the level of EGFR protein [73]. Besides its approved use in metastatic nonsmall cell lung cancer and metastatic pancreatic cancer, Erlotinib is also eYcacious with bevacizumab in renal cancer [84]. An interesting multicenter phase II clinical trial is examining the eVects of erlotinib and green tea extract (Polyphenon E) in preventing cancer recurrence in former smokers with resected UC [82]. The M.D. Anderson Cancer center is also conducting a phase II study that examines the value of neoadjuvant erlotinib in patients with muscleinvasive or recurrent superWcial (Ta-1) UC requiring cystectomy [82]. Cetuximab Cetuximab (Erbitux; ImClone, New York, NY) is one of two monoclonal antibodies against EGFR that has been licensed for clinical use. It is a chimeric murine immunoglobulin type G1 (IgG1). After the antibody binds to the extracellular domain of EGFR, the receptor is internalized and degraded without receptor phosphorylation and activation, which leads to receptor down-regulation at the cell surface, reducing the availability of EGFR on the cell surface and inhibiting downstream signaling. The antitumor activity of cetuximab includes inhibition of tumor cell proliferation, G0/G1 cell cycle arrest, induction of apoptosis, inhibition of invasion and metastasis, and enhancement of radiosensitivity [85]. Being an IgG1 isotype antibody, it also has the potential for mediating antibody-dependent cell-mediated cytotoxicity and complement Wxation [86]. The half-life of cetuximab is 7 days, allowing once-weekly dosing, which is convenient for chemotherapy regimens. Patients receiving cetuximab often have acneiform rashes that commonly develop over the face and upper trunk [70]. Cetuximab can inhibit bladder tumor cell growth in vitro
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EGFR TKI
Blocks EGFR
Blocks ErbB2
Reversible inhibition of EGFR and ErbB2
Inhibition of VEGFR2/3, PDGFR, Raf, C-Kit and Flt3
Inhibition of VEGFR1-3, PDGFR, C-Kit and Flt3
Inhibition of VEGFR, PDGFR and C-Kit
Delivery of functional TP53 into cells
VEGF antibody
Binds VEGF and prevents its interaction with VEGFR on endothelial cells
Erlotiniba,f
Cetuximabb,g
Trastuzumabb,g
Lapatiniba,h
Sorafeniba,i
Sunitiniba,i
Pazopaniba,i
AdCMV-TP53c,j
Bevacizumabb,g
AXiberceptb/d,k
Lung cancer; liver, pelvic, soft tissue tumors; age-related macular degeneration; diabetic retinopathy
Renal, hepatic, pancreatic cancers; melanoma; sarcomas; age-related macular degeneration; diabetic retinopathy
NA
Lung, breast, hepatic, colon, renal, ovarian cancers; sarcomas; age-related macular degeneration
Breast cancer; neuroendocrine tumors
Lung, pancreatic, colorectal, ovarian, prostate cancers; melanoma; sarcomas
Lung, renal, breast, ovarian, prostate, esophageal cancers; glioblastoma multiforme
Lung, breast, pancreatic, gastric, colorectal, hepatic, endometrial, cervical, ovarian cancers
Colorectal, renal, breast, ovarian, prostate cancers; glioblastoma multiforme
Restricted
Other indications and trials
Hemorrhage; proteinuria
Hemorrhage; thrombosis; hypertension; impaired wound healing; gastrointestinal perforation; proteinuria
Bladder spasm
Skin toxicity; hypertension
Skin toxicity (discoloration, stomatitis); myelosuppression
Skin toxicity (rash, hand-foot skin reaction); hypertension; myelosuppression
Skin toxicity (rash or acneiform eruptions)
Cardiac toxicity (cardiomyopathy, congestive heart failure); infusion reactions (dyspnea, tumor site pain, muscle weakness)
Skin toxicity (rash or acneiform eruptions); infusion reactions
Skin toxicity (rash or acneiform eruptions)
Skin toxicity (rash or acneiform eruptions); acute lung injury; interstitial lung disease
Adverse eVectse
k
Adenoviral vector Soluble decoy VEGF receptor NA not available, EGFR epidermal growth factor receptor, TKI tyrosine kinase inhibitor, VEGFR vascular endothelial growth factor receptor, PDGFR platelet derived growth factor receptor, IgG1 immunoglobulin type G1
j
i
h
g
f
e
d
c
b
NA
Colorectal cancer; lung cancer; breast cancer
NA
NA
Renal cell carcinoma; gastrointestinal stromal tumor
Renal cell carcinoma; hepatocellular carcinoma
Breast cancer
Breast cancer
Colorectal cancer; head and neck squamous cell cancer
Non-small cell lung cancer; pancreatic cancer
Non-small cell lung cancer
Approved indications
Oral administration Intravenous infusion Intravesical instillation Subcutaneous injection General gastrointestinal toxicity, Xu-like symptoms and fatigue not listed Small molecule Monoclonal antibody Small molecule dual TKI Small molecule multitargeted TKI
EGFR TKI
GeWtiniba,f
a
Mechanism of action
Agent
Table 1 Novel targeted therapeutic agents with potential activity in bladder cancer
14 World J Urol (2009) 27:9–20
Iressa and Taxotere study in patients with metastatic UC
Phase II Gemcitabine + Cisplatin § Iressa in bladder TCC
Neoadjuvant erlotinib in TCC
Randomized study of Gemcitabine and Cisplatin § Cetuximab in UC
Trastuzumab in treating patients with previously treated, locally advanced, or metastatic UC
Gemcitabine and Cisplatin + Sorafenib in chemotherapy-naïve patients with locally advanced or metastatic UC
Sorafenib in treating patients with advanced or metastatic cancer of the urinary tract
Sunitinib in treating patients with progressive metastatic TCC
Pazopanib in treating patients with metastatic UC
GeWtinibb,f
GeWtinibc,f
Erlotiniba,f
Cetuximaba,f
Trastuzumabc,f
Sorafeniba,f
Sorafenibb,f
Sunitiniba,f
Pazopaniba,f
Cisplatin, Gemcitabine and Bevacizumab in combination for metastatic TCC
VEGF Trap in treating patients with recurrent, locally advanced, or metastatic UC
Bevacizumaba,f
AXiberceptb,f
b
Recruiting Active, not recruiting c Completed d ClinicalTrials identiWer; available at http://www.clinicaltrials.gov e Phase I f Phase II g Phase III NCI National Cancer Institute, UC urothelial carcinoma, TCC transitional cell carcinoma
a
Cisplatin, Bevacizumab, and Gemcitabine followed by surgery, Bevacizumab, and Paclitaxel in treating patients with locally advanced non-metastatic bladder cancer that can be removed by surgery
Bevacizumaba,f
Gene therapy in treating patients with advanced bladder cancer
GeWtinib + combination chemotherapy in treating patients with locally advanced or metastatic bladder cancer
GeWtinibb,f
AdCMV-TP53
BCG § GeWtinib in treating patients with high-risk bladder cancer
GeWtiniba,g
c,e
Trial
Agent
Table 2 Major ongoing clinical trials using targeted therapeutics in bladder cancer
California Cancer Consortium; NCI
Hoosier Oncology; Genentech; Eli Lilly; Walther Cancer Institute
Medical University of South Carolina
MD Anderson; NCI
Mayo Clinic; NCI
Memorial Sloan-Kettering; NCI
Princess Margaret Hospital, Canada; NCI
Memorial Sloan-Kettering; Bayer
Cancer and Leukemia Group B; NCI
University of Michigan; National Comprehensive Cancer Network; Bristol-Myers Squibb; ImClone
MD Anderson; Genentech
AstraZeneca
MD Anderson; AstraZeneca
Cancer and Leukemia Group B; NCI
National Cancer Institute of Canada
Sponsors and collaborators
11/2006
11/2005
09/2005
05/1998
08/2008
09/2006
08/2005
07/2008
07/2002
03/2008
09/2008
05/2003
02/2004
07/2002
04/2006
Start date
NCT00407485
NCT00234494
NCT00268450
NCT00003167
NCT00471536
NCT00397488
NCT00112671
NCT00714948
NCT00004856
NCT00645593
NCT00749892
NCT00246974
NCT00479089
NCT00041106
NCT00352079
IdentiWerd
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and in vivo [87]. In combination with paclitaxel, cetuximab shows synergistic growth inhibition in mice with metastatic human UC [88]. A phase II randomized study comparing the eVects of chemotherapy (GC) with or without cetuximab in patients with locally advanced or metastatic UC is currently underway [82]. Trastuzumab Trastuzumab (Herceptin; Genentech, South San Francisco, CA) is the Wrst recombinant humanized monoclonal antibody directed against the ErbB2 receptor. It is associated with a signiWcant risk of non-dose dependent cardiac toxicity [70]. A multicenter phase II study investigating the combination of paclitaxel, carboplatin, gemcitabine, and trastuzumab in 57 ErbB2 positive UC patients reported a 70% response rate [89]. Median time to progression and survival were 9.3 and 14.1 months, respectively. Lapatinip Lapatinib (Tykerb; GlaxoSmithKline, Middlesex, UK) is an oral small molecule TKI that inhibits the tyrosine kinase activity associated with EGFR (ErbB1) and ErbB2. It inhibits receptor signal processes by binding to the ATPbinding pocket of the EGFR/ErbB2 protein kinase domain, preventing auto-phosphorylation and subsequent activation of the signaling mechanism [70, 73, 90]. The evidence of schedule-dependent synergy between lapatinib and varying chemotherapy regimens has been studied on UC cell lines [91]. Lapatinib reduces cell viability in a dose-dependent fashion and potentiates GC eYcacy. This suggests that lapatinib may have therapeutic utility in the management of chemotherapy-naive metastatic UC. It may also enable reduced-dose chemotherapy, a potential toxicity-sparing strategy. When patients with advanced UC and evidence of EGFR and/or ErbB2 overexpression by IHC who progressed after cisplatin-based Wrst-line chemotherapy received lapatinib daily as monotherapy, there were no complete and only one (although marked) partial remission by independent radiological review [92]. However, patients with strong expression of one or both markers seemed to beneWt from the treatment in terms of stabilization of the disease.
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and metastatic UC. The ECOG has opened a phase II trial (E1804) of sorafenib in patients with recurrent UC. The Princess Margaret Hospital and the National Cancer Institute of Canada are also conducting another phase II study on its eVect on advanced or metastatic UC (Table 2). The Memorial Sloan-Kettering Cancer Center (MSKCC) is now conducting a phase II study to determine the response and progression-free survival rates for previously untreated patients with advanced/metastatic UC treated with sorafenib, gemcitabine, and cisplatin [82]. Sunitinib Sunitinib (Sutent; PWzer, New York, NY) is an oral small molecule inhibitor that has potent activity against C-Kit, FMS-like TKR-3 (Flt3), VEGFR1-3, and PDGFR. MSKCC investigators recently reported the early results of the clinical activity of sunitinib in previously treated UC patients who have failed prior chemotherapy [94]. Sunitinib administration resulted in radiographic metastatic tumor regression in liver, lung, soft tissue and lymph nodes. A second study from Spain recently conWrmed this activity in the Wrst-line setting, and Wnal results from both studies are awaited [83]. Because sunitinib reportedly has a substantial impact on time to disease progression in other malignancies, the University of Michigan is using this as a trial endpoint in a randomized phase II trial evaluating the drug’s role as maintenance therapy immediately after Wrst-line chemotherapy [95]. Pazopanib Pazopanib (GW786034; GlaxoSmithKline, Middlesex, UK) is a second-generation multitargeted TKI against VEGFR1-3, C-Kit and PDGFR. Preclinical evaluation has revealed excellent anti-angiogenic and anti-tumor activity, and synergism was observed in combination with chemotherapeutic drugs. SigniWcant anti-tumor activity was found in animal models of a variety of tumors, accompanied by desirable pharmacokinetics and oral bioavailability. The Mayo Clinic along with the National Cancer Institute is conducting a phase II study in patients with metastatic UC to evaluate the response rate to pazopanib in these patients [82]. It will also evaluate the pre- and post-treatment changes in serum VEGF levels in these patients.
Sorafenib AdCMV-TP53 Sorafenib (Nexavar; Bayer, Leverkusen, Germany) is an oral small molecule multikinase inhibitor targeting various molecules along the EGFR/MAPK signal transduction pathway. Recent reports have suggested that it also targets the VEGFR and PDGF receptor (PDGFR) families [93]. This drug is currently in phase II clinical trials for advanced
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The deleterious eVects of an altered p53 genotype have prompted investigations into the feasibility of delivering functional TP53 genes into urothelial cells. ReplicationdeWcient adenoviral vectors bearing the wild-type TP53 gene (AdCMV-TP53) have demonstrated tumor inhibition
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in UC cell lines and xenograft models [96]. Phase I clinical trials involving intravesical instillation of the vector have revealed a high level of tolerance, with increased transduction eYcacy and overall expression when used in combination with transduction-enhancing agents [97, 98]. Combination of cisplatin with AdCMV-TP53 has been shown to have a synergistic eVect leading to increased apoptosis, thus suggesting that the combination of adenoviral vector-mediated TP53 delivery with DNA-damaging agents should be further investigated in the context of UC [99]. ConXicting reports on the expression of the coxsackie adenovirus receptor that is important for the attachment of the vector to the target cells has been reported in UCs [100, 101], although the use of transduction-enhancing and diVerentiating agents seem to surmount some of the problems of receptor downregulation [98, 102]. Bevacizumab Bevacizumab (Avastin; Genentech, South San Francisco, CA) is the Wrst VEGF inhibitor to be approved by the FDA. It is a humanized IgG1 murine monoclonal antibody that binds all VEGF isoforms, thereby preventing ligand binding to both VEGFR1 and VEGFR2. Subsequent regression of tumor vessels, inhibition of new vessel formation, and apoptosis of tumor endothelial cells can lead to stabilization or response of many solid tumors. Bevacizumab is being studied in combination with paclitaxel in muscle-invasive, non-metastatic UC, and in combination with GC for metastatic UC [82]. Positive response to bevacizumab in patients with metastatic chemotherapy-refractory UC has recently been reported [103]. Another ongoing phase II trial is aimed at investigating the eVect of neoadjuvant bevacizumab with GC followed by surgery, bevacizumab, and paclitaxel in patients with locally advanced non-metastatic surgically resectable UC [82, 104]. Combination therapy with sorafenib and bevacizumab has also shown promising clinical activity [105]. AXibercept AXibercept (VEGF Trap; Regeneron, Tarrytown, NY) is a fully humanized, soluble decoy VEGF receptor generated by fusing the extracellular domains of VEGFR1 and VEGFR2 to the Fc portion of human IgG1. Like bevacizumab, this agent binds and inactivates VEGF. However, this molecule may also bind other VEGF family members such as placental growth factor and VEGF-B. In addition, its binding aYnity for VEGF is similar to that of the highaYnity VEGFR1, resulting in binding that is potentially 100-fold tighter than is achieved with bevacizumab [106]. These unique features diVerentiate this agent from other anti-VEGF strategies. AXibercept has demonstrated dose-
17
dependent inhibition of tumor growth and angiogenesis in preclinical mouse and primate models [107]. This agent is currently in phase II clinical trials for treating patients with recurrent, locally advanced or metastatic UC [82].
Conclusion UC is a biologically intriguing disease. Its molecular pathogenesis is now increasingly understood. SigniWcant insight has been obtained into the mechanisms involved in the control of signal transduction, cell cycle regulation, and angiogenesis pathways. Management strategies now need to focus on the molecular alterations involved in each individual tumor besides the conventional histopatholgic prognostics. As carcinogenesis is clearly a multi-step process, synergistic therapeutic regimens that are aimed at multiple targets are more promising than targeting a single step of a pathway. While many agents have been developed to antagonize the upstream function of cell surface TKRs, very few therapeutics are currently available to inhibit or restore the function of key transcriptional factors that are crucial downstream eVectors. With the power of targeted therapeutics, the future management of UC will: (a) be tailored not only to histopatholgic parameters but also to the molecular alterations and predicted biological tumor behavior; (b) include multimodal approaches utilizing diVerent surgical and medical options including novel targeted therapies; and (c) be outcome-based, evidence-based and personalized. ConXict of interest statement The authors are not aware of any conXicts of interest that might be perceived as aVecting the objectivity of this paper.
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