Novel approaches with targeted therapies in bladder cancer: Therapy of bladder cancer by blockade of the epidermal growth factor receptor family

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Abstract

The improved understanding of the molecular biology of urothelial malignancies is helping to define the role of new targets and prognostic indices that can direct the most appropriate choice of treatment for advanced disease. Many human tumors express high levels of growth factors and their receptors that can be used as potential therapeutical targets. Tyrosine–kinase receptors, including many growth factor receptors such the receptors for epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and Her2/neu, have been found overexpressed in urothelial tumors. For many of these growth factor receptors, the degree of expression has been associated with the progression of cancer and a poor prognosis. Among the best studied growth factor receptors are the two members of EGF receptor familiy EGFr (ErbB-1), and Her2/neu (ErbB-2). Several preclinical studies in bladder cancer models, have confirmed that systemic administration of growth factor inhibitors inhibits the growth and metastasis of human transitional cell carcinoma established in the bladder wall of athymic nude mice. Additional studies indicate that therapy with EGFR inhibitors enhances the activity of conventional cytoreductive chemotherapeutic agents, in part by inhibiting tumor cell proliferation, angiogenesis, and inducing apoptosis. Novel targeted therapy hold promise to improve the current results of bladder cancer treatment. Based on the success seen with anti-HER2 monoclonal antibodies (Herceptin®) and the promising results with EGFR targeted agents (IMC-C225 Cetuximab®, ZD1389 Iressa®, OSI-774 Tarceva®, GW 57016) in other tumor types, and based on the results obtained in preclinical models, there is a great interest in assessing these agents in patients with bladder cancer. Several trials are now ongoing testing these new agents alone or in combination with chemotherapy in bladder cancer patients. The integration of these newer biologic agents, probably to supplement rather than to supplant chemotherapeutic drugs, should be a primary direction of research with the objective to interfere with multiple aspects of bladder cancer progression. However, the value of integration of biologically targeted agents into combined modality treatment for patients with bladder cancer has still to be proven.

Introduction

Transitional cell carcinoma of the bladder (TCC) is the fifth most common solid malignancy in the United States. It is diagnosed in approximately 54,000 patients and results in 12,000 deaths annually [1]. The standard treatment for operable invasive bladder cancer is radical cystectomy. Patients with metastatic TCC are usually treated with systemic chemotherapy [2], [3], [4], [5]. For more than a decade, the standard treatment for metastatic urothelial cancer has been combination therapy with methotrexate, vinblastine, adriamycin and cisplatin (MVAC). This regimen is consistently reported to produce a median survival in the range of 13–15 months [3], [4]. Despite considerable effort to dose-escalate or otherwise modulate the components of M-VAC [6], no improvement in survival has been observed. In the search for regimens more active than M-VAC, regimens based on gemcitabine, ifosfamide, and/or paclitaxel have attracted considerable interest [7], [8], [9], [10]. Although high response rates have been reported using these new agents in combination, a recent randomized trial of the combination of gemcitabine and cisplatin (GC) versus MVAC failed to demonstrate an improved survival with the doublet. However, GC had an improved toxicity profile [11].

The desire to improve outcome utilizing new active agents led to the development of a phase I/II trial testing the combination of paclitaxel, cisplatin, and gemcitabine [12]. The study gave an overall response rate of 78% and a median survival time for the phase II part of the study of 15.8 months. Based upon the favorable results obtained with this triplet, the EORTC, the Southwest Oncology Group (SWOG), National Cancer Institute of Canada (NCIC), the Radiation Therapy Oncology Group (RTOG), the Spanish Oncology Genito-Urinary Group (SOGUG) and several other collaborative groups have begun a randomized trial to compare the three drug regimen of paclitaxel–cisplatin–gemcitabine with the two-drug combination of GC. Similarly, investigators at Wayne State University conducted a phase II trial incorporating gemcitabine into the carboplatin, paclitaxel combination in previously untreated patients with advanced urothelial malignancy with also encouraging results. The median response rate was 68% with a median survival of 14.7 months [13]. However, to date there are no compelling data that survival could be definitively improved with the triplet regimens and the role of triplet therapy awaits outcome from ongoing randomized trials.

Currently, there is a growing conviction that the cytotoxic paradigm, as we have known it, will not provide the means to qualitatively change the outcome for patients with metastatic bladder cancer. Hence, the importance of developing novel therapeutic approaches. Although, relatively little is known about the biological markers governing advanced bladder cancer response to treatment, it is especially important to identify these cellular and molecular alterations, as well as the manner in which they influence host–tumor interactions since gaining such knowledge is essential for the design of more effective future therapies.

Section snippets

Targeted treatments in urologic malignancies

Cells must acquire a series of traits in order to become malignant and to develop advanced lethal cancers. These traits have been elegantly grouped in the following categories: growth factor independence; insensitivity to antiproliferative signals; escape from apoptosis; unlimited proliferative capacity; angiogenesis; and ability for invasion and metastasis. The knowledge of the molecular pathways that underlie each of these traits is critical to improve the treatment of cancer at least from

Biological role of EGF receptor family in malignancy

EGF receptor and HER2 are plasma membrane glycoproteins that belong to the EGF receptor family (also known as type I receptor tyrosine kinases (TKs) or ErbB TK receptors). This receptor family is comprised of four closely related receptors: the EGF receptor itself (ErbB1/EGFr/HER1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). Since the EGF receptor was the first one identified, this receptor family is also collectively described as the EGF receptor family. These receptors are composed of

McAb against EGF receptor

The demonstration that anti-EGF receptor monoclonal antibodies inhibited the growth of cancer cells expressing the EGF receptor [39], [40], [41], [42] lead to a series of clinical trials with anti-EGF receptor monoclonal antibodies in patients with EGF receptor positive tumors.

Of a series of anti-EGFR monoclonal antibodies under clinical development, IMC-C225 (Cetuximab™), is the one in a more advanced phase in clinical development, with particularly promising results. Cetuximab is a

Conclusions

The findings observed with different agents and in different tumor types validate EGFR and Her-2 as useful targets for cancer therapy. Preclinical studies in bladder cancer models, confirm that systemic administration of EGFR inhibitors inhibits the growth and metastasis of human TCC established in the bladder wall of athymic nude mice. Therapy with these agents has a significant antitumor effect mediated, in part, by inhibition of angiogenesis and invasion. The downregulation of angiogenic

Reviewers

Professor Hans von der Maase, Professor of Oncology, Department of Oncology, Aarhus University Hospital, DK-8000 Aarhus, Denmark.

Ronald de Wit, MD, PhD, Medical Oncologist, Erasmus Medical Center, Groene Hilledijk 301, Room G4-82, Postbus 5201, NL-3075 EA Rotterdam, The Netherlands.

Joaquim Bellmunt MD, Genitourinary Oncology at Vall d'Hebron University Hospital. Autónoma University of Barcelona. Barcelona. Consultant of the Chemotherapy Committee of the EORTC Genito-Urinary Group. EORTC-30987 Study Chairman. EORTC-30986 Study Co-Coordinator.

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    Joaquim Bellmunt MD, Genitourinary Oncology at Vall d'Hebron University Hospital. Autónoma University of Barcelona. Barcelona. Consultant of the Chemotherapy Committee of the EORTC Genito-Urinary Group. EORTC-30987 Study Chairman. EORTC-30986 Study Co-Coordinator.

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