Significant systemic therapeutic effects of high-LET immunoradiation by 212Pb-trastuzumab against prostatic tumors of androgen-independent human prostate cancer in mice

June 01, 2012

INTERNATIONAL JOURNAL OF ONCOLOGY 40: 1881-1888, 2012

ZONGQING TAN, PINGPING CHEN, NATHAN SCHNEIDER, SAMUEL GLOVER, LINGLING CUI, JULIEN TORGUE, OLIVIER RIXE, HENRY B. SPITZ and ZHONGYUN DONG

Abstract

The purpose of this study was to determine therapeutic effects and systemic toxicity of 212Pb-trastuzumab in an orthotopic model of human prostate cancer cells in nude mice. TCMC-Trastuzumab was radiolabeled with 212Pb. The 212Pb-trastuzumab generated from the procedure was intact and had high binding affinity with a dissociation constant (of 3.9±0.99 nM. PC-3MM2 cells, which expressed a lower level of HER2 both in culture and in tumors, were used in therapy studies. A single intravenous injection of 212Pb-trastuzumab reduced tumor growth by 60-80%, reduced aortic lymph node metastasis, and prolonged the survival of tumor-bearing mice. Treatment with 212Pb-trastuzumab did not cause significant changes in body weight, serum glutamic pyruvic transaminase (SGPT), blood urea nitrogen (BUN), hematological profiles, and histological morphology of several major organs of tumor-bearing mice. These findings suggest that a systemic delivery of 212Pb-trastuzumab could be an effective modality for management of advanced human prostate cancer.

Introduction

Prostate cancer is the most common cancer and the second most common cause of cancer death among men in the United States (1). As detection techniques improve, more patients are diagnosed with localized disease and can be cured by either surgery or radiation therapy. Metastasis in many patients, however, still occurs prior to the initial diagnosis. Because of natural resistance to most chemotherapeutic agents, hormonal therapy is the mainstay treatment for advanced diseases, however, this treatment is only palliative: delaying tumor progression to castration-refractory prostate cancer (CRPC) by an average of less than 18 months (2,3). Currently, there are limited effective therapies for management of advanced CRPC. Thus, there is a great need to develop novel and more effective therapies in this setting.

Numerous studies have clearly documented significant contribution of HER2/EGFR signaling in the progression of human prostate cancer and HER2 overexpression in prostate cancer occurs at relevant frequency without gene amplification. Increased HER2 expression correlates with an aggressive behavior of tumor cells through stimulation of tumor cell proliferation and was associated with Ki67 labeling index (4). HER2 is overexpressed in approximately 20-30% of prostate cancers and in 78% of androgen-independent cancers (5). It is, therefore, preferentially expressed in hormone-refractory and metastatic prostate cancers (6). The pretreatment serum HER2 and its extracellular domain (HER2 ECD) values were shown to be independent predictors of biochemical recurrence of prostate cancer (7,8) and were associated with prostate cancer progression after radical prostatectomy (9,10). Moreover, chronic treatment with bicalutamide induced overexpression of HER2 and a reduction of PTEN and EGFR/HER2 ratio, which was associated with an increase in Akt and Erk activity (11,12). In addition to stimulation of tumor cell proliferation through HER2/EGFR signaling, HER2 also contributes to prostate cancer progression through stabilizing AR protein in the absence of androgen (13) phosphorylating and trans-activating AR transactivation (14-16), as well as crosstalking with TrkA in a subset of prostate cancer cells (17).

Preclinical therapy studies showed that downregulation of HER2 expression and activation by BN/GRPR inhibitors AN-215 and RC-3095 inhibited growth of LNCaP and PC-3 human prostate cancer cells (18). Moreover, inhibitory effects of EGFR inhibitor erlotinib were much more potent on androgen-sensitive prostate cancer cells when compared to those on CRPC cells. Whereas the carnertinib efficacy may have therapeutical significance in HER2 overexpressing AR+ CRPC models in combination with hormone manipulation (19). However, preclinical studies in animal models of human prostate cancer using HER2-specific antibody trastuzumab alone showed limited therapeutic responses (20-22). Similarly, HER2 dimerization inhibitor pertuzumab as a single agent was found to be ineffective in patients with hormone-refractory prostate cancer (23). Two additional multicenter phase II trials using the EGFR-HER2 inhibitor lapatinib (24) and trastuzumab (25) confirmed that the treatment was well tolerated but demonstrated no significant antitumor activity even in a hormonal therapy-naive population of patients.

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