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ABSTRACT: Cancer remains one of the leading causes of death in the developed countries and cancer mortality is expected to rise globally. Despite encouraging developments regarding targeted drugs, the most prevalent cancer mortality remains metastatic disease. Therefore, drugs that target cancer progression, invasion and metastasis are clearly needed. One of the most interesting targets in this setting is transforming growth factor β (TGF-β). TGF-β can promote tumor growth, invasion and metastasis. However, TGF-β also has a physiological, opposing role: maintaining tissue homeostasis and suppression of tumor progression. The window of effective TGF-β targeting is therefore evidently small, which poses a clear challenge in selecting patients at the right time. Despite this complexity, several TGF-β inhibitors are currently in clinical development, modulating TGF-β production, activation or signaling. Still, specificity and long term toxicity remain unclear, emphasizing the importance of careful monitoring of clinical trials. Development and application of these drugs in the clinic require adequate insight and evaluation methods for the role of TGF-β during tumor invasion and metastasis. In this review, presently available methods for clinical evaluation will be discussed, such as an ex vivo stimulation assay, TGF-β response signature and molecular imaging techniques. Future clinical trials incorporating the validation of these evaluation methods will show which method will be most predictive and suitable for clinical application.
Pharmacology [?] Therapeutics 05/2012; 135(2):123-32. · 8.56 Impact Factor
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Thijs H Oude Munnink,
Marlous E A Arjaans,
Hetty Timmer-Bosscha, Carolina P Schröder,
Jan W Hesselink,
Silke R Vedelaar,
Annemiek M E Walenkamp,
Michael Reiss,
Richard C Gregory,
Marjolijn N Lub-de Hooge,
Elisabeth G E de Vries
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ABSTRACT: Transforming growth factor-β (TGF-β) promotes cancer invasion and metastasis and is therefore a potential drug target for cancer treatment. Fresolimumab, which neutralizes all mammalian active isoforms of TGF-β, was radiolabeled with (89)Zr for PET to analyze TGF-β expression, antibody tumor uptake, and organ distribution.
(89)Zr was conjugated to fresolimumab using the chelator N-succinyldesferrioxamine-B-tetrafluorphenol. (89)Zr-fresolimumab was analyzed for conjugation ratio, aggregation, radiochemical purity, stability, and immunoreactivity. (89)Zr-fresolimumab tumor uptake and organ distribution were assessed using 3 protein doses (10, 50, and 100 μg) and compared with (111)In-IgG in a human TGF-β-transfected Chinese hamster ovary xenograft model, human breast cancer MDA-MB-231 xenograft, and metastatic model. Latent and active TGF-β1 expression was analyzed in tissue homogenates with enzyme-linked immunosorbent assay.
(89)Zr was labeled to fresolimumab with high specific activity (>1 GBq/mg), high yield, and high purity. In vitro validation of (89)Zr-fresolimumab showed a fully preserved immunoreactivity and long (>1 wk) stability in solution and in human serum. In vivo validation showed an (89)Zr-fresolimumab distribution similar to IgG in most organs, except for a higher uptake in the liver in all mice and higher kidney uptake in the 10-μg group. (89)Zr-fresolimumab induced no toxicity in mice; it accumulated in primary tumors and metastases in a manner similar to IgG. Both latent and active TGF-β was detected in tumor homogenates, whereas only latent TGF-β could be detected in liver homogenates. Remarkably high (89)Zr-fresolimumab uptake was seen in sites of tumor ulceration and in scar tissue, processes in which TGF-β is known to be highly active.
Fresolimumab tumor uptake and organ distribution can be visualized and quantified with (89)Zr-fresolimumab PET. This technique will be used to guide further clinical development of fresolimumab and could possibly identify patients most likely to benefit.
Journal of Nuclear Medicine 11/2011; 52(12):2001-8. · 6.38 Impact Factor
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Journal of Clinical Oncology 05/2010; 28(21):e355-6; author reply e357. · 18.37 Impact Factor
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Thijs H Oude Munnink,
Maarten A de Korte,
Wouter B Nagengast,
Hetty Timmer-Bosscha, Carolina P Schröder,
Johan R de Jong,
Guus A M S van Dongen,
Michael Rugaard Jensen,
Cornelia Quadt,
Marjolijn N Lub-de Hooge,
Elisabeth G E de Vries
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ABSTRACT: NVP-AUY922, a potent heat shock protein (HSP) 90 inhibitor, downregulates the expression of many oncogenic proteins, including the human epidermal growth factor receptor-2 (HER2). Because HER2 downregulation is a potential biomarker for early response to HSP90-targeted therapies, we used the (89)Zr-labelled HER2 antibody trastuzumab to quantify the alterations in HER2 expression after NVP-AUY922 treatment with HER2 positron emission tomography (PET) imaging. The HER2 overexpressing human SKOV-3 ovarian tumour cell line was used for in vitro experiments and as xenograft model in nude athymic mice. In vitro HER2 membrane expression was assessed by flow cytometry and a radio-immuno assay with (89)Zr-trastuzumab. For in vivo evaluation, mice received 50mg/kg NVP-AUY922 intraperitoneally every other day. (89)Zr-trastuzumab was injected intravenously 6d before NVP-AUY922 treatment and after 3 NVP-AUY922 doses. MicroPET imaging was performed at 24, 72 and 144h post tracer injection followed by ex-vivo biodistribution and immunohistochemical staining. After 24h NVP-AUY922 treatment HER2 membrane expression showed profound reduction with flow cytometry (80%) and radio-immuno assay (75%). PET tumour quantification, showed a mean reduction of 41% (p=0.0001) in (89)Zr-trastuzumab uptake at 144h post tracer injection after NVP-AUY922 treatment. PET results were confirmed by ex-vivo (89)Zr-trastuzumab biodistribution and HER2 immunohistochemical staining. NVP-AUY922 effectively downregulates HER2, which can be monitored and quantified in vivo non-invasively with (89)Zr-trastuzumab PET. This technique is currently under clinical evaluation and might serve as an early biomarker for HSP90 inhibition in HER2 positive metastatic breast cancer patients.
European journal of cancer (Oxford, England: 1990) 02/2010; 46(3):678-84. · 4.12 Impact Factor
