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Sietske B M Gaykema,
Adrienne H Brouwers,
Marjolijn N Lub-de Hooge,
Rick G Pleijhuis,
Hetty Timmer-Bosscha,
Linda Pot,
Gooitzen M van Dam,
Sibylle B van der Meulen,
Johan R de Jong,
Joost Bart,
Jakob de Vries,
Liesbeth Jansen, Elisabeth G E de Vries,
Carolien P Schröder
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ABSTRACT: Vascular endothelial growth factor (VEGF)-A is overexpressed in most malignant and premalignant breast lesions. VEGF-A can be visualized noninvasively with PET imaging and using the tracer (89)Zr-labeled bevacizumab. In this clinical feasibility study, we assessed whether VEGF-A in primary breast cancer can be visualized by (89)Zr-bevacizumab PET. METHODS: Before surgery, breast cancer patients underwent a PET/CT scan of the breasts and axillary regions 4 d after intravenous administration of 37 MBq of (89)Zr-bevacizumab per 5 mg. PET images were compared with standard imaging modalities. (89)Zr-bevacizumab uptake was quantified as the maximum standardized uptake value (SUVmax). VEGF-A levels in tumor and normal breast tissues were assessed with enzyme-linked immunosorbent assay. Data are presented as mean ± SD. RESULTS: Twenty-five of 26 breast tumors (mean size ± SD, 25.1 ± 19.8 mm; range, 4-80 mm) in 23 patients were visualized. SUVmax was higher in tumors (1.85 ± 1.22; range, 0.52-5.64) than in normal breasts (0.59 ± 0.37; range, 0.27-1.69; P < 0.001). The only tumor not detected on PET was 10 mm in diameter. Lymph node metastases were present in 10 axillary regions; 4 could be detected with PET (SUVmax, 2.66 ± 2.03; range, 1.32-5.68). VEGF-A levels in the 17 assessable tumors were higher than in normal breast tissue in all cases (VEGF-A/mg protein, 184 ± 169 pg vs. 10 ± 21 pg; P = 0.001), whereas (89)Zr-bevacizumab tumor uptake correlated with VEGF-A tumor levels (r = 0.49). CONCLUSION: VEGF-A in primary breast cancer can be visualized by means of (89)Zr-bevacizumab PET.
Journal of Nuclear Medicine 05/2013; · 6.38 Impact Factor
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ABSTRACT: Placental growth factor (PlGF) is a member of the proangiogenic vascular endothelial growth factor family, which is upregulated in many tumors. RO5323441, a humanized monoclonal antibody against PlGF, showed antitumor activity in human tumor xenografts. We therefore aimed to radiolabel RO5323441 and preclinically validate this tracer to study drug tumor uptake and organ distribution by PET imaging. (89)Zr-RO5323441 was tested for stability and immunoreactivity in vitro. METHODS: The tumor uptake and organ distribution for 10, 50, and 500 μg of (89)Zr-RO5323441 was assessed in mice bearing human PlGF-expressing hepatocellular cancer (Huh7) xenografts or human renal cell carcinoma (ACHN) xenografts without detectable human PlGF expression. The effect of pretreatment with RO5323441 (20 mg/kg) on (89)Zr-RO5323441 tumor uptake was analyzed in Huh7 xenografts. (111)In-IgG served as a control for nonspecific tumor uptake and organ distribution. Cy5-RO5323441 was injected to study the intratumor distribution of RO5323441 with fluorescence microscopy. RESULTS: (89)Zr-RO5323441 showed a time- and dose-dependent tumor accumulation. Uptake in Huh7 xenografts at 10 μg of (89)Zr-RO5323441 was 8.2% ± 1.7% injected dose (ID)/cm(3) at 144 h after injection, and in ACHN xenografts it was 5.5 ± 0.3 %ID/cm(3) (P = 0.03). RO5323441 pretreatment of Huh7 xenograft-bearing mice reduced (89)Zr-RO5323441 tumor uptake to the level of nonspecific (111)In-IgG uptake. Cy5-RO5323441 was present in the tumors mainly in the microenvironment. CONCLUSION: The findings show that RO5323441 tumor uptake is PlGF-specific and time- and dose-dependent.
Journal of Nuclear Medicine 04/2013; · 6.38 Impact Factor
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ABSTRACT: In solid tumors, angiogenesis occurs in the setting of a defective vasculature and impaired lymphatic drainage that is associated with increased vascular permeability and enhanced tumor permeability. These universal aspects of the tumor microenvironment can have a marked influence on intratumoral drug delivery that may often be underappreciated. In this study, we investigated the effect of blood vessel normalization in tumors by the antiangiogenic drug bevacizumab on antibody uptake by tumors. In mouse xenograft models of human ovarian and esophageal cancer (SKOV-3 and OE19), we evaluated antibody uptake in tumors by PET imaging 24 and 144 hours after injection of 89Zr-trastuzumab (SKOV-3 and OE19), 89Zr-bevacizumab (SKOV-3) or 89Zr-IgG (SKOV-3) before or after treatment with bevacizumab. Intratumor distribution was assessed by fluorescence microscopy along with mean vascular density (MVD) and vessel normalization. Notably, bevacizumab treatment decreased tumor uptake and intratumoral accumulation compared to baseline in the tumor models relative to controls. Bevacizumab treatment also reduced MVD in tumors and increased vessel pericyte coverage. These findings are clinically important, suggesting caution in designing combinatorial trials with therapeutic antibodies due to a possible reduction in tumoral accumulation that may be caused by bevacizumab co-treatment.
Cancer Research 04/2013; · 7.86 Impact Factor
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ABSTRACT: Currently, tumour response following drug treatment is based on measurement of anatomical size changes. This is often done according to Response Evaluation Criteria in Solid Tumours (RECIST) and is generally performed every 2-3 cycles. Bone metastases, being the most common site of distant metastases in breast cancer, are not measurable by RECIST. The standard response measurement provides no insight in changes of molecular characteristics. In the era of targeted medicine, knowledge of specific molecular tumour characteristics becomes more important. A potential way to assess this is by means of molecular imaging. Molecular imaging can visualise general tumour processes, such as glucose metabolism with (18)F-fluorodeoxyglucose ((18)F-FDG) and DNA synthesis with (18)F-fluorodeoxythymidine ((18)F-FLT). In addition, an increasing number of more specific targets, such as hormone receptors, growth factor receptors, and growth factors can be visualised. In the future molecular imaging may thus be of value for personalised treatment-selection by providing insight in the expression of these drug targets. Additionally, when molecular changes can be detected early during therapy, this may serve as early predictor of response. However, in order to define clinical utility of this approach results from (ongoing) clinical trials is required. In this review we summarise the potential role of molecular imaging of general tumour processes as well as hormone receptors, growth factor receptors, and tumour micro-environment for predicting and monitoring treatment response in breast cancer patients.
European journal of pharmacology 03/2013; · 2.59 Impact Factor
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European journal of cancer (Oxford, England: 1990) 03/2013; · 4.12 Impact Factor
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ABSTRACT: Recent studies have revealed that BRCA1 and BRCA2 germline mutation-related breast cancers show frequent overexpression of hypoxia inducible factor-1α (HIF-1α), the key regulator of the hypoxia response. However, the question remained whether hypoxia is a late stage bystander or a true carcinogenetic event in patients with hereditary predisposition. We therefore studied HIF-1α overexpression in ductal carcinoma in situ (DCIS), an established precursor of invasive breast cancer.We used immunohistochemistry to examine the expression of the hypoxia markers HIF-1α, CAIX and Glut-1 in DCIS and available invasive carcinoma lesions of 32 BRCA1, 16 BRCA2 and 77 non-BRCA mutation-related cases. HIF-1α expression was detected in 63% of BRCA1 and 62% of BRCA2 as compared to 34% of non-BRCA mutation-related DCIS cases (p = 0.005). CAIX overexpression was present in 56% of BRCA1 and 44% of BRCA2 as compared to 6% of non-BRCA mutation-related DCIS cases (p = 0.000). Glut-1 overexpression was observed in 59% of BRCA1, 75% of BRCA2 and 67% of non-BRCA mutation-related DCIS cases (p = 0.527). Overall, HIF-1α, CAIX and Glut-1 expression in BRCA mutation-related DCIS matched the expression in the accompanying invasive cancers in 60% or more of cases. In non-BRCA mutation-related cases the expression of the hypoxia markers in DCIS matched the expression in the invasive part in 46% or more of the cases.Although BRCA1 and BRCA2 germline mutation-related invasive breast cancers are different in many ways, the hypoxia-related proteins HIF-1α, CAIX and Glut-1 are expressed in both DCIS and invasive lesions of BRCA1 and BRCA2 mutation carriers. This suggests that hypoxia may already play a role in the DCIS stage of BRCA1 and BRCA2 germline mutation related breast carcinogenesis, and may also drive cancer progression. Hypoxia-related proteins are therefore putative targets for therapy and molecular imaging for early detection and monitoring therapy response in BRCA mutation patients.
PLoS ONE 01/2013; 8(2):e56055. · 4.09 Impact Factor
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ABSTRACT: In murine testicular carcinoma (TC) cells wild-type p53 contributes to sensitivity to DNA-damaging drugs in a dose-dependent way. In human TC, however, the role of wild-type p53 functionality in chemotherapeutic response remains elusive. We analyzed functionality of wild-type p53 in cisplatin sensitivity in the human TC setting using a p53 short interfering (si)RNA approach. The cisplatin-sensitive TC cell line (Tera), the subline with acquired cisplatin resistance (Tera-CP) and a panel of intrinsically resistant TC cell lines (Scha and 2102EP), all expressing wild-type p53, were used. p53 and p53 transcriptional targets MDM2 and p21 (Waf1/Cip1) (p21) were expressed in a p53 transactivation-dependent way in all TC cell lines. Following cisplatin exposure, expression levels of p53 increased, with a subsequent increase in MDM2 and p21 mRNA and protein levels and Fas cell membrane levels. Downregulation of p53 with siRNA lowered cisplatin-induced apoptosis in Tera and Tera-CP, which was associated with a diminished Fas membrane expression. In contrast, p53 suppression augmented cisplatin-induced apoptosis in Scha and 2102EP and concomitantly strongly suppressed MDM2 and p21 mRNA and protein expression. Our results indicate that p53 is involved in transactivation of pro- and anti-apoptotic genes in untreated and cisplatin-treated TC cells, but subtle differences are present between TC cell lines. The opposite role of p53 in cisplatin-induced apoptosis among TC cell lines demonstrates the importance of the cellular context for the p53 transactivation pathway in TC cells.
Cell cycle (Georgetown, Tex.) 11/2012; 11(24). · 5.36 Impact Factor
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ABSTRACT: The multikinase inhibitor sorafenib is highly effective against certain types of cancer in the clinic and prevents colon cancer cell proliferation in vitro. Non-steroidal anti-inflammatory drugs such as acetylsalicylic acid (aspirin) have shown activity against colon cancer cells. The aims of this study were to determine whether the combination of aspirin with sorafenib has enhanced anti-proliferative effects and increases recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL)-induced apoptosis in the human SW948, Lovo, Colo205, Colo320, Caco-2, and HCT116 colon cancer cell lines. In four cell lines, aspirin strongly stimulated the anti-proliferative effects of sorafenib ( four-fold enhancement) by inducing cell cycle arrest. Furthermore, combining low doses of aspirin (≤ 5 mM) and sorafenib (≤ 2.5 µM) greatly sensitized TRAIL-sensitive and TRAIL-resistant colon cancer cells to rhTRAIL, much more potently than either drug combined with rhTRAIL. The increase in rhTRAIL sensitivity was due to inhibition of FLIP and Mcl-1 protein expression following aspirin and sorafenib co-treatment, as confirmed by knockdown studies. Next, the clinical relevance of targeting FLIP and Mcl-1 in colon cancer was examined. Using immunohistochemistry, we found that Mcl-1 expression was significantly increased in colon adenoma and carcinoma patient material compared to healthy colonic epithelium, similar to the enhanced FLIP expression we recently observed in colon cancer. These results underscore the potential of combining low doses of aspirin with sorafenib to inhibit proliferation and target the anti-apoptotic proteins FLIP and Mcl-1 in colon cancer cells. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The Journal of Pathology 11/2012; · 6.32 Impact Factor
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Arne R M van der Bilt,
Anton G T Terwisscha van Scheltinga,
Hetty Timmer-Bosscha,
Carolien P Schröder,
Linda Pot,
Jos G W Kosterink,
Ate G J van der Zee,
Marjolijn N Lub-de Hooge,
Steven de Jong, Elisabeth G E de Vries,
An K L Reyners
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ABSTRACT: PURPOSE: The mammalian target of rapamycin (mTOR) pathway is frequently activated in ovarian cancers. mTOR inhibitors, like everolimus, can reduce vascular endothelial growth factor-A (VEGF-A) production by cancer cells. We investigated whether early everolimus treatment effects could be monitored by positron emission tomography (PET) with 89Zr-bevacizumab. Experimental design: The effect of everolimus on VEGF-A secretion was determined in a panel of human ovarian cancer cell lines and in A2780luc+ ovarian cancer cells xenografted subcutaneously in BALB/c mice. Mice received daily 10 mg/kg everolimus intraperitoneally for 14 days. PET scans with the tracer 89Zr-labeled bevacizumab were performed before and after treatment. Ex vivo 89Zr-bevacizumab biodistribution and correlative tissue analyses were performed. Tumor VEGF-A levels were measured with ELISA and mean vascular density (MVD) was determined with immunohistochemistry. RESULTS: Everolimus treatment reduced VEGF-A levels in the supernatant of all cell lines. Everolimus lowered 89Zr-bevacizumab tumor uptake by 21.7 ± 4.0% (SUVmean 2.3 ± 0.2 versus 2.9 ± 0.2, P < 0.01). Ex vivo biodistribution also demonstrated lower tracer uptake in the tumors of treated compared to control animals (7.8 ± 0.8 %ID/g versus 14.0 ± 1.7 %ID/g, P < 0.01), while no differences were observed for other tissues. This coincided with lower VEGF-A protein levels in tumor lysates in treated versus untreated tumors (P = 0.04) and reduced MVD (P < 0.01). CONCLUSION: Tumor VEGF-A levels are decreased by everolimus. 89Zr-bevacizumab PET could be used to monitor tumor VEGF-A levels as an early biomarker of the antiangiogenic effect of mTOR inhibitor therapy.
Clinical Cancer Research 09/2012; · 7.74 Impact Factor
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ABSTRACT: Classical chemotherapeutic anti-cancer treatments induce cell death through DNA damage by taking advantage of the proliferative behaviour of cancer cells. The more recent approach of targeted therapy (usually protein-targeted) has led to many treatments that are currently available or are under development, all of which are designed to strike at the critical driving forces of cancer cells. The interaction of the cancer cells with their microenvironment is one of these fundamental features of neoplasms that could be targeted in such cancer treatments. Haematological and solid tumour cells interact with their microenvironment through membrane chemokine receptors and their corresponding ligands, which are expressed in the tumour microenvironment. Important representatives of this system are the chemokine ligand CXCL12 and its receptor chemokine receptor 4 (CXCR4). This interaction can be disrupted by CXCR4 antagonists, and this concept is being used clinically to harvest haematopoietic stem/progenitor cells from bone marrow. CXCR4 and CXCL12 also have roles in tumour growth and metastasis, and more recently their roles in cancer cell-tumour microenvironment interaction and angiogenesis have been studied. Our review focuses on these roles and summarises strategies for treating cancer by disrupting this interaction with special emphasis on the CXCR4/CXCL12 axis. Finally, we discuss ongoing clinical trials with several classes of CXCR4 inhibitors, and their potential additive value for patients with a (therapy resistant) malignancy by sensitising cancer cells to conventional therapy.
European journal of cancer (Oxford, England: 1990) 06/2012; · 4.12 Impact Factor
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ABSTRACT: Insight into the expression of multiple vascular endothelial growth factor (VEGF) family members can support the implementation of anti-angiogenic therapy. This study aimed to assess VEGF family member expression in ovarian cancers and related omental metastases.
Tissue microarrays encompassing 270 primary cancers and 112 paired metastases were immunostained for VEGF-A, VEGF-B, VEGF-C and VEGF-D. Staining intensities were categorized as absent, weak, moderate or strong. Expression was related to clinicopathological characteristics and survival.
Immunohistochemical positivity (defined as moderate or strong expression) was observed for VEGF-A in 90%, VEGF-B in 4%, VEGF-C in 41% and VEGF-D in 55% of the primary ovarian cancers. VEGF-A expression correlated with VEGF-C and VEGF-D expression (P < 0.01). Simultaneous positivity for VEGF-A and VEGF-C or VEGF-D was observed in 38% and 54% of the cancers, respectively. Metastases showed positivity for VEGF-A in 78%, VEGF-B in 5%, VEGF-C in 26% and VEGF-D in 45% of cases. VEGF family member expression showed no independent prognostic significance in multivariate survival analysis.
VEGF-A, VEGF-C and VEGF-D are widely and often simultaneously expressed in ovarian cancer, which may contribute to bevacizumab resistance. Measuring their expression could support a rational, individualized choice of anti-angiogenic therapy and might be of predictive value. Studies are warranted to determine whether combinatorial analysis of VEGF family member expression can be used to predict anti-angiogenic drug efficacy.
Current pharmaceutical design 05/2012; 18(25):3784-92. · 4.41 Impact Factor
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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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ABSTRACT: PurposePositron emission tomography (PET) using 6-[18F]fluoro-L-dihydroxyphenylalanine (18F-dopa) has an excellent sensitivity to detect carcinoid tumour lesions. 18F-dopa tumour uptake and the levels of biochemical tumour markers are mediated by tumour endocrine metabolic activity. We
evaluated whether total 18F-dopa tumour uptake on PET, defined as whole-body metabolic tumour burden (WBMTB), reflects tumour load per patient, as measured
with tumour markers.
MethodsSeventy-seven consecutive carcinoid patients who underwent an 18F-dopa PET scan in two previously published studies were analysed. For all tumour lesions mean standardised uptake values
(SUVs) at 40% of the maximal SUV and tumour volume on 18F-dopa PET were determined and multiplied to calculate a metabolic burden per lesion. WBMTB was the sum of the metabolic burden
of all individual lesions per patient. The 24-h urinary serotonin, urine and plasma 5-hydroxindoleacetic acid (5-HIAA), catecholamines
(nor)epinephrine, dopamine and their metabolites, measured in urine and plasma, and serum chromogranin A served as tumour
markers.
ResultsAll but 1 were evaluable for WBMTB; 74 patients had metastatic disease. 18F-dopa PET detected 979 lesions. SUVmax on 18F-dopa PET varied up to 29-fold between individual lesions within the same patients. WBMTB correlated with urinary serotonin
(r = 0.51) and urinary and plasma 5-HIAA (r = 0.78 and 0.66). WBMTB also correlated with urinary norepinephrine, epinephrine, dopamine and plasma dopamine, but not with
serum chromogranin A.
ConclusionTumour load per patient measured with 18F-dopa PET correlates with tumour markers of the serotonin and catecholamine pathway in urine and plasma in carcinoid patients,
reflecting metabolic tumour activity.
Keywords
18F-dopa PET–Carcinoid tumour–Whole-body metabolic tumour burden–5-HIAA
European journal of nuclear medicine and molecular imaging 04/2012; 38(10):1854-1861. · 4.99 Impact Factor
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ABSTRACT: Despite efforts to improve chemotherapeutic efficacy in epithelial ovarian cancer, outcome for patients with advanced disease has remained unchanged since the introduction of standard carboplatin and paclitaxel. Interest has therefore shifted toward molecularly targeted therapies that interfere with important features of ovarian carcinogenesis, such as angiogenesis. Several angiogenesis inhibitors, targeting vascular endothelial growth factor (VEGF) ligands (bevacizumab, VEGF-Trap) or their receptors (VEGFR-targeted tyrosine kinase inhibitors) have been clinically evaluated. These agents demonstrated efficacy in phase II clinical trials. Results from phase III trials, in which bevacizumab was added to standard frontline chemotherapy, show a modest effect. Although the initial expectations for angiogenesis inhibitors have been tempered, further research is warranted to define their precise place in the treatment of ovarian cancer. This review summarizes the performed and ongoing studies with regard to angiogenesis inhibitors in ovarian cancer, and the available data on biomarkers for response prediction. Preclinical studies evaluating alternative angiogenesis inhibitors will also be discussed.
Critical reviews in oncology/hematology 04/2012; 84(2):224-42. · 5.27 Impact Factor
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ABSTRACT: In cervical cancer, the p53 and retinoblastoma (pRb) tumor suppressor pathways are disrupted by the human papilloma virus (HPV) E6 and E7 oncoproteins, because E6 targets p53 and E7 targets pRb for rapid proteasome-mediated degradation. We have investigated whether E6 suppression with small interfering RNA (siRNA) restores p53 functionality and sensitizes the HPV16-positive cervical cancer cell line SiHa to apoptosis by cisplatin, irradiation, recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL), or agonistic anti-Fas antibody. E6 siRNA resulted in decreased E6 mRNA levels and enhanced p53 and p21 expression, demonstrating the restoration of p53 functionality in SiHa cells, without inducing high levels of apoptosis (<10%). Cell surface expression of the proapoptotic death receptors (DRs) DR4, DR5, and Fas was not affected by E6 suppression. E6 suppression conferred susceptibility to cisplatin-induced apoptosis but not to irradiation-, rhTRAIL-, or anti-Fas antibody-induced apoptosis. Combining cisplatin with rhTRAIL or anti-Fas antibody induced even higher apoptosis levels in E6-suppressed cells. At the molecular level, cisplatin treatment resulted in elevated p53 levels, enhanced caspase-3 activation, and reduced p21 levels in E6-suppressed cells. Cisplatin in combination with death receptor ligands enhanced caspase-8 and caspase-3 activation and reduced X-linked inhibitor-of-apoptosis protein (XIAP) levels in these cells. We showed using siRNA that the enhanced apoptosis in E6-supressed cells was related to reduced XIAP levels and not due to reduced p21 levels. In conclusion, targeting E6 or XIAP in combination with cisplatin can efficiently potentiate rhTRAIL-induced apoptosis in HPV-positive cervical cancer cells.
Molecular pharmacology 02/2012; 81(5):701-9. · 4.53 Impact Factor
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Frank Roossink,
Hylke W Wieringa,
Maartje G Noordhuis,
Klaske A ten Hoor,
Mirjam Kok,
Lorian Slagter-Menkema,
Harry Hollema,
Geertruida H de Bock,
Elisabeth Pras, Elisabeth G E de Vries,
Steven de Jong,
Ate G J van der Zee,
Ed Schuuring,
G Bea A Wisman,
Marcel A T M van Vugt
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ABSTRACT: Treatment of advanced-stage cervical cancers with (chemo)radiation causes cytotoxicity through induction of high levels of DNA damage. Tumour cells respond to DNA damage by activation of the 'DNA damage response' (DDR), which induces DNA repair and may counteract chemoradiation efficacy. Here, we investigated DDR components as potential therapeutic targets and verified the predictive and prognostic value of DDR activation in patients with cervical cancer treated with (chemo)radiation. In a panel of cervical cancer cell lines, inactivation of ataxia telangiectasia mutated (ATM) or its substrate p53-binding protein-1 (53BP1) clearly gave rise to cell cycle defects in response to irradiation. Concordantly, clonogenic survival analysis revealed that ATM inhibition, but not 53BP1 depletion, strongly radiosensitised cervical cancer cells. In contrast, ATM inhibition did not radiosensitise non-transformed epithelial cells or non-transformed BJ fibroblasts. Interestingly, high levels of active ATM prior to irradiation were related with increased radioresistance. To test whether active ATM in tumours prior to treatment also resulted in resistance to therapy, immunohistochemistry was performed on tumour material of patients with advanced-stage cervical cancer (n = 375) treated with (chemo)radiation. High levels of phosphorylated (p-)ATM [p = 0.006, hazard ratio (HR) = 1.817] were related to poor locoregional disease-free survival. Furthermore, high levels of p-ATM predicted shorter disease-specific survival (p = 0.038, HR = 1.418). The presence of phosphorylated 53BP1 was associated with p-ATM (p = 0.001, odds ratio = 2.206) but was not related to any clinicopathological features or survival. In conclusion, both our in vitro and patient-related findings indicate a protective role for ATM in response to (chemo)radiation in cervical cancer and point at ATM inhibition as a possible means to improve the efficacy of (chemo)radiation.
International Journal of Cancer 02/2012; 131(9):2056-66. · 5.44 Impact Factor
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ABSTRACT: 16α-(18)F-fluoro-17β-estradiol ((18)F-FES) is an estrogen receptor (ER)-specific PET tracer with various potential interesting applications. The precise contribution of this technique in current clinical practice, however, has yet to be determined. Therefore, the aim of this study was to evaluate the value of (18)F-FES PET in breast cancer patients presenting with a clinical dilemma.
(18)F-FES PET examination could be requested by referring physicians for patients with a history of ER-positive breast cancer and the presence of a clinical dilemma despite complete standard work-up. All requests for (18)F-FES PET required a positive arbitration by a dedicated medical oncologist and nuclear medicine physician. The referring physician was asked to fill in validated questionnaires before, shortly after, and at more than 3 mo after (18)F-FES PET to determine indication, diagnostic value, and therapeutic consequences of (18)F-FES PET. To further validate (18)F-FES PET findings, (18)F-FES PET lesions were quantified and compared with centrally reviewed conventional imaging.
Thirty-three patients underwent (18)F-FES PET between December 2008 and October 2010. (18)F-FES PET was requested to evaluate equivocal lesions on conventional work-up (n = 21), ER status in metastatic patients (n = 10), and the origin of metastases (n = 2). (18)F-FES-positive lesions were observed in 22 patients. (18)F-FES PET was especially sensitive for bone metastases, detecting 341 bone lesions, compared with 246 by conventional imaging. The sensitivity for liver metastases was poor, and quantification of (18)F-FES uptake in liver lesions was hampered by high physiologic background. (18)F-FES uptake was highly variable between all metastases (range of standardized uptake value, 1.20-18.81), and 45% of the patients with a positive (18)F-FES PET finding had both (18)F-FES-positive and (18)F-FES-negative metastases. (18)F-FES PET improved diagnostic understanding in 88% of the patients and led to therapy change in 48% of the patients.
With the exception of liver metastases, whole-body imaging of ER expression with (18)F-FES PET can be a valuable additional diagnostic tool when standard work-up is inconclusive. (18)F-FES PET supported therapy decisions by improving diagnostic understanding and providing information on ER status of tumor lesions.
Journal of Nuclear Medicine 02/2012; 53(2):182-90. · 6.38 Impact Factor
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ABSTRACT: It is currently unknown whether the in vitro effects observed with statins in acute myeloid leukemia (AML) cells, including lowering of cholesterol, inhibition of isoprenylation, and sensitization to chemotherapy, also occur in vivo. Therefore, AML mononuclear cells (MNCs) were isolated from 12 patients before and after 7 days of high-dose (7.5-15 mg/kg/day) simvastatin treatment. Parallel mouse studies were performed to have, in addition to AML cells, access to liver tissue, a major target of statins. Serum cholesterol levels were lowered by simvastatin in all patients, however, only limited changes in the messenger RNA expression of cholesterol metabolism genes were seen in patient and mouse MNCs compared to murine liver cells. Still, two out of seven patients displayed an increased in vitro chemosensitivity of their AML cells upon simvastatin treatment. Gene set enrichment analysis on microarray data of AML patient cells and Western blot analysis for the isoprenylated proteins DnaJ and Rap1 on murine and AML patient MNCs demonstrated that in vivo simvastatin treatment resulted in inhibition of geranylgeranylation in murine MNCs and in a subset of patient AML MNCs. In summary, our data demonstrate that simvastatin treatment results in chemosensitization and inhibition of geranylgeranylation in AML cells of a subset of patients.
Experimental hematology 11/2011; 40(3):177-186.e6. · 3.11 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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ABSTRACT: Lynch syndrome (LS) is caused by a germline mutation in one of the mismatch repair (MMR) genes. The resulting loss of MMR gene function induces a strong mutator phenotype and predisposition to colorectal cancer (CRC). LS mutation carriers undergo regular colonoscopic surveillance and have extensive colonic resection in case of cancer because of the chance of metachronous tumors. Given the high risk and early onset of CRC, LS mutation carriers are good candidates for chemoprevention. Furthermore, evidence increases indicating that the response of MMR-deficient tumors to standard chemotherapy and radiotherapy differs from that of MMR-proficient tumors. Efforts should thus be directed at designing tailored strategies concerning both chemoprevention and medical cancer treatment for LS individuals. This review provides guidance for future studies in this field based on results from clinical and preclinical research.
Critical reviews in oncology/hematology 11/2011; 80(2):264-77. · 5.27 Impact Factor
