Management of hepatocellular carcinoma: beyond sorafenib.

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Management of hepatocellular carcinoma: beyond sorafenib.

Curr Oncol Rep. 2012 Jun;14(3):257-66

Authors: Chan SL, Mok T, Ma BB

Abstract
The positive results of sorafenib have unveiled a new direction of research in the management of hepatocellular carcinoma (HCC). Since then intensive efforts have been focused on development of novel management strategy to further improve the outcome for patients with HCC. Emerging data have suggested that tumor progression of HCC is driven by a number of deregulated signaling pathways and/or epigenetic mechanism. Thus much effort is dedicated to identification of novel agents targeting these dysregulated pathways. Combinations of targeted therapeutics and transarterial chemoembolization (TACE), or different systemic therapeutics also hold the promise to improve treatment outcome beyond sorafenib. This review aims to summarize the current status of clinical development of treatment in HCC. Perspectives on future direction of research will also be discussed.

PMID: 22434314 [PubMed - indexed for MEDLINE]

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Rationale for anti-angiogenic therapy in pheochromocytoma and paraganglioma.

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Rationale for anti-angiogenic therapy in pheochromocytoma and paraganglioma.

Endocr Pathol. 2012 Mar;23(1):34-42

Authors: Favier J, Igaz P, Burnichon N, Amar L, Lib� R, Badoual C, Tissier F, Bertherat J, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP

Abstract
Pheochromocytomas and paragangliomas are highly vascularized tumors which are candidates for anti-angiogenic therapies. Several studies have reported the association of vascular endothelial growth factor (VEGF) overexpression with malignancy, but none took into account the genetic status of the patients or tumors, which may have a major influence on such observations. Transcriptome studies indeed revealed that pheochromocytomas and paragangliomas can be classified into two major clusters depending on their gene expression profile: Cluster 1 comprises samples associated with a hypoxic signature such as SDHx- and VHL-related tumors and cluster 2 includes RET, NF1, and TMEM127-mutated tumors, as well as most of sporadic tumors. The aim of this study was to provide a comprehensive rationale for the targeting of angiogenesis in patients with malignant forms of the disease. We used in situ hybridization, immunohistochemistry, and microarray gene expression profiling to evaluate angiogenesis and the expression of several angiogenic factors in a large cohort of pheochromocytomas and paragangliomas. We also studied the activation of mTOR by assessing the phosphorylation of its targets, P70 S6 kinase and 4E-BP1. These results were correlated with both malignancy and transcription signature. Our results reveal that cluster 1 tumors display a marked increase in both vascularization and in the expression of major angiogenic molecules, including VEGF, its receptors, HIF2?, Angiopoietin-2, and the endothelin receptors ETA and ETB. These overexpressions were observed in both benign and malignant samples of cluster 1 and thus appeared to be mainly dependent on the pseudo-hypoxic status of these tumors. The mTOR pathway was potentially activated in half of the tumors studied, with a slight increase in cluster 2 pheochromocytomas. Our results suggest that there is a strong rationale for anti-VEGF-based therapeutic strategies in malignant pheochromocytomas and paragangliomas, in particular in those associated with mutations in the SDHB gene.

PMID: 22183643 [PubMed - indexed for MEDLINE]

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Acute Podocyte Vascular Endothelial Growth Factor (VEGF-A) Knockdown Disrupts alpha(V)beta(3) Integrin Signaling in the Glomerulus.

Acute Podocyte Vascular Endothelial Growth Factor (VEGF-A) Knockdown Disrupts alpha(V)beta(3) Integrin Signaling in the Glomerulus.

PLoS One. 2012;7(7):e40589

Authors: Veron D, Villegas G, Aggarwal PK, Bertuccio C, Jimenez J, Velazquez H, Reidy K, Abrahamson DR, Moeckel G, Kashgarian M, Tufro A

Abstract
Podocyte or endothelial cell VEGF-A knockout causes thrombotic microangiopathy in adult mice. To study the mechanism involved in acute and local injury caused by low podocyte VEGF-A we developed an inducible, podocyte-specific VEGF-A knockdown mouse, and we generated an immortalized podocyte cell line (VEGF(KD)) that downregulates VEGF-A upon doxycycline exposure. Tet-O-siVEGF:podocin-rtTA mice express VEGF shRNA in podocytes in a doxycycline-regulated manner, decreasing VEGF-A mRNA and VEGF-A protein levels in isolated glomeruli to ?20% of non-induced controls and urine VEGF-A to ?30% of control values a week after doxycycline induction. Induced tet-O-siVEGF:podocin-rtTA mice developed acute renal failure and proteinuria, associated with mesangiolysis and microaneurisms. Glomerular ultrastructure revealed endothelial cell swelling, GBM lamination and podocyte effacement. VEGF knockdown decreased podocyte fibronectin and glomerular endothelial alpha(V)beta(3) integrin in vivo. VEGF receptor-2 (VEGFR2) interacts with beta(3) integrin and neuropilin-1 in the kidney in vivo and in VEGF(KD) podocytes. Podocyte VEGF knockdown disrupts alpha(V)beta(3) integrin activation in glomeruli, detected by WOW1-Fab. VEGF silencing in cultured VEGF(KD) podocytes downregulates fibronectin and disrupts alpha(V)beta(3) integrin activation cell-autonomously. Collectively, these studies indicate that podocyte VEGF-A regulates alpha(V)beta(3) integrin signaling in the glomerulus, and that podocyte VEGF knockdown disrupts alpha(V)beta(3) integrin activity via decreased VEGFR2 signaling, thereby damaging the three layers of the glomerular filtration barrier, causing proteinuria and acute renal failure.

PMID: 22808199 [PubMed - in process]

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Improved efficacy of a novel anti-angiogenic drug combination (TL-118) against colorectal-cancer liver metastases; MRI monitoring in mice.

Improved efficacy of a novel anti-angiogenic drug combination (TL-118) against colorectal-cancer liver metastases; MRI monitoring in mice.

Br J Cancer. 2012 Jul 17;

Authors: Edrei Y, Gross E, Corchia N, Abramovitch R

Abstract
Background:The poor prognosis of patients with colorectal-cancer liver metastases (CRLM) and the insufficiency of available treatments have raised the need for alternative curative strategies. We aimed to assess the therapeutic potential of TL-118, a new anti-angiogenic drug combination, for CRLM treatment, in a mouse model.Methods:The therapeutic potential of TL-118 was evaluated and compared with B20-4.1.1 (B20; anti-VEGF antibody) and rapamycin in CRLM-bearing mice. Tumour progression and the vascular changes were monitored by MRI. Additionally, mice survival, cell proliferation, apoptosis and vessel density were evaluated.Results:This study demonstrated an unequivocal advantage to TL-118 therapy by significantly prolonging survival (threefold) and reducing metastasis perfusion and vessel density (ninefold). The underlying mechanism for TL-118-treatment success was associated with hepatic perfusion attenuation resulting from reduced nitric-oxide (NO) serum levels as elucidated by using hemodynamic response imaging (HRI, a functional MRI combined with hypercapnia and hyperoxia). Further, systemic hepatic perfusion reduction during the initial treatment phase by adding NO inhibitor has proven to be essential for reaching maximal therapeutic effects for both TL-118 and B20.Conclusion:TL-118 harbours a potential clinical benefit to CLRM patients. Moreover, the reduction of hepatic perfusion at early stages of anti-angiogenic therapies by adding NO inhibitor is crucial for achieving maximal anti-tumour effects.British Journal of Cancer advance online publication, 17 July 2012; doi:10.1038/bjc.2012.322 www.bjcancer.com.

PMID: 22805330 [PubMed - as supplied by publisher]

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[Anti-angiogenesis effect of AMD3100 in oxygen-induced retinopathy mice].

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[Anti-angiogenesis effect of AMD3100 in oxygen-induced retinopathy mice].

Zhonghua Yan Ke Za Zhi. 2012 Apr;48(4):350-5

Authors: Xu QY, Yuan YZ, Wang LY, Yuan F

Abstract
OBJECTIVE: To observe the inhibition of neovascularation in the oxygen-induced retinopathy (OIR) mice by a stromal cell-derived factor 1 (SDF-1) antagonist.
METHODS: Experimental study. Fifty-eight 7-day-old C57BL/6 mice were divided into 3 groups randomly, the control group (n = 17), the test group (n = 17) and the medication group (n = 24). According to the dosage of AMD3100, the medication group (n = 24) were divided into low dose group, high dose group, low dose control group, and high dose control group (each group n = 6). Each group (19-day-old) was sacrificed to perform ADPase staining, paraffin sections and immunohistochemical staining (anti-VEGF and anti-SDF-1). The average positive staining area percentage (APSAP) was measured as the outcomes and processed with the Students' t-test.
RESULTS: Real-time PCR showed expression of both VEGF mRNA (0.080 � 0.022 vs. 0.123 � 0.032) and SDF-1 mRNA (0.731 � 0.099 vs.0.544 � 0.108) in retinas from the control group and test group, respectively. The expression of these factors in the test group was significantly higher (t = 2.488, P = 0.038;t = 2.864, P = 0.021). The number of neovascular endothelial nuclear that broke through the retinal internal limiting membrane in the paraffin section in the high dose group and the low dose group was significantly less than that in the self-control group (t = -9.507, P = 0.000; t = -10.761, P = 0.000). The appearance of ADPase staining sections in the medication group was more similar to the simple control group than that of the test group. Immumohistochemical staining sections showed that VEGF and SDF-1 expressed in neuroepithelial cells in each group. APSAP in the high dose group and the low dose group was significantly lower than that in the self-control group (VEGF: t = -7.249, P = 0.000; t = -9.02, P = 0.000; SDF-1: t = -5.246, P = 0.000; t = -5.216, P = 0.000).
CONCLUSION: These results indicate that AMD3100 block the SDF-1 receptor to reduce the effect of SDF-1, decrease the production of VEGF protein and inhibite neovascularization.

PMID: 22800457 [PubMed - in process]

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An Investigation of Growth Factors and Lactoferrin in Naturally Occurring Ovine Pulmonary Adenomatosis.

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An Investigation of Growth Factors and Lactoferrin in Naturally Occurring Ovine Pulmonary Adenomatosis.

J Comp Pathol. 2012 Jun 19;

Authors: Sozmen M, Beytut E

Abstract
Ovine pulmonary adenomatosis (OPA), also known as jaagsiekte, is a transmissible beta retrovirus-induced lung tumour of sheep that has several features resembling human bronchoalveolar carcinoma (BAC). Angiogenesis has been suggested to be one of the most important factors underlying tumour growth and invasion. This process involves the action of growth factors including vascular endothelial growth factor (VEGF)-C, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF)-C and its receptor (PDGFR-?). Bovine lactoferrin (bLF), an iron and heparin-binding glycoprotein secreted into various biological fluids, has been implicated in innate immunity and has anti-inflammatory and anti-tumour functions. Tissues from 16 cases of OPA were compared with tissues from seven healthy control sheep by immunohistochemistry. Expression of the markers was assessed semi-quantitatively by ascribing an immunoreactivity score (IRS) with a maximum value of 300. VEGF-C, bFGF, PDGF-C, PDGFR-? and bLF signals were detected in 10/16, 15/16, 12/16, 15/16 and 10/16 of the OPA cases studied, respectively. bLF expression was weak in the neoplastic epithelial cells (IRS 21.4���10.0) in contrast to high levels detected in infiltrating macrophages and plasma cells (IRS 141.3���24.8 and 140.0���25.1, respectively). The PDGFR-? IRS was elevated for neoplastic epithelial cells (108.9���18.2) and was lowest for macrophages and plasma cells (20.4���13.1 and 13.7���12.4, respectively). These results suggest that bFGF, VEGF-C and PDGF-C have roles in the pathogenesis of OPA. bLF may activate macrophages and plasma cells in these lesions, but limited expression of bLF by neoplastic cells may be a consequence of defective or impaired function of this molecule.

PMID: 22721818 [PubMed - as supplied by publisher]

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[Intravitreal bevacizumab pretreatment in vitrectomy for severe diabetic retinopathy: a series of six cases].

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[Intravitreal bevacizumab pretreatment in vitrectomy for severe diabetic retinopathy: a series of six cases].

J Fr Ophtalmol. 2012 Apr;35(4):260-5

Authors: Couzinet A, Auriol S, Lequeux L, Arn� JL, Pagot-Mathis V

Abstract
INTRODUCTION: Bevacizumab (Avastin(�), Roche) is a full-length humanized monoclonal antibody applicable to all subtypes of vascular endothelial growth factor (VEGF). The purpose of this study was to report the results of its use as a surgical additive in severe cases of proliferative diabetic retinopathy (PDR).
PATIENTS AND METHOD: This retrospective study focused on six eyes of six patients with complicated diabetic retinopathy. A vitrectomy was performed within 13.6 days after an intravitreal bevacizumab injection of 0.1 mL (2.5mg), with dissection of the fibrovascular proliferation using a mono- or bimanual delamination technique.
RESULTS: The mean follow-up after intravitreal injection was 13.3 months. The mean surgery time was 64 minutes. The bimanual technique was not necessary. Only one iatrogenic retinal tear was repaired. The intraoperative bleeding was negligible. No adverse events resulting from the drug nor recurrence were observed throughout the follow-up period.
CONCLUSION: Intravitreal bevacizumab is useful as a surgical additive in severe cases of PDR, significantly improving surgical conditions. Nevertheless, its use beyond approved indications should be reserved for complex surgical cases.

PMID: 21889820 [PubMed - indexed for MEDLINE]

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