Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: A randomized phase II trial for safety and optimal dosage

Liu, Chun‐Jen; Lee, Po‐Huang; Deng, Lin; Wu, Cheng Chung; Jeng, Long Bin; Lin, Pin Wen; Mok, King Tong; Lee, Wei Chen; Yeh, Hong Zen; Ho, Ming-Chih; Yang, Sheng‐Shun; Lee, Ching Chih; Yu, Ming; Hu, Rey‐Heng; Peng, Cheng Yuan; Lai, Kuan Lang; Chang, Shu‐Wen; Chen, Pei‐Jer

doi:10.1016/j.jhep.2008.12.023

Cited by 140 publications

(88 citation statements)

References 32 publications

(41 reference statements)

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“…However, other ECM components (e.g. integrins, heparanases, and matrix metalloproteinases) have inhibitors that are currently under study in phase I/II/III clinical trials [27][28][29][30][31][32][33]. Kinase genes have also recently been reported to be upregulated in metastatic tumors relative to primary ccRCC tumors [34].…”

Section: Discussionmentioning

confidence: 99%

Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes

Serie²,

Parasramka³

et al. 2017

Annals of Oncology

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Background: The majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases. Patients and methods:We compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors.Results: We identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM): DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P < 0.01). Conclusions:We evaluated gene expression profiles using the largest set to date, to our knowledge, of patient-matched primary and metastatic ccRCC tumors and identified up regulation of ECM genes in metastases. Our study implicates up regulation of ECM genes as a critical molecular event leading to visceral, bone and soft tissue metastases in ccRCC.

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Section: Discussionmentioning

confidence: 99%

Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes

Serie²,

Parasramka³

et al. 2017

Annals of Oncology

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“…One representative of these inhibitors, PI-88, is being evaluated in a multicenter phase II or III clinical trial (22,23). However, due to the multiple biologic activities of these inhibitors, the mechanism of their anti-tumor activity and their relation to heparanase inhibition are not clear (24).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of heparanase by RNA interference inhibits invasion and tumorigenesis of hepatocellular cancer cells in vitro and in vivo

et al. 2012

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Abstract.Heparanase is an endoglycosidase that degrades heparan sulfate, the main polysaccharide constituent of the extracellular matrix and basement membrane. The expression of heparanase is associated with invasion, as well as the angiogenic and metastatic potential of diverse malignant tumors. We used RNA interference strategies to evaluate the role of human heparanase in a liver cancer cell line and to explore the therapeutic potential of its specific targeting. Using an online siRNA tool, we designed three small interfering RNA sequences to target the heparanase coding region and cloned them into the pGenesil-1 vector. The siRNA vectors were transfected into HepG2 liver cancer cells. Heparanase expression was measured by real-time RT-PCR and Western blotting. Cell proliferation was detected by MTT staining and plate colony formation. Cell cycle analysis was performed by flow cytometry. In vitro invasion was measured by Matrigel invasion assay. We also analyzed tumorigenicity in heparanase-suppressed HepG2 cells in nude mice. We found that siRNA-1 (1214-1232) and siRNA-3 (611-629) targeting heparanase significantly downregulated the expression of heparanase in HepG2 liver cancer cells. Compared with its controls, siRNA-1 or siRNA-3 vectors efficiently inhibited the proliferation and invasion of HepG2 liver cancer cells in vitro and tumorigenesis in vivo. These results suggest that heparanase-specific RNA interference has potential value as a novel therapeutic agent for human liver cancer.

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“…No other modality has demonstrated equivalent effectiveness for decreasing recurrence after curative treatment of HCC as antiviral therapy has for viral hepatitis-related tumors. Chemoembolization [124] , internal radiation [125,126] , immune therapies [127] , retinoids [128] , and the heparanase inhibitor PI-88 [129] have been investigated as methods of reducing postoperative recurrence; however, none can be recommended as a preoperative/postoperative adjuvant/neo-adjuvant therapy for improving prognosis and diminishing the incidence of recurrence following curative therapy.…”

Section: Patients N Overall Survival Momentioning

confidence: 99%

Recent advances in multidisciplinary management of hepatocellular carcinoma

Gomaa¹

2015

WJH

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Heparanase inhibitor PI-88 as adjuvant therapy for hepatocellular carcinoma after curative resection: A randomized phase II trial for safety and optimal dosage

Cited by 140 publications

References 32 publications

Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes

Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes

Downregulation of heparanase by RNA interference inhibits invasion and tumorigenesis of hepatocellular cancer cells in vitro and in vivo

Recent advances in multidisciplinary management of hepatocellular carcinoma

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