RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma

Huynh, Hung; Chow, Pierce K. H.; Soo, Khee Chee; Toh, Han Chong; Choo, Su Pin; Foo, Kian Fong; Poon, Dennis; Ngo, Van Chanh; Tran, Elizabeth

doi:10.1111/j.1582-4934.2008.00364.x

Cited by 121 publications

(87 citation statements)

References 54 publications

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“…Each treatment group involved 8 to 10 independent tumor-bearing mice representing the same xenograft line. It is of note that the dose of everolimus used in this study was approximately 2.5 to 5 times lower than doses used in our previous reports (22) and the toxicity associated with daily 1 mg/kg everolimus treatment was well tolerated. As shown in Fig.…”

Section: Tsc2 Loss In Patient-derived Hcc Xenografts Predicts Everolimentioning

confidence: 92%

“…We had previously established a large panel of patient-derived HCC xenografts for testing the efficacy of various antitumor agents (21,22). To determine whether TSC2 loss also occurred in those HCC xenografts, we performed immunoblots on lysates from 13 randomly selected patient-derived HCC xenograft tumors.…”

Section: Tsc2 Loss In Patient-derived Hcc Xenografts Predicts Everolimentioning

confidence: 99%

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Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Huynh

Hao²,

Chan

et al. 2015

Molecular Cancer Therapeutics

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Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of mTOR signaling plays a pivotal role in HCC tumorigenesis. Tuberous sclerosis complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the current study, we discovered that TSC2 loss-of-function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus using an optimized immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV þ HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. Mol Cancer Ther; 14(5); 1224-35. Ó2015 AACR.

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Section: Tsc2 Loss In Patient-derived Hcc Xenografts Predicts Everolimentioning

confidence: 92%

Section: Tsc2 Loss In Patient-derived Hcc Xenografts Predicts Everolimentioning

confidence: 99%

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Huynh

Hao²,

Chan

et al. 2015

Molecular Cancer Therapeutics

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“…Various agents used for inducing autophagy are Rapamycin and its analogs, Tyrosine kinase inhibitors like sorafenib, NPC-16 a novel agent and cannabinoids and its agonists. [79][80][81] Autophagy inhibitors have also been tried for their possible role in potentiating the effect of chemotherapeutic agents in treatment of cancer by abolishing the protective effect of autophagy on cell survival. Chloroquine and Hydroxychloroquine have been used as autophagy inhibitors due to their action on suppression of lysosome formation and its function.…”

Section: Targeting Autophagy In Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

Puri

Chandra

2014

Journal of Clinical and Experimental Hepatology

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Autophagy is a critical intracellular pathway which maintains cellular function by lysosomal degradation of damaged proteins and organelles besides elimination of invading pathogens. Its primary function is to prevent cell death. Autophagy has diverse physiological functions namely; starvation adaptation, prevention of tumorigenesis, energy homeostasis, intracellular quality control and degradation of abnormal intracellular protein aggregates. Understanding the molecular mechanisms of autophagy has given key insights into the pathogenesis of various diseases like Non Alcoholic Steato-Hepatitis, Hepatitis B and C infections, Alpha-1 antitrypsin deficiency and hepatocellular carcinoma. Pharmacological modulation of autophagy may have a therapeutic potential in management of these liver diseases. ( J CLIN EXP HEPATOL 2014;4:51-59) O urobros or Urobros is an ancient symbol depicting a serpent or a dragon eating its own tail, which symbolizes cyclicality in the sense of something recreating itself. In living organisms, cells and intracellular organelles need to be constantly remodeled and renewed. Autophagy is a term derived from Greek terminology for self-eating and signifies the process of cellular selfdigestion in which cytoplasmic components are degraded in lysosomes. Reminiscent of the serpent eating its own tail in the symbol of Ourobros, the cells are able to survive by using autophagy to remove damaged proteins and organelles, eliminate invading microbes and generate nutrients during starvation.After Metchnicoff, a Russian zoologist, first described phagocytosis, the role of lysosomes and autophagy in degrading cytoplasmic components has been elucidated. 1,2 The control of autophagy has been recently delineated by identification of over 30 Autophagy-related (ATG) genes. 3 Autophagy functions to prevent rather than promote cell death. Autophagy has effects of increased cytoprotection, decreased stem cell attrition, decreased oncogenic transformation, decreased dysfunctional mitochondria and decrease in dysfunctional aggregate prone proteins. 4

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“…Second, anti-angiogenic agents mainly interfere with newly formed blood vessels, but not with mature blood vessel supported by pericytes [107,108], leaving the mature vessels fully functioning. Third, some anti-angiogenic agents can block the cell cycle of tumor cells, but cannot induce tumors apoptosis [109], therefore, weakening its antitumor effect.…”

Section: Strategies Of Anti-angiogenic Therapy Against Hccmentioning

confidence: 99%

Angiogenesis: multiple masks in hepatocellular carcinoma and liver regeneration

Chen

Shi

et al. 2010

Hepatol Int

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Hepatocellular carcinoma (HCC) is naturally resistant to radiotherapy and cytotoxic chemotherapy, leaving surgery as the mainstream therapeutic approach. However, the 5-year recurrence rate after curative resection is as high as 61.5%. The background hepatitis B-or C-induced cirrhosis and the presence of micrometastases at the time of surgery have been regarded as two main causes of recurrence. Recently, accumulating evidence suggests that growth factors and cytokines released during the physiological process of post-surgical liver regeneration could induce the activation of dormant micrometastatic lesions. The establishment of neovasculature to support either liver regeneration or HCC growth involves multiple cell types including liver sinusoidal endothelial cells, Kupffer cells, hepatic stellate cells, and circulating endothelial progenitors. The crosstalks among these cells are driven by multiple molecules and signaling pathways, including vascular endothelial growth factors and their receptors, platelet-derived growth factor, the angiopoietin/Tie family, hepatocyte growth factor/c-Met signaling, and others. Anti-angiogenic agent targeting liver cancer vasculature has been reported to be able to generate limited survival benefit of the patients. In this review, discussions are focused on various angiogenic mechanisms of HCC and liver regeneration, as well as the prevailing anti-angiogenic strategies.

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RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma

Cited by 121 publications

References 54 publications

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Autophagy Modulation As a Potential Therapeutic Target for Liver Diseases

Angiogenesis: multiple masks in hepatocellular carcinoma and liver regeneration

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