The search for precision models clinically relevant to human liver cancer

Xue, Wen; Wang, Xin Wei

doi:10.2217/hep.15.24

Cited by 6 publications

(4 citation statements)

References 32 publications

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“…The reasons for the unsatisfactory phase III clinical trial results thought to be multifaceted. Among them incomplete understanding of the key molecular changes that lead to HCC development, broad range of liver dysfunction seen in HCC patients, liver toxicity, errors in trial design and marginal antitumor potency [109][110][111].…”

Section: Challenges In Drug Developmentmentioning

confidence: 99%

“…In addition, specific phase II studies exploring potential liver-related toxicities of new agents are required in patients with cirrhosis and HCC before new agents should be tested in phase III randomized controlled trials [110]. Furthermore, liver cirrhosis that coexist with HCC may leads to portal hypertension may result in hypersplenism with platelet sequestration, thrombocytopenia, esophagogastric varices and GI bleeding, hepatic encephalopathy, hypotension, and hypoalbuminemia that may result in differential drug binding and altered pharmacokinetics [109].…”

Section: Challenges In Drug Developmentmentioning

confidence: 99%

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Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

Mekuria¹,

Abdi²

2017

J Cancer Sci Ther

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Hepatocellular Carcinoma (HCC) is a common type of primary liver cancer. According to the recent world cancer report, the disease ranked as the sixth most common cancer worldwide and the third largest cause of cancer-related death. Deregulation of numerous signaling pathways have been implicate in pathogenesis of HCC, including IGF, EGF/TGF, HGF/cMet, WNT, Hedgehog, notch, hippo, VEGF, PDGF, and FGF. Besides, intracellular mediators such as MAPK and PI3K/AKT/mTOR play a role in HCC development and progression. Currently sorafenib is the only molecularly targeted drug available to treat advanced HCC. It only extends survival by a matter of months. Moreover, there is no alternative agent for patients progressing under treatment with sorafenib. Thus, there remains a critical need for both continued molecular characterization and aggressive drug development. This review provided and updated appraisal of the deregulated signaling and epigenetic pathways, targeted therapeutics that is being investigated and possible challenges in drug development for HCC. Nevertheless, c-Met over-expression was reported to be related to increased metastatic potential and poor prognosis in patients with HCC, providing a rationale for its therapeutic inhibition [26]. Pathways related to neo-angiogenesisHigh vascularization is a hallmark of human HCC [8]. This angiogenesis process relies on autocrine and paracrine interactions between tumor cells, vascular endothelial cells, and pericytes. Tumor cells release pro-angiogenic factors in response to hypoxic conditions and nutrient deprivation and thus activate endothelial cells [27]. Activated endothelial cells break down extracellular matrix and basement membrane which result in a release of angiogenic factors which includes VEGF, FGF, PDGF, and TGF β [16]. These angiogenic factors in turn activate endothelial cells through TKR and their intracellular mediator's MAPK and PI3K/Akt/mTOR pathways, which lead to proliferation and migration of endothelial cells to form a new tubular structure and lumen for new vessels and finally, pericytes are activated and recruited to stabilize the new blood vessels [27,28]. has become a potential investigating area of research to identify target(s) to inhibit proliferation of HCC and metastasis. IGF pathwayThe pathway consists of circulating ligands IGF-I, IGF-II, and the receptor IGF-IR. It has been known for its involvement in the regulation of cell growth and energy metabolism [17]. According to studies, overexpression of IGF-II and IGF-IR has been implicated in cell proliferation and inhibition of apoptosis [18]. In support of this, low expression of IGF I and progressive increase in the level of expression of IGF-IR, IGF-II, and IGF substrates during the hepatocarcinogenesis process was detected at mRNA and protein level, which was associated with cell increased proliferation and reduced apoptosis has been observed in HCC cell lines and rat models as well as in human HCC samples [18]. Other studies also indicated that the major tumorpromoting e...

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Section: Challenges In Drug Developmentmentioning

confidence: 99%

Section: Challenges In Drug Developmentmentioning

confidence: 99%

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

Mekuria¹,

Abdi²

2017

J Cancer Sci Ther

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“…New methods of rapid in vivo modeling are needed to understand cancer biology. Liver cancer is a major cancer type with poor prognosis [14, 15]. Specifically, liver cancer incidence in the USA has tripled in the last 40 years, and liver cancer deaths have been increasing since 2000 [16].…”

Section: Introductionmentioning

confidence: 99%

CRISPR-SONIC: targeted somatic oncogene knock-in enables rapid in vivo cancer modeling

et al. 2019

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CRISPR/Cas9 has revolutionized cancer mouse models. Although loss-of-function genetics by CRISPR/Cas9 is well-established, generating gain-of-function alleles in somatic cancer models is still challenging because of the low efficiency of gene knock-in. Here we developed CRISPR-based Somatic Oncogene kNock-In for Cancer Modeling (CRISPR-SONIC), a method for rapid in vivo cancer modeling using homology-independent repair to integrate oncogenes at a targeted genomic locus. Using a dual guide RNA strategy, we integrated a plasmid donor in the 3′-UTR of mouse β-actin, allowing co-expression of reporter genes or oncogenes from the β-actin promoter. We showed that knock-in of oncogenic Ras and loss of p53 efficiently induced intrahepatic cholangiocarcinoma in mice. Further, our strategy can generate bioluminescent liver cancer to facilitate tumor imaging. This method simplifies in vivo gain-of-function genetics by facilitating targeted integration of oncogenes. Electronic supplementary material The online version of this article (10.1186/s13073-019-0627-9) contains supplementary material, which is available to authorized users.

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“…Current approved advanced HCC treatments include multikinase inhibitors regorafenib, lenvatinib and sorafenib, which extend patient survival by several months only, and the immune checkpoint inhibitors nivolumab and pembrolizumab, which show approximate 20% response rates as a second line of therapy . The clinical need for more effective HCC treatments remains unmet, partially because HCC is genetically heterogeneous and because HCC driver genes amenable to targeted therapy are largely unknown . Identifying genes whose depletion can inhibit HCC growth, and determining the mechanisms involved, will aid the development of targeted therapies for HCC patients.…”

mentioning

confidence: 99%

Depletion of TRRAP Induces p53‐Independent Senescence in Liver Cancer by Down‐Regulating Mitotic Genes

et al. 2019

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Hepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer with few effective treatments, and the underlying mechanisms that drive HCC pathogenesis remain poorly characterized. Identifying genes and pathways essential for HCC cell growth will aid the development of new targeted therapies for HCC. Using a kinome CRISPR screen in three human HCC cell lines, we identified transformation/transcription domain‐associated protein (TRRAP) as an essential gene for HCC cell proliferation. TRRAP has been implicated in oncogenic transformation, but how it functions in cancer cell proliferation is not established. Here, we show that depletion of TRRAP or its co‐factor, histone acetyltransferase KAT5, inhibits HCC cell growth through induction of p53‐independent and p21‐independent senescence. Integrated cancer genomics analyses using patient data and RNA sequencing identified mitotic genes as key TRRAP/KAT5 targets in HCC, and subsequent cell cycle analyses revealed that TRRAP‐depleted and KAT5‐depleted cells are arrested at the G2/M phase. Depletion of topoisomerase II alpha (TOP2A), a mitotic gene and TRRAP/KAT5 target, was sufficient to recapitulate the senescent phenotype of TRRAP/KAT5 knockdown. Conclusion: Our results uncover a role for TRRAP/KAT5 in promoting HCC cell proliferation by activating mitotic genes. Targeting the TRRAP/KAT5 complex is a potential therapeutic strategy for HCC.

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The search for precision models clinically relevant to human liver cancer

Cited by 6 publications

References 32 publications

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

CRISPR-SONIC: targeted somatic oncogene knock-in enables rapid in vivo cancer modeling

Depletion of TRRAP Induces p53‐Independent Senescence in Liver Cancer by Down‐Regulating Mitotic Genes

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