HBV and HCV-associated Liver Cancer: Important Insights from the Genome
Author: Ritu Saxena, PhD
UPDATED on 7/21/2022
HBV drug shifts to next-gen approaches
“While we respect Assembly’s decision to discontinue clinical development of VBR, we believe that it is premature to make any conclusions about any results in this triple combination clinical trial,” Arbutus CEO William Collier said in a separate release, referring to the study that involved his company’s drug. “We intend, in collaboration with Assembly, to continue the clinical trial in order to fully and accurately assess the results.”
So as Assembly shuts the door to future trials and wraps
Study 203 — a Phase II study testing VBR plus NrtI (nucleoside analogue reverse transcriptase inhibitor) plus interferon —
Study 204 will go on, with primary endpoints being safety and tolerability.
Patients are given either
- VBR, NrtI and Arbutus’ AB-729,
- VBR plus NrtI, or
- NrtI plus AB-729.
The RNAi drug is designed to reduce all HBV viral proteins and antigens.
For Assembly Bio, the focus now shifts to two next-generation core inhibitors that it hopes could prove potent treatments for HBV. At the same time, it’s also working on earlier-stage research programs, including
- a hepatitis D virus entry inhibitor,
- a liver-focused interferon-α receptor agonist and
- new antivirals to be introduced later.
With CMO Luisa Stamm and CFO Michael Samar set to leave in the next few weeks, McHutchison — a former Gilead CSO — will now lead a remaining team of 70.
Meanwhile, Michele Anderson, SVP of development operations, is being promoted to chief development officer; and COO Jason Okazaki will add president to his title and finance to his slate of duties. The company now expects to have a cash runway into the first half of 2024.
SOURCE
Updated on July 5, 2013
(research article published in New England Journal of Medicine regarding the role of SALL4 gene in aggressive hepatocellular carcinoma)
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. The incidence of HCC varies considerably with the geographic area because of differences in the major causative factors. Chronic hepatitis B and C, mostly in the cirrhotic stage, are responsible for the great majority of cases of HCC worldwide.
Hepatitis B and C viruses (HBV/HCV) can be implicated in the development of HCC in an indirect way, through induction of chronic inflammation, or directly by means of viral proteins or, in the case of HBV, by creation of mutations by integration into the genome of the hepatocyte.http://www.wjso.com/content/3/1/27
With the advent of genome sequencing methodologies, it was about time that the scientists look clues within the genome of HCC tumor cells that would provide clues for disease progression via virus integration into the liver cells.
Two studies published in the recent issue of Nature Genetics (May 2012) explored the genome of HCC cells for genetic mutations that might be related to HBV and HCV highlighting the types of genetic mutations that underlie the liver cancer hepatocellular carcinoma, including forms of the disease related to hepatitis B and hepatitis C virus infection.
In the first study, Sung et al performed an extensive whole genome analysis using a large sample size of 88 Chinese individuals with HCC http://www.ncbi.nlm.nih.gov/pubmed?term=Genome-wide%20survey%20of%20recurrent%20HBV This was in the fact first unbiased, genome-wide, HBV-integration map in HCC leading to new recurrent integration sites and molecular mechanisms.
Although integration of viral DNA sequence within HCC genome has been reported in several studies, however, fewer cases of recurring mutations within genes during these integrations have been studied. The reason might be limited sample size in these studies. Tumor and non-tumor adjacent liver cells were surveyed in 81 HBV positive and 7 HBV negative HCC tumor samples. After the survey of whole genome of the 88 patients, several viral integration sites were discovered referred to as breakpoints. The breakpoints were found to be much more common in tumor than normal samples. Although the observed breakpoints were randomly distributed across the genome, a handful or frequently occurring sites referred to as ‘hotspots’ were discovered. The frequency of integration revealed that there were five genes with recurring integrations in HBV tumors- TERT, MLL4, CCNE5, SENP1, and ROCK1.
Apart from genome analysis, expression levels of the 5 genes implicated in the study were determined. In other words, the levels of proteins formed from the genes were compared and it was observed that samples with HBV integration had significantly higher level of protein expression of TERT, MLL4 and CCNE5 than the samples harboring no HBV integration sites. Although not statistically significant, overexpression of SENP1 and ROCK1 genes was also observed in HBV integration samples. This lead to an important conclusion from the study that the five genes that harbor recurrent HBV integrations might be implicated in HCC tumor development and that overexpression of these proteins is a probable molecular mechanism of tumorigenesis.
Interestingly, analysis of the HBV analysis revealed that almost 40% of the HBV genomes were cleaved at approximately 1,800 bp and then integrated into the human genome. The cleaved HBV sites had the necessary machinery (enhancers and ORF replication sites) for protein formation.
The study also confirmed the popular belief that HBV integrations might worsen the prognosis of HCC patients revealing a significant correlation between the number of HBV integrations and the survival of patients.An interesting observation from the study that had not been reported before was that HBV integration was associated with the occurrence of HCC at a younger age.
The study presented convincing evidence that chromosomal instability of HCC genome may originate from HBV integration.
A parallel study published in the same issue of Nature Genetics explored the genome of HCC tumors to gain insights into HBV and HCV-related genomic alterations. The research team sequenced whole-exon (protein forming genomic regions) of 27 liver tumors from 25 patients and compared with the corresponding genome sequences from matched white blood cell samples.
The study involved both HBV-related and HCV-related tumors along with two samples of tumors from individuals without HBV or HCV infection. The genome wide sequencing of HCC tumor cells revealed several mutations that included deletions and mutations of genes with predicted functional consequences. “Considering the high complexity and heterogeneity of [hepatocellular carcinomas] of both etiological and genetic aspects,” they concluded, “further molecular classification is required for appropriate diagnosis and therapy in personalized medicine.” Additionally, recurrent alterations were observed in the four genes – ARID1A, RPS6KA3, NFE2L2 and IRF2 that had not been previously described in HCC. The comprehensive mutation pattern observed in the study might be indicative of specific mutagenesis mechanisms occurring in tumor cells.
Authors said “Although no common somatic mutations were identified in the multicentric tumor pairs,” further stating “their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns.”The researchers suggested a major role of chromatin remodeling complexes and involvement of both interferon and oxidative stress pathways in hepatocellular malignant proliferation and transformation based on the genes showing recurrent mutations in the observed genes.
http://www.ncbi.nlm.nih.gov/pubmed?term=Genome-wide%20survey%20of%20recurrent%20HBV
Thus, in both the studies new genes recurrently altered in HCC were identified along with uncovering some important clues relating to the molecular mechanism of virus-associated HCC.
Role of SALL4 in HCC
The oncofetal gene SALL4 is a marker of a subtype of HCC with progenitor-like features and is associated with a poor prognosis. Investigators at Cancer Science Institute of Singapore, National University of Singapore studied the role of oncofetal gene, SALL4 in HCC and the results were published were in a recent issue of New England Journal of Medicine ((Yong KJ, et al, Oncofetal Gene SALL4 in Aggressive Hepatocellular Carcinoma. http://www.ncbi.nlm.nih.gov/pubmed/23758232). Yong and colleagues (2013) screened specimens from patients with primary HCC for the expression of SALL4 and carried out a clinicopathological analysis. Loss-of-function studies were then performed to evaluate the role of SALL4 in hepatocarcinogenesis and its potential as a molecular target for therapy. Furthermore, in vitro functional and in vivo xenograft assays were performed to assess the therapeutic effects of a peptide that targets SALL4.
According to the results, SALL4 is an oncofetal protein that is expressed in the human fetal liver and silenced in the adult liver, but it is reexpressed in a subgroup of patients who have HCC and an unfavorable prognosis. Gene-expression analysis showed the enrichment of progenitor-like gene signatures with overexpression of proliferative and metastatic genes in SALL4-positive HCC. Loss-of-function studies confirmed the critical role of SALL4 in cell survival and tumorigenicity. The peptide targeting SALL4 blocked SALL4-corepressor interactions that released suppression of PTEN and inhibited tumor formation in xenograft assays in vivo. In conclusion, the results from the study indicate that SALL4 is a marker for a progenitor subclass of HCC with an aggressive phenotype. The absence of SALL4 expression in the healthy adult liver enhances the potential of SALL4 as a treatment target in HCC.
Major role of chromatin remodeling complexes and involvement of both interferon and oxidative stress pathways in hepatocellular malignant proliferation — new findings of great importance to Personalized Medicine.
Thank you for the two papers review on this blood born pathogen- HBV and HCV implicated in acceleration of Cirrhosis of the Liver and HCC. Potential therapy is liver transplantation. When is a liver transplant indicated for cirrhosis?
A liver transplant is considered when complications cannot be controlled by treatment. Liver transplantation is a major operation in which the diseased liver is removed and replaced with a healthy one from an organ donor. A team of health professionals determines the risks and benefits of the procedure for each patient. Survival rates have improved over the past several years because of drugs that suppress the immune system and keep it from attacking and damaging the new liver.
The number of people who need a liver transplant far exceeds the number of available organs. A person needing a transplant must go through a complicated evaluation process before being added to a long transplant waiting list. Generally, organs are given to people with the best chance of living the longest after a transplant. Survival after a transplant requires intensive follow-up and cooperation on the part of the patient and caregiver.
http://digestive.niddk.nih.gov/ddiseases/pubs/cirrhosis/#liver
Thanks for the comments Aviva!
What I found interesting is that the studies have chosen large sample sizes to decipher the common patterns in mutations narrowing down the most frequently affected genes in viral-associated HCC.The researchers then extended the study to functional analysis defining possible molecular pathways and overexpressed genes. Thus, as you pointed out, chormatin remodeling complexes (especially Swi/Snf) have been implicated along with both interferon and oxidative stress pathways in hepatocellular malignant proliferation. This conclusion might be valuable in developing effecting therapeutic agents.
Great comment. Next step, may I suggest to be (a) identify the journals that specializes in HCC, both cancer and Liver Research, please submit an Editorial Note based on your post above (b) define this topic to be a topic of a lecture that you are now to propose to ALL departments of biology, Genetics and Medical Schools in 2-3 Universities in the Chicago area. After selection of the schools, you are to contact by phone the Organizers of the weekly Seminar and you are submitting an abstract and request a date for your talk to be scheduled. I am very pleased that you have produced a produce defined as Scientific Syndication of Research Results which is now ready to become an Editorial Note and a Lecture Series. Cheers to you, Aviva
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Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette