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Developing successful treatments for HCC and NASH

Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the second most common cause of cancer deaths worldwide.[1] There is not currently a successful therapy to treat HCC in advanced stages.[2] NASH is a primary risk factor for liver cancer.

Devanand Sarkar and his team have uncovered the molecular mechanisms leading to NASH and HCC, shedding light on the connections between obesity and cancer. He is leveraging this knowledge to develop targeted treatments for both NASH and advanced HCC. We asked him to give us a brief insight into his work ahead of his presentation at the 3rd Global NASH Congress, 2020.

With my team I study the functions of a number of understudied genes, including oncogenes, tumor suppressor genes and genes that regulate metabolism, in a hepatocellular carcinoma model, some of which I have discovered and cloned with colleagues. A lot of the phenotypes that are associated with NASH or HCC are observed only in vivo and my work has depended on the use of the Massey Cancer Centre’s Transgenic/Knock-out Mouse Shared Resource.

For 10 years, I have been developing an in-depth understanding of the mechanisms by which AEG-1 and SND1 promote HCC; and working to identify a combination of drugs to inhibit both proteins in a mouse model to develop a successful therapy for advanced HCC. In the process we have been able to better understand NASH and also propose a new therapeutic treatment option for NASH.

From HCC to NASH

Hepatocellular carcinoma always develops on a diseased liver. The liver is first destroyed by cirrhosis, from either hepatitis or NASH or alcoholism, and then the cancer develops. My work explains these connected processes on a molecular level.

I have been working on a gene called Astrocyte Elevated Gene 1 (AEG-1). The other name of the gene is Metadherin. It is known to be an oncogene and it has been studied as an oncogene in many cancers (including hepatocellular carcinoma.) In HCC, this gene is overexpressed in almost 90% cases.

To better understand the function of this gene, we created a liver specific transgenic mouse. We expected that when this AEG-1 is overexpressed in the liver, HCC will develop. To our surprise, we observed that this transgenic mouse also developed NASH. This gave a crucial access point to understanding the mechanism of both diseases: AEG-1 regulates both lipid metabolism as well as inflammation.

NASH has two components: one is steatosis – abnormal retention of lipids in the liver – and then, steatohepatitis – inflammation in the liver. AEG-1 regulates both of these components of NASH. Most of the genes that promote NASH are active in steatosis, or inflammation, or fibrosis, but AEG-1 regulates everything. This discovery made AEG-1 a good target for a treatment for NASH if it could be inhibited.

Developing new treatments for NASH and HCC

My work mechanistically explains the process of NASH and HCC and is also developing a new therapeutic tool that can be used in clinics. The research is particularly significant because it provides an alternative, non-drug-based, strategy to treat these diseases. This is a key development as it could be a lot more tolerable for patients and enable longer standing treatment.

The issue with a lot of anti-cancer drugs is that if you give these to an HCC patient, the damaged liver cannot metabolize the drugs. Frequently patients stop treatment, not because the treatment is not working but, because the patients cannot tolerate the treatment itself.

We believe that a significantly less toxic treatment, such as a gene or immune therapy, is required to properly manage HCC patients. We have been using (FDA approved) liver targeted nanoparticles delivering siRNA or proteins to target specific oncogenes or overexpress specific cytokines to induce an immune-modulatory response or a gene therapy response.

And at the same time, we have been able to use the same liver targeted nanoparticle siRNA strategy to develop a non-drug based treatment for NASH. We put mice on high fat diet to induce NASH and then treated these mice with this liver specific nanoparticles delivering siRNA for AEG-1. This resulted in profound inhibition in development of NASH upon high fat diet feeding.

The benefit of the targeted treatment is avoiding the toxicity to other organs.  The ligands in the lipid-based nanoparticles, the PAMAM dendrimers, bind to specific receptors on hepatocytes and can deliver a conjugated payload specifically to the hepatocytes without effecting other organs. We have demonstrated in mice that when injected intravenously with these nanoparticles with AEG-1 siRNA, there is selective down regulation of AEG-1 in the liver only, not in any other organ.

Another advantage of nanoparticle delivered siRNA is that it doesn’t induce an immune response in animals; or in humans. The strategy can be applied multiple times. This is especially required when, as in the development of NASH to HCC there are additional mutations. We are now combining siRNA for multiple genes using the same strategies so that we get a much stronger effect.

We have also demonstrated in mice, that the treatment needs to go hand in hand with lifestyle modification. The therapeutic strategy we are developing will need to be delivered alongside the work of dietitians, nutritionists and others in order to be effective.

We are now doing further studies to get a fuller picture of the pharmacokinetics of the formulation so that our next step could be starting a Phase 1 Clinical Trial of the therapies in the next year or two to see if what we observed in mice is verified in humans.

 

Devanand Sarkar is Professor of human and molecular genetics at Virginia Commonwealth University (VCU), and Associate Director for education and training of Massey Cancer Center at VCU.

 

Devanand will be speaking on RNAi strategy for the treatment of NASH: focus on astrocyte elevated Gene-1 (AEG-1) at the 3rd Global NASH Congress, London, 2020. Explore the full programme.

[1] Blake Belden, ‘Massey researcher awarded $5.4 million to investigate novel therapies for liver cancer’, Massey News Centre, June 21, 2019, https://www.massey.vcu.edu/about/news-center/2019-archive/massey-researcher-awarded-54-million-to-investigate-novel-therapies-for-liver-cancer/, accessed 22/10/2019.

[2] Ibid.

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