Enhancing the immune system.
Liver cancer is a calculating killer. Its tumors have their own defenses that prevent a cancer victim’s body from defeating the disease. But thanks to the investigative epigenetics of Prof. Alfred Cheng Sze-lok, that may be about to change.
The leading form of liver cancer is hepatocellular carcinoma, the third-largest cause of cancer deaths worldwide. The cancer’s prevalence is highest in East Asia, partly as a result of hepatitis B infections, but is increasingly common in Western nations as well due to the rising level of diabetes and obesity.
The existing treatment for that form of liver cancer involves immunotherapy. The drugs contain immune-checkpoint inhibitors, which activate cancer-killing T cells. The cancer suppresses those T cells, so stimulating them can shrink tumors and increase survival rates.
However, only around 15% of patients respond to immunotherapy.
One problem is that liver cancer is a ‘cold’ cancer that walls itself off and prevents T-cells from entering the tumor.
The cancer also co-opts host cells to suppress T cells.
Professor Cheng has striven to find out how those defenses work, therefore, how they can be overcome.
His investigation led to the discovery of an epigenetic regulator, an enzyme known as histone deacetylase 8, or HDAC8. To protect the cancer, HDAC8 prevents the production of chemokines, a molecular signal that encourages
T-cells to come to the body’s assistance.
When mice are treated with a drug that inhibits HDAC8, chemokines are expressed in the normal way, and T cells finally start being able to infiltrate
the tumor. Professor Cheng likens it to police finally being able to break into Kowloon Walled City, a former citadel within Hong Kong that for decades functioned as a law unto itself.
According to lab results shown in the graph above, mice that are implanted with a liver tumor all die within 30 days without treatment. When treated with immunotherapy on its own, the animals survive longer, but all die within 180 days. Likewise, they live longer with epigenetic treatment on its own, but all the animals die within 180 days. When mice are treated with both immunotherapy and epigenetic treatment, all the animals survive longer than 360 days.‘I was quite surprised, but we re-tested it,’ Professor Cheng says. ‘The duration of the effect is very long.’
Dissection (pictured above) reveals that when mice are given one form of treatment, the cancer shrinks but remains present on the liver. When mice are given both immunotherapy and epigenetic treatment, the cancer is eradicated, leaving only a perfectly healthy liver, which can recover. The findings were recently published in the journal Science Translational Medicine.Professor Cheng discovered the importance of HDAC8 by investigating which epigenetic genes are active in two animal models: mice that are genetically bred to become obese and develop liver cancer; and mice that develop liver cancer because they are fed with a high-fat, high-carb diet, the equivalent of Coca-Cola and hamburgers.
The team started out with a list of 115 genes to investigate. The HDAC8 gene was the only one ‘upregulated’ in both experiments. ‘We found that it has indeed very prominent tumor-promoting abilities,’ Professor Cheng explains.
The epigenetic work takes the study of cancer beyond what’s going on inside the tumor cell to look at the broader immune microenvironment. Unlike our genetics, which are fixed and determine issues such as our eye color, the field of epigenetics studies genes that are expressed given the influences exerted on them.
‘Epigenetics is a totally different ballgame,’ Professor Cheng says. Gene expression often ‘can be reversed, and the damage is not permanent.
‘That’s why I wanted to study epigenetics.’
It’s likely that the same treatment would work for other ‘cold’ or immune-excluded cancers, a category that includes ovarian and pancreatic cancers.
‘They also have a high expression of HDAC8 contributing to the coldness of
the tumor,’ Professor Cheng notes. ‘Targeted epigenetic treatment may also be effective.’
The studies in mice have yet to be followed up with human clinical trials. Professor Cheng is collaborating with a drug-development team in Germany, who have produced a series of drugs that can deliver the treatment. Professor Cheng and colleagues from CUHK’s School of Pharmacy will now test which of the German-developed drugs is most effective in mice.
Prof. Alfred Cheng with his lab members Prof. Zhou Jingying (left) and Dr. Yang Weiqin (right). The BD FACSymphonyTM A5.2 machine behind them is the only one in Hong Kong and a state-of-the-art cell analyser that can unravel the complexity of tumour ecosystem
The profile of the drug, if it works, will then need to be adapted for human use. Professor Cheng, who is the chief of cancer biology and experimental therapeutics in CUHK’s School of Biomedical Sciences, is applying for funding to work on that formulation, which may take around a year.
Professor Cheng estimates that, if all goes well with the safety profile and delivery of the drug, a human trial could begin within three years. If that in turn goes well, work could begin for a drug for clinical use.
Around 70% of liver-cancer patients produce high levels of HDAC8. ‘It can be quite beneficial to a substantial portion of patients,’ Professor Cheng says.
Such drugs would be part of the progression towards precision medicine, in which patients are treated differently depending on their genetic makeup and disease profile. Every person has their own different tumor. This way, they would not have to fight the disease alone.
Why men contract liver cancer far more often than women?
Unlocking the difference between the sexes in liver cancer.
Prof. Alfred Cheng, School of Biomedical Sciences.
The difference between the sexes in contracting various diseases is what fascinates Prof. Alfred Cheng Sze-lok. After first studying estrogen and its impact on breast cancer, he has shifted focus to analyze how the male sex hormone connects to a high incidence of liver cancer.
In men, liver cancer is the second-most common cause of cancer deaths worldwide. It also has a poor range of treatments. The disease is far more prevalent among men than it is with women. The ratio of incidence ranges from 2:1 to as much as 5:1 in some nations.
‘Why are men at a loss?’ Professor Cheng has puzzled over what he calls a ‘remarkable phenomenon.’
The first response is to blame the ‘bad habits’ that men tend to pursue more than women: drinking and smoking. Obesity and hepatitis viruses also play a part. But experiments in animals have shown those extrinsic factors are not enough to explain the gender gap. When exposed to the same ‘insult,’ such as a hepatitis virus, male mice still have a much-higher likelihood of contracting liver cancer than female ones.
Androgen is the male sex hormone that governs the appearance, muscle tone and strength of males. If it is overstimulated—perhaps by the Hepatitis B virus that is most common in China, or the Hepatitis C found very often in Japan—it can lead to the development of cancer. Being overweight can also release the same effect.
Why are men at a loss? Professor Cheng’s research team unveiled a male sex hormone-deregulated pathway that might contribute to liver cancer induced by either hepatitis virus or obesity
His research has honed in on the molecular activity promoted by the male sex hormone in androgen-receptor pathways. If the receptor is overstimulated, it interacts with DNA to activate a cancer-promoting gene, cell-cycle-related kinase (CCRK), that is a potential carcinogen. Professor Cheng has found that CCRK is silent in a normal liver. But in a diseased liver, it can produce abnormal cells, and ultimately tumors.
No one had identified CCRK before, and it’s exacting work to pinpoint such
a gene among the estimated 25,000 in the human body. Of the 200 human samples examined together with clinicians, two-thirds had an over-activated CCRK pathway.
‘The more we study this gene the more different functions we find,’ Professor Cheng notes. No one is yet sure what function if any it serves in a healthy liver. But highly expressed CCRK in a diseased liver modifies proteins that stimulate key ‘signaling cascades,’ ultimately leading to liver cancer.
Even worse, it appears to suppress the immune system of cancer patients, according to the latest findings from Professor Cheng’s team. ‘CCRK can alter or affect the phenotypes of one type of immune cells, and change them from helping the body to being harmful to the body,’ he explains.
So CCRK poses two threats to men.
CCRK structure overlay with small molecules in kinase pocket.
Professor Cheng is working closely with experts in chemistry and computer engineering to discover CCRK-targeted drugs. Combating the disease is vital. Most liver-cancer patients remain asymptomatic and undiagnosed until they have an advanced stage of the disease. At that point, it resists most conventional chemotherapy treatments. The survival rate beyond five years is only 18%. The U.S. Food and Drug Administration has approved only one drug, sorafenib, for late-stage liver cancer. It normally only extends life by a couple of months.
Professor Cheng, who holds a post in CUHK’s School of Biomedical Sciences, came to his key findings via a genome-wide analysis of more than 17,000 genes. He found that around 250 genes bind with the androgen receptor. Computational software drawing on the known functions of those genes then identified around 20 that are particularly influential in cell growth. He then pinpointed CCRK as the likeliest to study in cancer formation because this gene binds the most actively with the androgen receptor.
Cross-studies in cellular and animal models validated the approach. CCRK acts as an important ‘signalling hub’ within a gene network. His team also found that CCRK may be induced by obesity and diabetes, twin epidemics worldwide. These findings recently lured sizable funding from the Hong Kong government to conduct a more-detailed investigation.
‘As the research goes on, we’re finding more and more interesting things,’ Professor Cheng says. ‘Kinase is a very promising target for cancer treatment, and it’s important to focus as a researcher or scientist.’
Ultimately this should lead to implications for clinical medicine, including the production of novel molecular therapeutics to reduce liver-cancer risk. Professor Cheng has been working with drug-discovery experts at the University of Sussex to develop small molecules that inhibit CCRK. He also stays in touch with clinical doctors at the Prince of Wales Hospital to keep tabs on what they are seeing first-hand.
‘This complimentary strength and mutual interest is very important,’
Professor Cheng notes. Although he is now a molecular biologist,
he draws on his background in clinical work during his doctorate.
Professor Cheng: ‘I really hope that CCRK targeted therapy can be actuated, but for the drug development, we still have a long way to go.’ Estrogen balancing diet – Bing video
Professor Cheng originally studied how estrogen regulates breast cancer
while pursuing that at Ohio State University. At CUHK, he was encouraged by Vice-Chancellor Joseph Sung to look at liver cancer in males, since it is prevalent in Hong Kong.
The drug-discovery process now involves chemists, computer engineers and oncologists around the world. Professor Cheng would like to work with even more collaborators, to form a network that can work towards generating a
drug for clinical use. His findings have appeared in noteworthy articles in publications such as the Journal of Hepatology and the Journal of Clinical Investigation.
Iodine (I) is essential, which clearly means we need it. Just as we need zinc
or magnesium, we need I. The common iodine deficiency disorders include goiter, hypothyroidism, mental retardation, reproductive impairment, and decreased child survival; however that short group is only the beginning of health problems with a lack of iodine.
Iodine is a powerful antibiotic which destroys viruses, bacteria, fungi and parasites. For Cancer prevention – Iodine is an important factor in cell apoptosis – the programmed death of unhealthy cells — which results in a reduced risk of sick cells turning malignant.
While he calls that cross-disciplinary approach exciting, its equally challenging. The drug-discovery process requires a cross-border effort that may well take years to bear fruit. At this stage, it is not yet clear that it will, although chances look promising.
Even if the work succeeds, drug approval takes virtually a decade to secure.
‘I really hope that CCRK targeted therapy can be actuated,’ Professor Cheng says. ‘But for drug development, we still have a long way to go.’
I Taught Shotokan 空手
Bonus Read: Early Life of Shigeru Takashina.
Takashina was born on 28 September 1943 in Hiroshima, Japan. He and his family survived the atomic bomb dropped on the city, by America on 6 August 1945. His family lived on the outskirts of Hiroshima, so escaped most of the deadly damage caused by the bomb. It should be noted that another JKA legend, Hiroshi Shirai, survived the atomic bomb dropped on Nagasaki, three days later.
Eat good fat avoid bad fat TO PREVENT CANCER.
Eat good fat avoid bad fat – Bing video
Reduce stress to stop the spread of cancer.
(1) Cancer and Qigong – Bing
(2) German New Medicine – Bing video
(3) Stress and Yoga – Bing video
Alfred Sze-Lok Cheng’s research works | The University of Hong Kong, Hong Kong (HKU) and other places (researchgate.net)
Alfred Cheng’s epigenetic treatment defeats liver cancer’s specialized defenses
Fighting Liver Cancer from Within | CUHKUPDates | CUHK