March 17, 2012

Systemic Treatment of Liver Cancer

Hepatocellular carcinoma LSF inhibition via FQI1

By: Travis Giddings

Published: Mar 16, 2012 10:28 am Reviewed By: Joseph V. Madia, MD


While no systemic treatment currently exists for liver cancer (hepatocellular carcinoma), a series of experiments in rats has identified viable target worthy of further investigation.

A gene called LSF (Late SV40 Factor) may be a target in liver cancer that drugs could be developed to target and wipe out.

Every cancer has a series of common mutations that predispose the transformation from normal cell to cancer. These genes are called oncogenes. Some cancers have a unique profile with specific oncogenes for that cancer, or may share similar mutations with other, closely related cancers.

In the search for a systemic treatment for liver cancer, the LSF gene has been shown in previous studies to appear specifically in hepatocellular carcinoma.

LSF, like many oncogenes, regulates cellular growth. After completing their laboratory experiments and transplating human cancers into rats, researchers concluded that LSF inhibition is worthy of further study and remains a promising drug target.

Boston University researchers began testing 20 compounds of isoquinolinones, with one candidate quickly outperforming the others.

Factor Quinolinone Inhibitor 1 (FQI1) is the lead candidate for further study, and was proven to inhibit DNA replication of LSF in studies performed both in a laboratory setting and inside the cell.

Most notably, FQI1 increased cellular death in cancer, but did not affect normal cells.

Supplementary information provided by the publication of the study extensively documents the methods used by the team to make the isoquinolinones compounds referenced.

Research was published in the journal Proceedings of the National Academy of Sciences of the United States of America.

The authors of the study declared that there was no financial conflict of interest in the publication of their research.

Liver Cancer (Hepatocellular Carcinoma)

The American Cancer Society estimates that there are over 26,000 new cases of primary liver cancer and bile duct cancer in the United States each year, and they are responsible for over 19,000 deaths. The average man has about a 1% chance of developing this cancer over his lifetime, while the average woman has about a half percent chance.

Primary liver cancer most commonly includes hepatocellular carcinoma (HCC) and can coexist with cholangiocarcinoma, a cancer of the bile ducts between the liver and gall bladder. It is important to note that most cases of cancer in the liver are metastases from other cancers, such as those from the colon, breast, or prostate. Primary liver cancers begin in the liver itself. Other less common forms of primary liver cancer include angiosarcomas and hemangiosarcomas (cancers that begin in the blood vessels of the liver), lymphoma of the liver, and hepatoblastoma (a rare pediatric cancer usually occurring in children under three years of age). There are also several variants of benign liver tumors. Hepatocellular adenomas (a benign liver tumor associated with oral contraceptive use and glycogen storage disease) must be watched closely, as they have a potential to turn cancerous.

Hepatocellular carcinoma, the most common form of liver cancer, is strongly associated with infection by chronic hepatitis B and C. These infections cause liver cancer more often in Asian and African countries where hepatitis viruses are endemic and people acquire the disease early in their life.

Cases of liver cancer in the United States have tripled over the past three decades. While the most common cause of liver cancer used to be from alcohol abuse and the resulting cirrhosis of the liver, hepatitis C infection is now a leading cause. Obesity, particularly fatty liver disease, is also implicated. Other causes include hemochromatosis (a disease that causes the body to store too much iron), high exposure to aflatoxins (a mold found in peanuts, rice, soybeans and corn; rare in developed countries), and Type 2 diabetes.

Symptoms of HCC usually present with classic signs of liver dysfunction such as jaundice (yellowing of the skin due to too much bilirubin), bruising and blood clotting problems (due to the liver making the clotting factors in our blood), and ascites (fluid buildup in the abdomen from liver dysfunction). Other general symptoms include nausea, fatigue, vomiting, and unintentional weight loss.

In patients who are at high risk for HCC, screening is usually done with ultrasound and CT scan, as well as MRI. While there is no reliable blood test for liver cancer screening, a high level of alpha-fetoprotein (AFP) should be considered suspicious for liver cancer. Liver biopsy is also done, although this is not necessary for diagnosis if imaging is definitive.

Treatment for HCC is difficult, as many patients with liver cancer also have damaged livers from cirrhosis. Treatment must be balanced between treating the cancer and also mitigating the risk of liver failure. Early stage cancer has the potential for surgical removal, however most cases of liver cancer are discovered when they are advanced, making surgery difficult. Other treatments are dependent on the size and location of the tumors, such as ethanol injection into the tumor (small tumors), radiofrequency ablation (using high-frequency radiowaves to destroy the tumor), transcatheter arterial chemoembolization (cuts off the blood supply to unresectable tumors), and cryosurgery (destroying cancerous tissue with subzero temperatures). Liver transplantation is a relatively successful option for patients without metastatic spread. Sorafenib (marketed as Nexavar) is a tyrosine kinase inhibitor that has shown efficacy in treating HCC.

Ultimately, HCC is a difficult cancer to treat and survival rates are low, with most cancers being unable to be completely removed. These patients usually succumb to the disease within three to six months. Across the board, patients with a solitary small tumor of less than three centimeters in size have a five-year survival rate of 20%. Patients with advanced disease have a one-year survival rate of 30%.

Prevention of liver cancer is extremely effective if vaccinated against hepatitis B. Avoidance of alcohol abuse is also effective. Other patients with different causes of cirrhosis or chronic liver inflammation will benefit from routine ultrasound screening and AFP measurements in the hope of detecting cancer early.


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