TASIN represents a promising approach for prevention of colorectal cancer


View:743 Time:2016-10-21


Colorectal cancer attracts the attention of the scientific community as well as the general population because of its relatively high incidence compared with other types of cancer. According to estimates, colorectal cancer is the third most common cancer in the world that approximately 700,000 people die from it each year.


The cause of cancer is a complex question that has not been fully understood. What is clear is that an error in the genes plays a key role in this process.


Recently, a new study has found a method to fight against the most common genetic mutation in colorectal cancer. The method uses a small molecule, named TASIN-1, to target and destroy cancer cells carrying mutations in a gene called APC. Considering the high prevalence of APC mutations in patients with colorectal cancer, the method should be a very effective strategy for the treatment and prevention of the lethal disease.


The study is a collaboration of several institutions in the USA and an institution in Korea. Jerry Shay, Ph.D., Distinguished Teaching Professor at the University of Texas (UT) Southwestern Medical Center, is the lead researcher, and his major research interests include cell biology of the cancer genome.


Shay noted that "Even though such mutations are common in colorectal cancer, there are currently not any therapeutics that directly target these types of mutations, so this represents fresh avenues to approach."


You can read the full paper, entitled Selective targeting of mutant adenomatous polyposis coli (APC) in colorectal cancer, in the journal Science Translational Medicine (2016).


The gene APC, short for adenomatous polyposis coli, is classified as a tumor suppressor gene, meaning that it acts to prevent the development and progression of cancer. This gene codes for a protein that has a role in many fundamental cellular processes, such as the regulation of canonical WNT signaling pathway, cell proliferation, migration, differentiation, and apoptosis.


Mutation of APC is found in more than 80% of all colorectal tumors, and it's thought that APC mutations contribute to the initiation of colorectal cancer. The vast majority of APC mutations generate stable truncated gene products, referred to as APC truncations. These truncated proteins not only lead to the loss of APC tumor-suppressing functions but also may exert functions that contribute to colorectal tumorigenesis. Although APC is frequently mutated in colorectal cancer, currently there is no known drug that could directly target this type of mutation.


To find drugs that target APC mutations, Shay and co-workers from UT Southwestern Medical Center, along with researchers from Inha University College of Medicine, screened more than 200,000 small molecules to see which of them could selectively inhibit cell growth of human colorectal cancer cell lines with truncated APC. A compound named TASIN-1 (truncated APC selective inhibitor–1) stood out. It effectively killed cancer cells with truncated APC in vitro but did not exhibit potent toxicity toward cancer cells with normal APC.


Next, the researchers examined the anti-tumor activity of TASIN-1 in vivo. Mice transplanted with human cancer cells were treated with TASIN-1. Results showed that TASIN-1 treatment reduced the tumor-forming ability of human cancer cells with truncated APC in mice, but did not affect cancer cells that had normal APC.


The researchers also tested TASIN-1 in mice genetically engineered to develop colorectal cancer that carried truncated APC and found that TASIN-1 treatment greatly reduced tumor burden in the colons of these animals, without causing detectable toxicity in other tissues of them such as livers, kidneys, and spleens.


Finally, the researchers explored the mechanisms underlying the anti-tumor effects of TASIN-1. They identified that the compound interferes with cholesterol biosynthesis and pinpointed EBP (emopamil-binding protein) as a potential target of TASIN-1. "TASIN-1 exerts its killing effects primarily by depleting cholesterol through inhibition of EBP activity," the researchers concluded.


Taken together, these data suggest that the compound TASIN-1 could selectively target and destroy cancer cells carrying APC truncations while sparing cancer cells with wild-type APC as well as healthy cells. An advantage of the compound is that it triggers no apparent toxicity. This is significant because side effects or safety is an important factor that must be taken into consideration during drug development.


Targeting the APC gene is believed to be a potential therapeutic strategy for colorectal cancer, given that most colorectal tumors carrying APC mutations. TASIN-1 and similar small molecules might be a potential drug to target APC mutations since the current study demonstrates the potent cancer-killing effect of TASIN-1 both in vitro and in vivo.


"Our latest finding confirms that targeting TASINs is a viable approach," said Shay.


The current study would facilitate the development of a novel anti-cancer drug for the treatment and prevention of colorectal cancer, but more investigation is required to validate the results.


Colorectal cancer (which is often used interchangeably with the term 'colon cancer') originates from the out-of-control growth of cells in our colon and/or rectum, which form the lower part of our digestive system, as shown in Fig. 1 below. Cancer is thought to result from the complex interactions between genetic and environmental factors. To date, a variety of environmental factors and lifestyle choices have been associated with colorectal cancer, such as an unbalanced diet, overweight or obesity, a sedentary lifestyle, alcohol use, smoking, etc.


Fig. 1 The colon and rectum

(By Indolences created it on the English Wikipedia. This SVG image was created by Medium69. Cette image SVG a été créée par Medium69.Please credit this : William Crochot - US PD picture., Public Domain, https://commons.wikimedia.org/w/index.php?curid=1521879)


Shay's study and studies by many other groups deepen our understanding of the genetic aspect of colorectal cancer and key molecular mechanisms involved in it and might also open doors for research into the complex interactions between genetic and environmental factors implicated in colorectal cancer and therefore help develop preventive strategies.


If there was a choice, no one wanted to develop cancer. Individuals with genetic risk factors are more prone to a specific disease compared with the general population. Even though we know this, there is often a lack of drugs that can target these genetic factors, such as in the case of APC mutations in colorectal cancer. Development of drugs that target disease-causing mutations might offer opportunities for prevention of disease, and of course, requires a great deal of work, and may face a lot of failures.

 
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