Inhibition of ASCT2 combats cancer in vitro and in vivo

Novel target for anti-cancer therapy

Cancer cell metabolism is different from normal cell metabolism. This difference offers targets for the development of therapeutics to treat cancer. Cell function is dependent on many important nutrients. One such nutrient is glutamine, an α-amino acid that has a vital role in many biochemical processes, such as protein and lipid synthesis. Some studies have shown that the presence of a tumor produces great changes in host glutamine metabolism in a way that meets the tumor-enhanced requirements of glutamine.

A protein called ASCT2 is an important glutamine transporter. ASCT2 is involved in tumor growth and the proliferation of cancer cells. Overexpression of ASCT2 has been seen in various cancers and this overexpression appears to be a predictor of poor prognosis. ASCT2 provides cancer cells with glutamine and coordinates tumor cell growth. Therefore, inhibition of ASCT2 represents a potential therapeutic strategy for many cancers.

Now, a team composed of researchers from Vanderbilt University Medical Center (VUMC) has developed an inhibitor of ASCT2, known as V-9302. They have demonstrated that the inhibitor contributed to anti-tumor responses in vitro and in vivo. This study is the first to demonstrate the efficacy of a pharmacological inhibitor of ASCT2 in oncology, according to the researchers. Findings of the study have been summarized in a paper titled “Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models,” appearing online in the journal Nature Medicine[1].

The corresponding author of the paper is Dr. H. Charles Manning, who is a professor of radiology and radiological sciences at VUMC and who is among 37 recipients of the 2015 Distinguished Investigator Award from the Academy of Radiology Research (ARR).

In the study, Dr. Manning and his team tested the ASCT2 inhibitor V-9302 in both cultured cancer cells and animal models. They discovered that treatment with V-9302 reduced cancer cell growth and proliferation and increased cell death and oxidative stress. The results suggest that pharmacological inhibition of ASCT2 is a promising way to combat cancer. But further research is still needed to test the effect of V-9302.

Dr. Manning and his multidisciplinary team are committed to developing non-invasive molecular imaging metrics to evaluate disease progression and response to therapy. They hope to use non-invasive methods to investigate whether V-9302 acts as desired.

The current study would have profound implications for the development of anti-cancer drugs that targeting cancer cell metabolism.

Cancer cells divide rapidly than normal cells. Proliferatively active cells require both a source of carbon and of nitrogen for the production of various essential molecules. In many tumor cells, glutamine uptake is markedly enhanced. Scientists have been trying to develop drugs that target glutamine metabolism in cancer cells for many years. However, many of these efforts have not succeeded due to reasons like multiple toxic effects, lack of specificity and/or ineffectiveness of the treatments.

Cause of cancer

Cancer refers to a large group of diseases that are characterized by uncontrolled growth of abnormal cells. At the advanced stage, these abnormal cells may spread from their original site to distant sites, causing systemic problems. The process in which cancer cells spread to other parts of the body is called metastasis, which is the leading cause of cancer-related death.

Scientists have been seeking strategies to overcome cancer because it's one of the largest killers of mankind. Although there is still a long way toward achieving this goal, great improvement has been made in cancer screening and cancer treatment, saving many lives. And now, we have a better knowledge of what causes cancer.

It’s believed that cancer is caused by changes or mutations to the DNA of cells. DNA contains instructions that tell the cell how to behave. When errors occur in DNA, the cell may grow and divide in an uncontrolled manner, invading normal tissues and organs.

Where do these errors come from? A small percentage of them are inherited from the parents. This means that you may be born with a genetic mutation that contributes to cancer development. But most gene mutations are not from your patients but instead, they occur after birth. Previous studies have identified many factors that could trigger gene mutations. Here are some examples:

1. Smoking

Smoking has been found to increase the risk of a variety of cancer, including lung cancer. Tobacco exposure appears to drive the mutation of a set of genes such as the tumor suppressor p53[2].

2. Radiation

The mutagenic effects of radiation were first recognized in the 1920s. Radiation can weaken and break up DNA, either causing cells to mutate in ways that may eventually lead to cancer or damaging cells enough to kill them. Exposure to high levels of radiation is detrimental to your health. But radiation is used as a therapy against cancer due to its ability to induce DNA damage in cancerous cells.

3. Microorganisms

Many types of pathogens have been found to increase the risk of developing certain types of cancer. For example, HPV (human papillomavirus) has been established as a risk factor of cervical cancer, anal cancer, and oropharyngeal cancers; EBV (Epstein-Barr virus) has been implicated in several cancers such as Hodgkin lymphoma, naso-pharyngeal cancer, and Burkitts lymphoma; Hepatitis viruses like HBV have been associated with liver cancer; and infection with the bacterium Helicobacter pylori predisposes to gastric cancer.

4. Toxic chemicals

Some substances are known as cause cancer. A few well-known carcinogenic agents are asbestos, nickel, cadmium, radon, vinyl chloride, benzidene, and benzene. People who are often exposed to these substances are at a higher risk of developing cancer.

5. Obesity

Cancers most consistently associated with overweight and obesity are breast (in postmenopausal women), colon/rectum, endometrium, pancreas, adenocarcinoma of the esophagus, kidney, gallbladder, and liver. How obesity causes cancer has not been fully understood. One hypothesis is that obesity increases DNA damage[3].

6. Chronic inflammation

Inflammation is a part of innate immunity -- the first line of defense to pathogens or diseases. But having chronic inflammation can drive cancer development. A recent study has suggested that inflammation stimulates a rise in levels of a molecule called microRNA-155. This, in turn, causes a drop in levels of proteins involved in DNA repair, resulting in a higher rate of spontaneous gene mutations, which can lead to cancer[4].

7. Unhealthy lifestyle

A high-fat diet, physical inactivity, sleep deprivation, and other bad habits seem to increase cancer risk. The underlying mechanism may also involve alterations in the DNA within cells.

Types of cancer

There are more than 100 types of cancer in humans. It can affect just about every organ in the body, ranging from the lungs and stomach to the eyes and heart.

According to the World Health Organization (WHO), the most common cancers are cancers of the lung, breast, colorectal, prostate, skin, and stomach, and the most common causes of cancer death are cancers of the lung, colorectal, stomach, liver and breast.

Table 1. Six Most Common Cancers

Rank Type of cancer Number of cases (/million)
1 Lung cancer 2.09
2 Breast cancer 2.09
3 Colorectal cancer 1.80
4 Prostate cancer 1.28
5 Skin cancer (non-melanoma) 1.04
6 Stomach cancer 1.03

Table 2. Five Most Common Causes of Cancer Death

Rank Type of cancer Number of deaths (/million)
1 Lung cancer 1.76
2 Colorectal cancer 0.86
3 Stomach cancer 0.78
4 Liver cancer 0.78
5 Breast cancer 0.63

Worldwide cancer rates are expected to increase by 50% by 2020 and by 75% by 2030. Many factors explain this increase. The biggest factor is that we live a lot longer. As people get older, more cases of cancer will occur. Besides, lifestyle changes, stress, exposure to radiation and toxic chemicals, obesity are also important factors.

[1] Michael L Schulte et al, Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models, Nature Medicine (2018).
[2] Don L. Gibbons et al, Smoking, p53 Mutation, and Lung Cancer, Molecular Cancer Research (2014).
[3] Concha Cerdá et al, Oxidative Stress and DNA Damage in Obesity-Related Tumorigenesis, Advances in Experimental Medicine and Biology (2014).
[4] Esmerina Tili et al, Mutator activity induced by microRNA-155 (miR-155) links inflammation and cancer, PNAS (2011).


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