Researchers have discovered a way to tag cancer cells of tumors that are difficult to target because they lack suitable receptors. They suggest that their approach, which they tested in mice, could lead to new targeted therapies for cancers that do not respond to those currently available, such as triple-negative breast cancer.

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Some cancers do not respond to current targeted therapies because their tumor cells do not have suitable surface receptors.

The team – including scientists from the University of Illinois at Urbana-Champaign and research centers in China – reports the findings in the journal Nature Chemical Biology.

The method uses small-molecule sugars to produce unique, artificial cell surface receptors on cancer cells.

Study leader Jianjun Cheng, a professor in materials science and engineering at Illinois, explains that there is a lack of targeted therapies for certain cancers because they do not have any of the receptors that available treatments normally target.

One such cancer is triple-negative breast cancer – an aggressive cancer with a low survival rate.

Prof. Cheng says that this got them thinking that perhaps they could create an artificial receptor.

Targeted cancer therapies are treatments that target specific molecules involved in the growth, progression, and spread of cancer. They belong to a relatively new field called precision medicine.

There are several differences between targeted cancer therapy and conventional chemotherapy, the main one being that most chemotherapy treatments target all rapidly dividing cells, including healthy ones.

Targeted cancer therapy aims to single out only cancer cells and leave healthy cells intact. In order to do this, researchers must find features that distinguish the tumor cells of a particular cancer from healthy cells, so that the treatment can target those features specifically.

One feature that can differentiate cancer cells from healthy cells is the cell surface receptor, a type of molecule that protrudes on the outside of the cell and acts as a conduit for signals between the cell and its environment.

Scientists can devise antibodies that seek out the receptors that are specific to cancer cells in order to deliver targeted drugs or imaging agents.

However, some cancers are notoriously difficult to distinguish in this way because they lack suitable surface receptors.

One such cancer is triple-negative breast cancer. Tumor cells of this type of cancer lack the three most common types of receptor known to drive most breast cancer growth: estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2 (HER2).

Prof. Cheng and colleagues found a way to insert unique molecules into cancer cells that the cells metabolize into cell surface receptors, without the molecules affecting healthy cells.

The molecules belong to a class of small-molecule sugars called azides. The cancer cell metabolizes the molecules and expresses them on their cell surfaces, where they can be uniquely targeted by another molecule called DBCO, as Prof. Cheng explains:

“It’s very much like a key in a lock. They are very specific to each other. DBCO and azide react with each other with high specificity. We call it click chemistry. The key question is, how do you put azide just on the tumor?”

To ensure that the azide would only be expressed by the cancer cells, the team attached a chemical group to the azide that only enzymes in the cancer cell can remove.

The modified azide just passes through healthy tissue. In tumor cells, however, the enzymes digest the attached group and express the azide as a cell surface receptor that binds uniquely to DBCO, which can be used to deliver cancer drugs or imaging agents.

After showing that the method works in cells cultured in the laboratory, the team tested it in mice with triple-negative breast cancer, colon cancer, and metastatic breast cancer tumors, and they found that the tumors expressed very strong signals compared with other types of tissue.

For the first time, we labeled and targeted tumors with small molecule sugars in vivo, and we used the cancer cell’s own internal mechanisms to do it.”

Prof. Jianjun Cheng

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