Home Cellular health Developing a drug to identify and target tricky cancer cells

Developing a drug to identify and target tricky cancer cells


Cancer is a difficult disease to fight. The simplicity and universality of the name belies the extent and diversity of cancers. They attack every inch of the body in a myriad of ways, using a variety of tactics and DNA that they can modify on the fly to evade capture and bypass our body’s defenses.

One thing they have in common, however, is that they all come from within (with the exception of a few contagious cancers like Tasmanian devil‘s facial tumor disease). They are built from your cells. And that’s one of the biggest obstacles to treating cancers with broad-spectrum immunotherapies: it’s really hard for your immune system to tell cancer cells from normal cells.

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The quest for cancer-targeting drug treatments

“People have been looking for what we call cancer-specific antigens for a very long time,” says Kevan Shokat, who directs a cellular and molecular pharmacology lab at the University of California, San Francisco. In theory, these antigens are proteins present on the surface of cancer cells, but not cells in the rest of the body. “And, in essence, there isn’t,” he says.

Since the 1990s, Shokat has been interested in protein kinases, proteins that modify other proteins. They are important targets for cancer treatment because of the role they play in regulating cancer-related cellular functions, such as proliferation, apoptosis and growth. Mutated kinases are often found oncogenemeaning they cause tumors to grow or develop.

Before becoming oncogenes, they are called proto-oncogenes. And one in particular, K-RAS, is thorny. So Shokat—along with fellow UCSF professor Charles Craik, graduate students Ziyang Zhang and Peter Rohweder, and half a dozen other collaborators—set out on an ambitious quest. They aimed to make the mutated K-RAS G12C cell, one of the main drivers of lung and colon cancer, targetable by the immune system.

“It’s this protein that doesn’t have any drug pockets,” Shokat says. In other words, there was no way that a drug detectable by the immune system could bind to it and initiate an immune response. How they overcame the “irreducible nature of K-RAS,” he says, is a bit of an odyssey.

Develop a synthetic drug

The first step was to develop a drug capable of detecting cancer cells. Although these cells are extremely similar to normal cells, at least externally, there is a crucial common difference in K-RAS G12C: the oncogene mutation in the proto-oncogene converts one of amino acids in the cellglycine, to cystine.

“That’s what drives cancer,” says Shokat. So, in the absence of cancer-specific antigens, researchers had to develop a drug that could permeate cancer cells, grab that cystine, and pull it to the surface.

A potential problem was the shape. The human body uses what are called MHC molecules to bind to foreign peptides (two or more amino acids linked in a chain) and mark them for destruction. But the drug that drove the cystine to the surface also changed the overall shape of the peptide, Shokat says, and that raised the question of whether the modified molecule could still attach to MHC molecules.

“Once we showed it worked, we were pretty much up and running,” says Shokat. Their findings were Posted in cancer cell this month of September.

Build a custom antibody

From there, Craik’s team took over; the next step was to develop an antibody that could recognize the drug.

“There’s a whole wonderful system that his lab uses,” says Shokat, “which is kind of like an immune system in a bottle. He’s got all these antibodies from a lot of human donors, and they’re doing some sort of fishing experiment to see which of the antibodies will bind [with the drug].” From there, a synthetic antibody could be mass-produced.

It worked – but there was still another hurdle to clear. The antibodies had a fatal flaw, he says, that they also recognized the drug before it had yet attached itself to the target cells. This means that when the researchers ran tests on the antibody, it couldn’t find the target cells because it had already attached itself to the free drug.

He was back to the drawing board to find a modified version of the antibody that was more inclined to bind to the whole complex: the drug attached to the target cell.

Still in its infancy

Although the results are an exciting step towards treating certain cancers, Shokat notes that there are some limitations to the process. Notably? Much of the work has been done in vitrooutside of a living organism, although animal studies were done early in the research.

“We haven’t demonstrated that we can shrink a tumor in a mouse with this approach,” for example, says Shokat. “Until we do that, there are potentially other hurdles ahead of us.” However, the potential of the approach is exciting for him, especially in the case of a disease as delicate as cancer.

In general, there are two main approaches to treating cancer: targeted treatments that help the immune system fight cancer, such as checkpoint inhibitors that prevent cancer cells from turning off an immune response, and treatments that work at inside cancer cells, such as drugs that inhibit signaling. cancer cells depend on their growth and spread.

“But those two things don’t overlap very well,” says Shokat. “Our approach has really been to tie them together very tightly.” And they did it in a flexible way that makes the technique applicable to even more advanced drug candidates.