[Svisio/Canva]

The One Mutation That Could Change Cancer Therapy Forever

A single mutation in the HER2 protein is being targeted with unprecedented precision, offering a new, less toxic approach to cancer therapy
Engineered Human Therapies
by
|
October 22, 2024

In the intricate, microscopic world of proteins, sometimes all it takes is a single errant building block to flip the switch between normal cellular life and the chaotic growth we call cancer. It’s as if a benign force, quietly going about its business, suddenly takes a malevolent turn. One mutation—a tiny, almost imperceptible change—can set off a cascade of events, transforming a routine protein into a lethal agent. But catching these rogue proteins in the act, especially without harming their normal counterparts, has been the elusive goal of cancer researchers for decades.

Now, a team of scientists at NYU Langone Health’s Perlmutter Cancer Center believes they may have found a way to do just that. The team has engineered a drug that can spot the subtle difference between a normal protein and its nearly identical, mutated form that triggers cancer. The target is HER2, a protein notorious for its role in certain aggressive cancers. If this early-stage research bears out, it could mean cancer treatments that are not only more effective but also kinder to the body—eliminating cancer cells without laying waste to healthy ones. Their findings were published recently in Nature Chemical Biology.

“We set out to do something people said was nearly impossible,” says Shohei Koide, PhD, a professor at NYU Grossman School of Medicine and a lead author on the study. “We wanted to create an antibody that could recognize a single difference in the 600 amino acids that make up the HER2 protein. To be honest, we were surprised by how well it worked.”

The Shape of a Killer

The story of HER2 is a tale of how small changes can have catastrophic consequences. HER2, short for human epidermal growth factor receptor 2, is a protein that sits on the surface of many cells. Normally, it’s part of the cell’s communication system, helping to regulate how cells grow and divide. However, when a single amino acid in the protein mutates, it locks HER2 in an “always-on” mode, sending signals that make the cell divide uncontrollably. This is how cancer begins.

In some cases, the problem isn’t a mutation but an overabundance of HER2, with cells making too many copies of the gene that codes for the protein. That, too, drives excessive cell growth. The resulting cancers—often breast, stomach, and ovarian—can be aggressive and difficult to treat.

There are drugs on the market that target HER2, like trastuzumab and pertuzumab, but these therapies aren’t perfect. They attack HER2 on the surface of cells indiscriminately, which means they can harm healthy cells as well as cancerous ones. The result? Side effects that can sometimes be as grueling as the cancer itself.

What Koide and his team set out to do was craft a drug that could tell the difference between mutant HER2—the kind that causes cancer—and the normal version of the protein. Their breakthrough came when they realized that, by using advanced protein-engineering techniques, they could train antibodies to ignore normal HER2 and zero in on the mutant version alone.

Engineering Antibodies, One Round at a Time

Antibodies are nature’s guided missiles. These large, Y-shaped proteins are built to recognize and latch onto specific targets, usually with impressive precision. But designing an antibody that can distinguish between two versions of HER2 that are almost identical? That’s like trying to tell the difference between two nearly identical keys—one of which can unlock destruction.

The researchers took a natural process and sped it up in the lab. They exposed antibodies to multiple rounds of mutation and selection, refining the process until they had versions that recognized only the mutant HER2 protein. Each round brought them closer to their goal: an antibody that could spot the rogue version of HER2 while ignoring its well-behaved sibling.

Once they had the antibody, they faced a new challenge: getting it to do more than just stick to the mutant HER2. They needed it to recruit the immune system to finish the job.

A Two-Pronged Attack

Even if their antibody could find the mutant HER2, cancer cells don’t always make a lot of it. That means an antibody, on its own, might not be enough to kill the cancer. Koide and his team needed to turn their antibody into something more powerful. They came up with a clever solution: a bispecific T cell engager. In essence, they fused their HER2-targeting antibody with another one that grabs onto T cells, the immune system’s natural assassins.

Here’s how it works: one end of the bispecific molecule latches onto a cancer cell by recognizing the mutant HER2. The other end sticks to a T cell, which then attacks the cancer cell and kills it. It’s like bringing a sharpshooter to the scene and handing them the exact coordinates of the enemy.

In lab tests, this approach worked. The bispecific T cell engager was able to kill cancer cells that had mutant HER2 while sparing those with the normal protein. When the researchers tested it on mice with tumors, the treatment shrank the tumors without causing the usual side effects like weight loss or sickness.

Hope, with Caution

As always, with promising new treatments, there’s a catch. “We saw very few side effects in mice,” Koide says, “but there are important differences between mouse and human proteins. It’s possible that the treatment had fewer side effects in mice because the antibody binds more weakly to mouse HER2 than to human HER2.” In other words, the success in mice might not fully translate to humans.

Still, the potential is clear. Koide and his team are continuing to refine their antibody, hoping to eventually bring this kind of treatment to human patients. They’re also exploring how the same engineering technique could be used to target other cancer-causing proteins beyond HER2.

“It’s the dream of precision medicine,” Koide says. “To go after what’s causing the cancer and leave the rest of the body alone.”

For now, it’s still early days. But in the world of cancer research, this kind of breakthrough, where a tiny mutation can be hunted down and neutralized without collateral damage, feels like nothing short of a miracle.

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The One Mutation That Could Change Cancer Therapy Forever

by
October 22, 2024
[Svisio/Canva]

The One Mutation That Could Change Cancer Therapy Forever

A single mutation in the HER2 protein is being targeted with unprecedented precision, offering a new, less toxic approach to cancer therapy
by
October 22, 2024
[Svisio/Canva]

In the intricate, microscopic world of proteins, sometimes all it takes is a single errant building block to flip the switch between normal cellular life and the chaotic growth we call cancer. It’s as if a benign force, quietly going about its business, suddenly takes a malevolent turn. One mutation—a tiny, almost imperceptible change—can set off a cascade of events, transforming a routine protein into a lethal agent. But catching these rogue proteins in the act, especially without harming their normal counterparts, has been the elusive goal of cancer researchers for decades.

Now, a team of scientists at NYU Langone Health’s Perlmutter Cancer Center believes they may have found a way to do just that. The team has engineered a drug that can spot the subtle difference between a normal protein and its nearly identical, mutated form that triggers cancer. The target is HER2, a protein notorious for its role in certain aggressive cancers. If this early-stage research bears out, it could mean cancer treatments that are not only more effective but also kinder to the body—eliminating cancer cells without laying waste to healthy ones. Their findings were published recently in Nature Chemical Biology.

“We set out to do something people said was nearly impossible,” says Shohei Koide, PhD, a professor at NYU Grossman School of Medicine and a lead author on the study. “We wanted to create an antibody that could recognize a single difference in the 600 amino acids that make up the HER2 protein. To be honest, we were surprised by how well it worked.”

The Shape of a Killer

The story of HER2 is a tale of how small changes can have catastrophic consequences. HER2, short for human epidermal growth factor receptor 2, is a protein that sits on the surface of many cells. Normally, it’s part of the cell’s communication system, helping to regulate how cells grow and divide. However, when a single amino acid in the protein mutates, it locks HER2 in an “always-on” mode, sending signals that make the cell divide uncontrollably. This is how cancer begins.

In some cases, the problem isn’t a mutation but an overabundance of HER2, with cells making too many copies of the gene that codes for the protein. That, too, drives excessive cell growth. The resulting cancers—often breast, stomach, and ovarian—can be aggressive and difficult to treat.

There are drugs on the market that target HER2, like trastuzumab and pertuzumab, but these therapies aren’t perfect. They attack HER2 on the surface of cells indiscriminately, which means they can harm healthy cells as well as cancerous ones. The result? Side effects that can sometimes be as grueling as the cancer itself.

What Koide and his team set out to do was craft a drug that could tell the difference between mutant HER2—the kind that causes cancer—and the normal version of the protein. Their breakthrough came when they realized that, by using advanced protein-engineering techniques, they could train antibodies to ignore normal HER2 and zero in on the mutant version alone.

Engineering Antibodies, One Round at a Time

Antibodies are nature’s guided missiles. These large, Y-shaped proteins are built to recognize and latch onto specific targets, usually with impressive precision. But designing an antibody that can distinguish between two versions of HER2 that are almost identical? That’s like trying to tell the difference between two nearly identical keys—one of which can unlock destruction.

The researchers took a natural process and sped it up in the lab. They exposed antibodies to multiple rounds of mutation and selection, refining the process until they had versions that recognized only the mutant HER2 protein. Each round brought them closer to their goal: an antibody that could spot the rogue version of HER2 while ignoring its well-behaved sibling.

Once they had the antibody, they faced a new challenge: getting it to do more than just stick to the mutant HER2. They needed it to recruit the immune system to finish the job.

A Two-Pronged Attack

Even if their antibody could find the mutant HER2, cancer cells don’t always make a lot of it. That means an antibody, on its own, might not be enough to kill the cancer. Koide and his team needed to turn their antibody into something more powerful. They came up with a clever solution: a bispecific T cell engager. In essence, they fused their HER2-targeting antibody with another one that grabs onto T cells, the immune system’s natural assassins.

Here’s how it works: one end of the bispecific molecule latches onto a cancer cell by recognizing the mutant HER2. The other end sticks to a T cell, which then attacks the cancer cell and kills it. It’s like bringing a sharpshooter to the scene and handing them the exact coordinates of the enemy.

In lab tests, this approach worked. The bispecific T cell engager was able to kill cancer cells that had mutant HER2 while sparing those with the normal protein. When the researchers tested it on mice with tumors, the treatment shrank the tumors without causing the usual side effects like weight loss or sickness.

Hope, with Caution

As always, with promising new treatments, there’s a catch. “We saw very few side effects in mice,” Koide says, “but there are important differences between mouse and human proteins. It’s possible that the treatment had fewer side effects in mice because the antibody binds more weakly to mouse HER2 than to human HER2.” In other words, the success in mice might not fully translate to humans.

Still, the potential is clear. Koide and his team are continuing to refine their antibody, hoping to eventually bring this kind of treatment to human patients. They’re also exploring how the same engineering technique could be used to target other cancer-causing proteins beyond HER2.

“It’s the dream of precision medicine,” Koide says. “To go after what’s causing the cancer and leave the rest of the body alone.”

For now, it’s still early days. But in the world of cancer research, this kind of breakthrough, where a tiny mutation can be hunted down and neutralized without collateral damage, feels like nothing short of a miracle.

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