A Breakthrough for Breast Cancer

By Sarah Vogelsong

For cancer researchers, life can be one long cat-and-mouse game. 

We’ve all seen the familiar pattern unfold. The cat studies the behavior of the mouse: how it comes and goes, where it hides. Watching, waiting, the cat stalks and then pounces. For a moment, you think it’s got the prey captured between its paws, the tiny invader stilled. But then, there goes the mouse, skittering away, just out of reach — back to the other mice who are inevitably waiting in the wings for their turn to emerge. 

“That’s what cancers do; they have these escape mechanisms,” said Kandace McGuire, M.D., a surgical oncologist who is chief of breast surgery and leader of the breast cancer program at VCU Massey Comprehensive Cancer Center. “The nature of cancer is that what we find to destroy it ... it will try to find a way to get around that.” 

Medical advancements over the past few decades have meant that in many cases, humans can now get ahead of cancer cells, stopping them in their tracks through interventions like surgery and radiation. But not every situation follows such a smooth path. 

“For some people, that’s not the case,” Dr. McGuire said. “The cancer outpaces the medications. It changes before we can kill all the cells.” 

HER2

A particular challenge for patients and doctors has been a kind of breast cancer known as HER2-positive breast cancer. HER2 — a shorthand for human epidermal growth factor receptor 2 — is a protein receptor that, when present in higher-than-normal quantities, causes cancer cells to multiply quickly. Researchers estimate that in about 20% of all breast cancers, the gene that makes this protein goes into overdrive, producing too much HER2 and thereby spurring wild growth of cancer cells. 

For years, patients with HER2-positive breast cancers faced steep odds in fighting the disease. Then, in 1998, the U.S. Food and Drug Administration approved a drug known as Herceptin, or trastuzumab, that targets the protein receptor by inhibiting its ability to receive the chemical signals that tell breast cancer cells to keep growing. Clinical trials showed the drug significantly slowed the spread of the disease and reduced its recurrence; one book about its development labeled the treatment “revolutionary.”

Since then, other drugs targeting the HER2 receptor have appeared on the market, appreciably improving the prognosis for patients diagnosed with this form of breast cancer. Still, some cases manage to elude treatment. The mouse found new ways to slip from the cat’s grasp. 

“We still get patients who die of this cancer because the cells figure out a way around everything, or patients don’t tolerate some of the medications that we currently have available,” said Dr. McGuire. Furthermore, she continued, cancers that have managed to spread to the brain are virtually untreatable with current drugs because of what’s known as the blood-brain barrier, a membrane that stops nearly everything in the circulatory system from crossing over into the central nervous system. That barrier, she said, “is supposed to protect your brain, but in this case, it doesn’t let the good stuff in.”

A Potential Game-Changer

Now, however, Massey research recently published in Drug Resistance Updates shows a promising new drug could prove groundbreaking for HER2-positive breast cancer patients who have been resistant to other treatments. 

The drug, a human protein generated in the lab as a recombinant protein known as PEPDG278D, goes a step further than existing treatments by not just inhibiting the HER2 protein from acting but by eradicating it. At the same time, it wipes out another protein that drives cancer cell growth known as the epidermal growth factor receptor, or EGFR. 

Current drugs on the market “don’t really eliminate the protein itself that well. In fact, sometimes the protein responds to the inhibition by increased expression,” said Yuesheng Zhang, M.D., Ph.D. “But this agent, we found, is very powerful in eliminating the existence of the protein. So this is very novel. We haven’t seen any drug that is doing that.” 

Dr. Zhang holds the Harrigan, Haw and Luck Families Chair in Cancer Research and is a professor in the VCU School of Medicine Department of Pharmacology and Toxicology. He is also an author of the study and has been working to develop PEPDG278D for nearly a decade, including at his prior institution, the Roswell Park Comprehensive Cancer Center in Buffalo, N.Y. 

The latest research shows that when combined with the anticoagulant enoxaparin, the drug reduced tumor growth by 98% in mice after just two weeks of treatment. When combined with a monoclonal antibody called garadacimab, the drug led to “complete remission of all tumors after less than three weeks of treatment.” While both enoxaparin and garadacimab were used to stabilize the PEPDG278D protein in the mice used for testing, Dr.  Zhang said garadacimab may prove the most promising combination for human use because it only needs to be given to patients once every three weeks, while enoxaparin has to be given daily. 

All of the tumors studied had been removed from patients and transplanted to animal models — an approach Dr. Zhang said is “well known to better predict treatment response in patients.” And in all of the situations tested, trastuzumab, the drug approved in 1998, was ineffective, demonstrating that the new drug may be capable of overcoming even treatment-resistant cancers.

“In both cases, the combination is very powerful. It just eliminated the tumor completely,” said Dr. Zhang. And because the drug specifically targets cells with higher-than-normal levels of HER2 and EGFR, leaving normal cells unaffected, he said researchers “think the toxicity is going to be very, very little.” 

Additionally, recent research found the drug reduced metastatic brain tumor growth by 64% in animal models — a finding that indicates it can cross the blood-brain barrier. 

“This is a game-changer,” Dr. McGuire said. “Is it going to cure every patient with brain metastasis? No, because there’s always going to be those cells that aren’t going to respond to this drug. But it makes it possible where currently it’s impossible.” 

National Cancer Institute Testing

For now, drug testing remains in what’s known as the preclinical stage — the phase before it’s tested on humans. 

But clinical trials involving humans are expensive, Dr. Zhang noted. He estimated it would take more than $3 million to manufacture several grams of the new drug for testing, and those grams would have to be manufactured at a facility certified by the FDA. 

Every year and every day, we get better and better. … The pace at which we are improving is insane. It’s almost like computer technology how fast we learn new things.

Kandace McGuire, M.D., chief of breast surgery and leader of the breast cancer program at VCU Massey Comprehensive Cancer Center

Consequently, even before Dr. Zhang arrived at Massey from his Roswell Park laboratory, he had submitted an application to the National Cancer Institute for support in developing the drug for FDA approval. He was successful: The institute accepted the drug into the pipeline of its NCI Experimental Therapeutics Program, which supports the development of the most promising new cancer treatment discoveries. 

Reaching that stage is a milestone itself, said Dr. McGuire: “Maybe about 1% of all basic science research will actually make it to a clinical trial.” 

Drug development remains a grueling process. Dr. Zhang said the NCI is still validating the findings. Once it does, it will work to manufacture the drug, and an additional study known as an investigational new drug-enabling study will be conducted. Finally, the data will be presented to the FDA, which will have to approve clinical evaluation of the drug at Massey.

“Once the FDA is OK with it, then we can quickly move it to patients,” Dr. Zhang said. “We don’t have a shortage of patients. There are patients waiting for this sort of thing.” 

Even before then, the most recent findings can inform medical teams about how best to approach treatment-resistant cases of HER2-positive breast cancer, said Dr. Zhang. Particularly significant is the discovery that to overcome cancers that have been resistant to treatment, drugs should target not only the HER2 protein but also the EGFR protein — and should seek to eliminate both. 

“It actually guides the field in terms of what you should do in developing the next generation of HER2 treatments,” Dr. Zhang said. 

For Dr. McGuire, who can recall a childhood friend losing her mother to HER2-positive breast cancer, the recent findings offer a welcome dose of optimism in the ongoing fight against the disease. 

“We’re going to figure out a way someday to kill these cells so quickly and hit them with the right combination that we will eliminate them before they can change,” she said. “Every year and every day, we get better and better. … The pace at which we are improving is insane. It’s almost like computer technology how fast we learn new things.” 

One contributor to those advancements? Team science, said Dr. McGuire. This runs counter to the typical Hollywood portrayal of medical breakthroughs that sees a scientist having a “Eureka!” moment while bent over a microscope late at night, alone in a lab. Most discoveries today are the product of scientific collaboration and knowledge sharing. A university’s embrace of team science is one of the factors the NCI considers in granting the coveted comprehensive cancer center status — a recognition Massey achieved in 2023. 

“Research like this is happening in our backyard. The next big thing may not come from an MD Anderson or a Memorial Sloan Kettering,” Dr. McGuire said, referring to the two traditional heavyweights of cancer research in the U.S. “It may come from VCU.”

If you are interested in supporting research at VCU Massey Comprehensive Cancer Center, please contact Caitlin Doelp, Massey’s executive director of development, at 804-828-1450 or doelpc@vcu.edu.