Protein eIF4A may be Potential Achilles’ Heel for Triple-Negative Breast Cancer

It has been difficult to improve treatments for triple-negative breast cancer (TNBC), an aggressive malignancy with a dismal prognosis and few therapeutic targets. Responding to the need for better treatments, Baylor College of Medicine researchers and collaborators studied potential vulnerabilities in TNBC that could lead to novel therapeutics and improved outcomes for this terrible disease. The researchers report in The Journal of Clinical Investigation that targeting protein eIF4A with the small molecule drug Zotatifin not only suppresses tumor cell proliferation by robustly inhibiting the production of several tumor-promoting proteins but also remodels the tumor immune microenvironment to favor tumor elimination in various TNBC animal models. The encouraging findings justify the conduct of clinical trials to evaluate the potential patient benefits of this method.

“Our strategy has been to control cancer growth by interfering with the production of proteins that promote its progression,” stated first author Dr. Na Zhao of Dr. Jeffrey Rosen’s group at Baylor. “The protein eIF4A is important for TNBC because it promotes the production of other proteins that aid in the growth of the tumor.” We wanted to see if blocking eIF4A with Zotatifin, a medicine that inhibits proteins that, like eIF4A, regulate protein synthesis, would lessen or remove eIF4A’s potential to promote cancer growth.”

The outcomes are encouraging. In animal models, Zotatifin not only reduced tumor size but also induced an interferon response, which enhanced the tumor’s immunological microenvironment.

“Zotatifin is currently being tested in an estrogen receptor-positive breast cancer Phase I/II clinical trial.” “We observed a similar interferon response after Zotatifin treatment in patient biopsies from this trial, in which TNBC patients were not enrolled,” Zhao added.

The researchers also looked at how Zotatifin worked in conjunction with chemotherapy and immunotherapy. “We observed increased DNA damage and cell death after three days of a combination treatment with Zotatifin and chemotherapy drug carboplatin,” Zhao told Reuters. “In addition, we found that the combination treatment also modified the composition of immune cells within the tumor mass, recruiting more tumor-fighting cells than tumor-protecting cells.”

“This is important for effective tumor elimination,” said Rosen, Distinguished Service Professor of molecular and cellular biology at Baylor and a member of the Dan L Duncan Comprehensive Cancer Center. He is also the work’s corresponding author. “TNBC tumors are typically ‘cold tumors,’ which means they have more immune cells that protect the tumor than cells that fight it.” As a result, most TNBC immunotherapies are rendered useless because they rely on immune cells attacking the tumor. Zotatifin converted cold tumors into “hot tumors,” which contained more cancer-fighting immune cells. This modification made the tumors more susceptible to a type of immunotherapy known as immune checkpoint blockade, which enhanced treatment.”

Combining Zotatifin with the chemotherapeutic medication carboplatin, which is normally used as standard treatment for TNBC, gave considerably better results than either treatment alone, significantly extending survival in animal models. “I have been working with these animal models for many years,” Zhao told me. “Seeing that a combination treatment significantly improves survival is very exciting.”

“Another positive outcome of the small molecule is that it allows for lowering the dose of chemotherapy,” he added. “At the moment, patients are given a maximum tolerated dose of chemotherapy, which has many toxicities and negative side effects.” When we combine chemo with the tiny inhibitor, we can cut the chemo dose to half the lowest effective dose while still achieving good survival benefits and reducing toxicity. Patients are quite pleased about the prospect of less chemo because it would reduce the terrible side effects that they have all encountered.”

It’s encouraging and exciting seeing that this approach to cancer treatment, targeting the process for synthesizing proteins the cancer needs to grow, is producing promising results,” Zhao went on to say. “We are hoping that our studies could help inform future clinical trials and positively impact the treatment of TNBC patients.”

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