Targeting eIF4A with Zotatifin: A Promising Strategy for TNBC Treatment

Enhancing treatment options for triple-negative breast cancer (TNBC), a highly aggressive tumor with a grim prognosis and limited therapeutic possibilities has proven to be a formidable challenge.

In response to the pressing demand for improved therapies, a team of researchers from Baylor College of Medicine and collaborating institutions embarked on an exploration of potential weaknesses within TNBC.

Their aim was to uncover fresh avenues for therapies that could ultimately yield better outcomes for those grappling with this devastating condition.

In a recent publication in The Journal of Clinical Investigation, the research team reveals their discoveries. Through experiments conducted on a variety of TNBC animal models, they found that targeting the protein eIF4A with the small molecule drug Zotatifin had a dual effect.

Not only did it robustly impede the production of several proteins that promote tumor growth, thus effectively restraining tumor cell proliferation, but it also brought about a transformation in the tumor’s immune microenvironment. This transformation favored the elimination of the tumor.

These promising findings offer compelling support for advancing to clinical trials to evaluate the potential benefits of this approach for patients.

Our strategy has been to control cancer growth by interfering with the production of proteins that promote its progression.”

Dr Na Zhao, Study First Author and Instructor, Molecular and Cellular Biology, Baylor College of Medicine

Zhao added, “The protein eIF4A is important for TNBC because it promotes the production of other proteins that help it grow. In this study we investigated whether inhibiting eIF4A with Zotatifin, a drug that inhibits proteins that, like elF4A, regulate protein synthesis, would reduce or eliminate the ability of eIF4A to promote cancer growth.”

The results are encouraging. Treatment with Zotatifin not only reduced tumor size in animal models but also stimulated an interferon response, which improved the immune microenvironment of the tumor.

Zotatifin is currently undergoing a Phase I/II clinical trial in estrogen receptor-positive breast cancers. We observed the induction of a similar interferon response following Zotatifin treatment in patient biopsies from this trial in which, unfortunately, TNBC patients are not enrolled.”

Dr Na Zhao, Study First Author and Instructor, Molecular and Cellular Biology, Baylor College of Medicine

The group also tested the effect of Zotatifin in combination 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. 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.”

Dr Na Zhao, Study First Author and Instructor, Molecular and Cellular Biology, Baylor College of Medicine

“This is important for effective tumor elimination,” stated Rosen, Distinguished Service Professor of Molecular and Cellular Biology and Member of the Dan L Duncan Comprehensive Cancer Center at Baylor. He also is the corresponding author of the work.

Rosen notes, “TNBC tumors are typically ‘cold tumors,’ meaning they have more immune cells that protect the tumor than cells that fight the tumor. This in turn makes immunotherapies ineffective in most TNBC as these therapies depend on having immune cells that would attack the tumor. Zotatifin changed cold tumors into ‘hot tumors’ carrying more cancer-fighting immune cells. This change sensitized the tumors to a type of immunotherapy called immune checkpoint blockade and improved the treatment.”

The combination of Zotatifin with the chemotherapy drug carboplatin, a standard therapy for TNBC, yielded markedly superior outcomes compared to each treatment in isolation. This combined approach substantially extended the survival of the animal models.

Zhao stated, “I have been working with these animal models for many years. Seeing that a combination treatment significantly improves survival is very exciting.”

Rosen stated, “Another positive outcome of the small molecule is that it allows for lowering the dose of chemotherapy. Currently, patients are treated with a maximum tolerated dose of chemo, which carries many toxicities and negative side effects.”

Rosen added, “But when we combine chemo with the small inhibitor, we can lower chemo to half the dose, which is the minimum effective dose, and achieve good survival benefits and reduce the toxicity. Patients are very excited about the aspect of reducing chemo because it would decrease the negative side effects they have all experienced.”

Zhao stated, “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. We are hoping that our studies could help inform future clinical trials and positively impact the treatment of TNBC patients.”