Study offers novel therapeutic opportunities to prevent breast tumor recurrence

A team of German, Norwegian, and British researchers examined tumor cells that were resistant to the original treatment and identified molecular targets for therapies that could evade breast cancer recurrence. Current advancements in early detection and targeted therapy led to an emerging success in treating breast cancer on the first presentation.

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This is accomplished by silencing tumor-inducing oncogenes and causing tumor regression. The survival of small numbers of tumor cells after initial therapy is a great challenge as these cells result in recurrence of incurable cancer in 20% to 40% of patients after a few years or even decades.

The observations are relevant for breast cancer treatment outcomes as they aid in handling tumor recurrence. The research was published on October 25^th, 2021 in the Molecular Systems Biology journal.

Genes whose increased expression is linked to various cancers are called oncogenes. This elevated expression might be due to mutations or changes in control over their expression. Altered DNA methylation—attachment of methyl groups to DNA molecules inducing changes in gene expression—is a major process involved in increased oncogene expression during tumorigenesis.

The researchers examined methylation changes in the small number of cells that survived the initial treatment responsible for Minimal Residual Disease (MRD). MRD proliferates after a considerable dormancy phase and induces incurable relapse of cancer. The researchers used sophisticated data-intensive methods in a mouse model of breast cancer and incorporated various levels of cellular behavior.

They compared the metabolism and methylation of MRD cells with similar mechanisms in original tumor cells and normal healthy cells.

The major observation was that the resistant cells showed similar metabolic behavior and methylation patterns to cells of the original tumor, but not to normal cells. They did not exhibit other characteristics of the original tumor cells—like high proliferation propensity and the presence of oncogenic signaling.

The scientists deduced that MRD cells hold on to a certain kind of “metabolic and epigenetic memory” of the tumor state. The observation was confirmed through transcriptomic data acquired from patients who received neoadjuvant therapy—a kind of chemotherapy that contracts the tumor before surgical excision.

The scientists illustrated that memorized elevated glycolysis in MRD cells is vital for their survival, producing the energy in the form of adenosine triphosphate (ATP) from glucose necessary to sustain cellular metabolism. This memory mechanism is an evident therapeutic target and the scientists discovered a small molecule that inhibits that pathway in MRD without affecting normal healthy cells.

The chances of the small molecule directly leading towards future therapies are slim. A vital aspect of this research is that it provided a detailed molecular view of MRD by comparisons of the normal, tumor, and treatment-resistant state of the cells.

Employing organoids—3D cell cultures—enabled the scientists to analyze the rare residual cells that are hard to obtain in a clinical setting. The research thus offers a specific target to tackle breast cancer relapse along with an organoid approach that in the future could be extended to patient-derived cells for precision medicine.