Team discovers new strategy to tame aggressive breast cancer and begins clinical trial

Research results suggest that neoadjuvant therapy with retinoids may promote the conversion of highly aggressive mesenchymal cancer cells to less aggressive epithelial cancer cells in breast cancer. This can make breast tumors more responsive to subsequent chemotherapy and produce a lasting therapeutic result. A clinical trial is underway to examine this new concept of treatment. Credit: Singapore National Cancer Center

A team of clinicians and scientists from the National Cancer Center Singapore (NCCS), Singapore General Hospital (SGH) and the Genome Institute of Singapore (GIS) A * STAR have identified a new method to treat cancer of the triple negative breast (TNBC). They found that cancer cells switch between different cellular states and are able to switch from less aggressive (“epithelial”) to more aggressive (“mesenchymal”), and vice versa. By converting very aggressive cancer cells to become less aggressive, doctors can prime tumors to respond better to chemotherapy, which works to kill cancer cells. This discovery led to the launch of a three-year human clinical trial, BEXMET (Bexarotene-Induit Mesenchymal-Epithelial Transition), to study this unconventional approach to the treatment of TNBC.

TNBC is more aggressive than other breast cancer subtypes, with limited treatment options and a poor prognosis. TNBC tests negative for estrogen receptor (ER), progesterone receptor (PR) and human epithelial growth factor-2 (HER2) receptor, hence the reference to “triple negative” in its name. It also means that treatments targeting ER, PR and HER2 are not effective. For this reason, chemotherapy remains the basic standard treatment for TNBC.

The development of new oncology drugs is expensive, and affordability and accessibility can be a challenge. The concept tested by the NCCS, SGH and GIS team consists of modifying the state of cancer cells so that they are more sensitive to the chemotherapy currently available. This may be a cost-effective way to treat TNBC, with the potential to treat a wider range of other cancers.

The team began by studying breast cancer tissue from NCCS and SGH patients in 2017 to understand the pathways that control the behavior of cancer cells, in terms of their ability to invade and spread. Taking advantage of the highly advanced genome sequencing and functional genomic capabilities of GIS, research has revealed that bexarotene, which belongs to a class of drugs called retinoids, is able to convert the more aggressive “mesenchymal” cellular state to a more aggressive state. less aggressive “epithelial” cell. This biological process is also called the mesenchymal-to-epithelial transition (MET). This is the first time that bexarotene has been used to aid the MET process in preclinical breast cancer work.

Singapore team discovers new strategy to tame aggressive breast cancer, begins clinical trial

Scientific model illustrating the different uses of fatty acids in specific cancerous cell conditions. In the more aggressive mesenchymal cell state, beta-oxidation is activated to burn fatty acids; this generates acetyl-CoA – a bioactive metabolite – for the epigenetic control of genes responsible for epithelial-mesenchymal transition and cancer metastasis. During the mesenchymal to epithelial transition, which is induced by retinoid therapy, fatty acids are stored as lipids instead. By preventing cancer cells from oxidizing fatty acids, less aggressive epithelial cancer cells are unable to behave aggressively and are less likely to metastasize. Credit: Singapore National Cancer Center

These results were published in the journal Scientists progress on October 7, 2021. The study was led by co-lead author Dr Tam Wai Leong, associate director and group leader of the Translational Cancer Biology Laboratory at GIS.

“Cancer cells are crafty and have ways of evading treatment, sometimes by taking on this drug-resistant ‘mesenchymal’ cellular state. Instead of attacking tumors in the conventional way with direct administration of chemotherapy, the solution can be to get them to adopt state before the administration of chemotherapy. This is a departure from the standard cancer treatment, “said Dr. Tam.” Taming the behavior of these malignant cells before they are removed may function better and lead to longer lasting clinical responses. ”

In preclinical tests performed in animal models, bexarotene altered the state of TNBC cells from mesenchymal to epithelial, making TNBC cells more sensitive to conventional chemotherapy, resulting in longer lasting responses that prevented relapse of the drug. Cancer.

Singapore team discovers new strategy to tame aggressive breast cancer, launches clinical trial

Members of the team leading the preclinical study and the BEXMET clinical trial. (Left) Dr Loo Ser Yue, Principal Investigator, Genome Institute of Singapore, A * STAR; (middle) Dr Elaine Lim, Senior Consultant, National Cancer Center Singapore; (Right) Dr Tam Wai Leong, Group Leader, Genome Institute of Singapore, A * STAR. Credit: Singapore National Cancer Center

These laboratory results were directly transposed in human environment with the BEXMET clinical trial. The aim of the trial is to validate the changes in state of TNBC cells induced by bexarotene that have been observed preclinically, and to assess the tolerability and efficacy of the bexarotene-capecitabine chemotherapy combination.

“Laboratory results published in a scientific journal do not always translate into clinical settings for various reasons. For our study, there is a clinical grade version of the MET inducer (Bexarotene), which significantly facilitated direct translation into the clinical setting. We hope that the results of BEXMET will be the first step towards the introduction of a new concept in the treatment of cancer, ”said co-lead author and principal investigator of BEXMET, Dr Elaine Lim, senior consultant, Department of Breast and Gynecology, Division of Medical Oncology, NCCS.

Researchers identify drug resistance mechanisms for triple negative breast cancer

More information:
Ser Yue Loo et al, Fatty Acid Oxidation is a Drug Gateway Regulating Cell Plasticity to Metastasize in Breast Cancer, Scientists progress (2021). DOI: 10.1126 / sciadv.abh2443

Provided by the Singapore National Cancer Center

Quote: Team discovers new strategy to tame aggressive breast cancer and begins clinical trial (2021, October 6) retrieved October 6, 2021 from strategy-aggressive-breast-cancer.html

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