Photo: Team members leading the preclinical study and the BEXMET clinical trial. (Left) Dr Loo Ser Yue, Senior Research Fellow, Genome Institute of Singapore, A*STAR; (Middle) Dr Elaine Lim, Senior Consultant, National Cancer Centre Singapore; (Right) Dr Tam Wai Leong, Group Leader, Genome Institute of Singapore, A*STAR​

Using Bexoratene, a clinical-grade oral retinoid, tumour cells of triple-negative breast cancer become more responsive to chemotherapy.

Triple-negative breast cancer (TNBC), an aggressive and treatment-resistant form of the disease may now finally be outsmarted, thanks to a team of clinicians and scientists from the National Cancer Centre Singapore (NCCS), Singapore General Hospital (SGH) and A*STAR’s Genome Institute of Singapore (GIS).

TNBC is much feared because of its poor prognosis compared to other more common breast cancer sub-types. It is called “triple-negative” because it tests negative for estrogen receptor (ER), progesterone receptor (PR) and human epithelial growth factor receptor-2 (HER2). Hence treatments that target the latter three sub-diseases are not effective here.

Also, with immunotherapy being very costly, the standard treatment is chemotherapy.

But positive news may be on the way soon for the TNBC-afflicted, which makes up about 10% of all breast cancer patients, many of whom are younger than 40.

Researchers have discovered that TNBC cancer cells can oscillate between less aggressive (epithelial) and more aggressive (mesenchymal) states. By reprogramming cells to become less aggressive with Bexarotene, an orally administered retinoid, tumour cells respond better to chemotherapy.

Now, a three-year human clinical trial, known as BEXMET (Bexarotene-induced Mesenchymal-Epithelial Transition) is underway to investigate its real-life translational benefits.

“Breast cancer research is of paramount importance precisely because of the size of the problem we have. The societal impact is huge.”
~ Dr Elaine Lim, BEXMET prinicipal investigator and Senior Consultant, Department of Breast and Gynaecology, Division of Medical Oncology, NCCS

A novel strategy for a complex disease

Rather than developing a new cancer drug, BEXMET is an innovative and cost-effective way to fight TNBC, especially for those with metastatic disease (late-stage cancer that has spread to other parts of the body).

“With Bexarotene, we are not looking to kill the cancer cells, but make them more receptive to therapy,” explained Dr Tam Wai Leong, Associate Director and Group Leader of the Laboratory of Translational Cancer Biology at GIS.

By first taming malignant cells using Bexarotene, the effects of chemotherapy are longer lasting, keeping cancer relapse at bay.

In bench research, the changing of cell states from mesenchymal to epithelial occurs within a few days with cells on a petri dish, and in animal models, a couple of weeks, he added.

The idea originated from the study of breast cancer tissue of NCCS and SGH patients that began in 2017 to understand how cancer cells invade and spread and leveraged highly advanced genome sequencing and functional genomic capabilities at GIS. The team’s findings were published in the journal Science Advances in October 2021.

Now the researchers are keenly watching the effects of the drug on patients—they hope to recruit between 12 and 20 participants for the study. If successful, the results may even be applied to other kinds of cancer that may be resistant to conventional therapies.

“This is one of the first target validation studies of its kind being demonstrated in humans as a proof of concept. The clinical trial will really add new information to what we know of the complexity of breast cancer,” said Dr Tam.

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“An alignment of the stars”

A crucial factor for the quick progression of the bench-to-bedside study is that Bexarotene is an existing drug that has been used overseas to treat cutaneous T-cell lymphoma.

“A lot of times, when we publish papers, the study ends there. With clinical-grade Bexarotene available, we don’t need to develop a new drug,” said Dr Elaine Lim, BEXMET’s principal investigator. She is also a Senior Consultant in the Department of Breast and Gynaecology, Division of Medical Oncology at NCCS.

Dr Lim is optimistic that the new strategy will make a difference in survival rates in patients with metastatic TNBC.

“We hope to eradicate or live harmoniously with cancer like a chronic disease. It’s the new paradigm,” she added.

More work needed for breast cancer

While breast cancer, owing to its prevalence, appears well-studied, clinicians and scientists like Dr Lim and Dr Tam have good reason to advance research in this area.

Based on Singapore Cancer Registry statistics from 2014 to 2018, the disease registered the highest number of new cases in women, and the trend is that the numbers are rising steeply, shared Dr Lim. At over 11,000 cases during this period, this would be more than the number of new cases of colorectal cancer in men and women combined, colorectal cancer having the highest number of new cases in men, and second highest in women.

According to a 2017 cancer registry report, one in 14 women here will develop the condition before the age of 75.

“Breast cancer research is of paramount importance precisely because of the size of the problem we have. The societal impact is huge,” added Dr Lim, who credited the strides made in this area to the strong collaborative relationship she’s had with scientists like Dr Tam.

“What Wai Leong does in the lab such as stem cell studies is more upstream so there is a lot of room for new ideas and concepts to be tested out. We are interested to see how upstream research can trickle down to the clinical setting,” she shared.

Dr Tam concurred, “Between research organisations like A*STAR and hospitals, there is room to grow collaborations with translational value. This leverages our different strengths and capabilities.”

Armed with complementary skills and wide-ranging perspectives, where clinicians and scientists find convergence is their desire to bring about a difference in patients’ lives. Said Dr Tam, “Cancer in general is going to affect one in three people in their lifetime. If we don’t stop it in its tracks, it will become a pandemic. Working on treatments will help us improve cancer curability.”

Nip breast cancer in the bud

Regular mammogram screening is the best defense against breast cancer. Women 50 years and above should get a screening once every two years. You can register for a screening at participating screening centres using this form.

Want to do more? Find out how you can support breast cancer research here.

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