Singapore Researchers Launch Clinical Trial Testing Novel Cell State Conversion Approach for Triple-Negative Breast Cancer
核心洞察
Singapore researchers have launched the BEXMET clinical trial to test Bexarotene's ability to convert aggressive triple-negative breast cancer (搜索) cells into less aggressive states, making them more responsive to chemotherapy.
The novel approach uses the retinoid drug Bexarotene to induce mesenchymal-to-epithelial transition, potentially offering a cost-effective treatment strategy for this aggressive cancer subtype.
Preclinical studies showed that converting cancer cells from mesenchymal to epithelial states resulted in longer-lasting responses and reduced cancer relapse in animal models.
A team of Singapore researchers has initiated a groundbreaking clinical trial testing an unconventional approach to treating triple-negative breast cancer (搜索) (TNBC (搜索)) by converting aggressive cancer cells into less aggressive states before chemotherapy treatment. The BEXMET trial, launched in October 2021, represents the first clinical application of using retinoids to facilitate mesenchymal-to-epithelial transition in breast cancer (搜索) treatment.
Novel Cell State Conversion Strategy
The research team from National Cancer Centre Singapore (NCCS (搜索)), Singapore General Hospital (SGH (搜索)), and A*STAR (搜索)'s Genome Institute of Singapore (搜索) (GIS (搜索)) discovered that TNBC (搜索) cells can switch between different behavioral states. Cancer cells in the more aggressive "mesenchymal" state are highly invasive and resistant to treatment, while those in the "epithelial" state are less aggressive and more responsive to chemotherapy.
"Cancer cells are crafty and have ways to evade treatment, sometimes through taking on this drug-resistant 'mesenchymal' cell state," said Dr Tam Wai Leong, Associate Director and Group Leader of the Laboratory of Translational Cancer Biology at GIS (搜索). "Instead of tackling the tumours conventionally with direct administration of chemotherapy, the solution may be to first coax them into a less aggressive state before chemotherapy is given."
The team identified Bexarotene, a retinoid drug, as capable of converting the aggressive mesenchymal cell state to the milder epithelial state. This biological process, termed mesenchymal-to-epithelial transition (MET), primes cancer cells to better respond to chemotherapy and allows for more effective tumor elimination with lower chances of relapse.
Clinical Trial Design and Implementation
The BEXMET trial began recruiting patients in October 2021, with four patients enrolled as of the initial reports. The study aims to recruit 12 patients, potentially expanding to 20 participants. Eligible patients must have metastatic TNBC (搜索) and meet specific criteria assessed by physicians.
The treatment protocol involves a unique cycling approach. Patients receive Bexarotene during a two-week lead-in period before starting treatment cycles. Each cycle comprises two weeks of oral chemotherapy drug Capecitabine, followed by one week of Bexarotene. This cycle repeats as long as patients remain responsive to treatment.
To monitor the biological changes, researchers collect four tumor tissue biopsies throughout the trial: pre-treatment, after the two-week Bexarotene lead-in period, after two weeks of Capecitabine in the first cycle, and upon disease progression if it occurs.
Preclinical Evidence and Scientific Foundation
The research began in 2017 with studies of breast cancer (搜索) tissue from NCCS (搜索) and SGH (搜索) patients to understand pathways controlling cancer cell behavior. Using advanced genome sequencing and functional genomic capabilities at GIS (搜索), the team published their findings in Science Advances in October 2021.
In preclinical tests using animal models, Bexarotene successfully changed TNBC (搜索) cell states from mesenchymal to epithelial, making the cancer cells more susceptible to conventional chemotherapy. This resulted in longer-lasting responses that kept cancer relapse at bay.
Addressing Treatment Challenges in TNBC
TNBC (搜索) represents 10-15% of all breast cancers and is more aggressive than other subtypes. It tests negative for estrogen receptor (搜索), progesterone receptor (搜索), and human epithelial growth factor receptor-2 (搜索), hence the "triple-negative" designation. Without these receptor targets, TNBC is more difficult to cure, and chemotherapy remains the primary treatment option.
"The risk of recurrence for TNBC (搜索) is also higher compared with other breast cancer (搜索) types," said Dr Elaine Lim, Senior Consultant in the Department of Breast and Gynaecology at NCCS (搜索) and the clinical trial lead. The BEXMET trial uses this novel concept of changing cell states to increase susceptibility to available chemotherapy.
Cost-Effective Treatment Potential
The development of new oncology drugs is costly, making affordability and accessibility challenging. The Singapore team's approach of altering cancer cell states to enhance chemotherapy effectiveness may provide a cost-effective treatment strategy for TNBC (搜索) and potentially other cancers.
Currently, immunotherapy serves as a treatment option for TNBC (搜索) patients, employing the patient's immune system to fight cancer. However, it is expensive and typically requires multiple sessions. A cycle of the Bexarotene-Capecitabine treatment is expected to be much more affordable, given the lower costs of both drugs.
Outside Singapore, Bexarotene is already approved for treating cutaneous T-cell lymphoma (搜索), a rare cancer affecting T cells. This existing clinical-grade version of the drug significantly facilitated the direct translation from laboratory findings to clinical application.
Research Collaboration and Funding
The BEXMET trial is supported by the National Research Foundation under the Clinical Trials Grant–Investigator-Initiated Trials Scheme and administered by Singapore's National Medical Research Council. Preclinical work received funding from A*STAR (搜索), the NMRC, and the NCC Research Fund.
"The BEXMET clinical trial is a testament to the strong bench-to-bedside research pipeline that the National Cancer Centre Singapore has built, in collaboration with partners like A*STAR (搜索)'s Genome Institute of Singapore (搜索)," said Professor Teh Bin Tean, Deputy Medical Director of Research at NCCS (搜索).
The research is conducted under Breast Cancer (搜索) Research Singapore, a consortium of clinicians and scientists dedicated to breast cancer research, operating under the patronage of President Halimah Yacob. This collaborative effort represents a significant step toward introducing a novel concept in cancer treatment that could benefit patients with limited therapeutic options.