Cancer breakthroughs
The Cancer Science Institute of Singapore (CSI Singapore) at NUS have made recent discoveries that may lead to new approaches for countering breast and ovarian cancers.
Principal Investigator Assistant Professor Sudhakar Jha and colleagues found that controlling the levels of a tumour suppressor called TIP60 could potentially prevent the spread of breast cancer cells. The group ascertained that the TIP60 protein interacts with two other proteins called DNMT1 and SNAIL2 to inhibit the spread of cancer cells. This work is the first to report the novel function of TIP60 in regulating DMNT1 and SNAIL2 to stop metastasis.
Zhang Yanzhou, a PhD student from CSI Singapore’s Graduate Programme in Cancer Biology and first author of the study, explained that the absence of TIP60 raises the levels of DNMT1, resulting in the activation of SNAIL-2 function. “When this molecular programme is turned on, epithelial cells — which protect or enclose organs — acquire migratory and invasive properties. This leads to the spreading of cancer cells. Understanding this mechanism holds the important key to suppressing the migration of cancer cells,” he said.
The knowledge is crucial for breast cancer patients with poor overall survival and disease-free survival prognoses. Previous research has observed low TIP60 levels in such patients, which reduce their defence against cancer cell metastasis.
This breakthrough published in Journal of Molecular Cell Biology also has important implications for colon and cervical cancers which show irregular TIP60 levels.
“This study provides important evidence that TIP60 levels could possibly serve as prognostic marker of breast cancer progression, and the stabilisation of TIP60 could be a promising strategy to treat cancers. We are currently developing inhibitors which can increase TIP60 levels and in turn, prevent the spread of cancer,” said Asst Prof Jha, who is also with NUS Biochemistry. He revealed that the team plans to work with clinician scientists from the National University Health System to initiate clinical trials using DNMT1 inhibitors to treat breast cancer patients.
Asst Prof Jha (left) and Yanzhou found that controlling the levels of a tumour suppressor could potentially prevent the spread of breast cancer cells
Another CSI Singapore team headed by Dr Ruby Huang pinpointed a molecule called AXL which triggers the spread of an aggressive form of ovarian cancer called the Mes subtype. This is one of two aggressive subtypes of ovarian cancer — the other being Stem-A — identified by Dr Huang’s group in an earlier study.
The two subtypes have a higher tendency to undergo Epithelial-Mesenchymal Transition, a process by which epithelial cells transform into mesenchymal cells, and is associated with aggressive metastatic cancer. The team observed that AXL, when activated, was able to interact with other proteins in the cell to form a cellular pathway that contributes to the rapid spread of ovarian cancer cells.
No specific treatment exists presently for the Mes ovarian cancer subtype. The findings, published in the October issue of Science Signaling, suggest that blocking AXL could be an effective treatment option for these patients.
The scientists are collaborating with several pharmaceutical companies to develop anti-AXL drugs for ovarian cancer treatment. Dr David Tan, who holds joint appointments at CSI Singapore and the National University Cancer Institute, will be leading the clinical development of the anti-AXL treatment.
This study was conducted in collaboration with clinicians from the National University Hospital and scientists from Imperial College London. First author Dr Jane Antony recently graduated from the joint PhD programme between NUS Graduate School for Integrative Sciences and Engineering and Imperial College London
