Dr Kue Chin Siang from the Management and Science University was awarded a research grant worth RM29,480 from the National Cancer Council Malaysia (MAKNA) for his proposed work to specifically tag aggressive breast cancer cells and signal them for destruction by the host's immune system afterwards.

Breast Cancer in Malaysia

Breast cancer has a high disease burden in Malaysia. A local study reported that, in 2011, a Malaysian woman has a 1-in-20 chance of developing a breast cancer in her lifetime. (1)

Several studies indicated that 5-year overall survival for breast cancer patient was 49%.(2) Additionally, the breast cancer mortality rate in Malaysia hovers at a level higher than other neighbouring countries, accounting for an estimated one-quarter of cancer-related deaths.(3)

There are multiple treatment models for breast cancers. Chemotherapy has been the mainstay treatment in addition to surgery. Studies have shown that chemotherapy is effective to improve survival in women, but concerns regarding chemotherapy’s efficacy and side effect profiles remain.

“[Chemotherapies] are non-selective in killing the cancer cells, they silence the immune response, they have a low depository of the drugs in the tumour environment, and the cancer cells will tend to develop a resistance against these drugs. All of these can lead to a poor therapeutic outcome,” said Dr Kue in his presentation during the MAKNA award ceremony.

Tagging the cancer cells

To overcome the limitations of chemotherapy, researchers have been exploring the use of unique surface molecules to identify cancer cells. In recent years, there was an increasing interest in the tropomyosin-related kinase (TRK) oncogene family as studies demonstrated that these could be effectively inhibited.(4)

It was found that, in metastasized breast cancer cells, tropomyosin receptor kinase C (Trk C) receptors were overexpressed. However, such overexpression was not detected in other breast cancer cells. Dr Kue and colleague wrote in Molecular Pharmaceutics that TrkC plays an essential role in breast cancer growth. The metastasis and suppression of TrkC expression in highly metastatic mammary carcinoma cells inhibit their growth in vitro as well as their ability to metastasize from the mammary gland to the lung in vivo.(5)

The expression of TrkC is highly associated with the invasiveness of the cancer. The higher level of TrkC, the tumour grows even faster and more aggressively.

He postulated that, by targeting this specific overexpressed TrkC, researchers could effectively deliver cancer drugs to the intended target. Dr Kue and his team had designed a TrkC-targeted ligand, which he described as a “navigator” that searches exclusively for TrkC. The “navigator” will in turn carry a specific cargo that will ultimately cause the killing and clearance of these cancer cells.

The cargo that can be used for such purpose, he explained, is dinitrophenol. It is a small molecule that can stimulate the host body immune system. When combined with the navigator, Dr Kue anticipated that the resultant complex – named TrkC targeted DNP conjugate – can promote clearance of aggressive breast cancer cells via actions of the phagocytes.

“The phagocyte will come and bind to the antibody and they will ‘eat’ the cancer cells so to promote the clearance of the cancer cells,” he said.

Preclinical Study

With the MAKNA research grant, Dr Kue proposed to conduct the experiments on mice that are inoculated with cancer cells. It is hoped that the novel treatment will exhibit satisfactory efficacy in clearing the cancer cells in the mouse model while maintaining a low enough toxicity level before such treatment is to be tested in human. MIMS

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Sources
1. Dahlui M., Ramli S., Bulgiba A.M. (2011). Breast cancer prevention and control programs in Malaysia. Asian Pac J Cancer Prev.;12:1631–4.
2. Yip C.H., Bhoo P.N., Teo S.H. (2014). A review of breast cancer research in malaysia. Med J Malaysia;69 Suppl A:8–22.
3. Youlden D.R., Cramb S.M., Yip C.H., Baade P.D. (2014). Incidence and mortality of female breast cancer in the Asia-Pacific region. Cancer Biol Med.;11(2):101–15.
4. Doebele R.C., et al. (2015). An oncogenic NTRK fusion in a patient with soft-tissue sarcoma with response to the tropomyosin-related kinase inhibitor LOXO-101. Cancer Discov.;5(10):1049–57.
5. Kue C.S., et al. (2015). Targeted PDT agent eradicates TrkC expressing tumors via photodynamic therapy (PDT). Mol Pharm.;12(1):212–22.