ne day doctors may be able to individualise cancer treatment according to a patient's unique genetic profile to achieve the best results with the least toxicity, instead of giving a standard drug in a standard dose to all patients.

At present, doctors cannot always predict how a patient will react to a cancer drug. Dr Goh Boon Cher, a consultant at The Cancer Institute, and Department of Haematology-Oncology, National University Hospital (NUH), says there is evidence that genes existing in different forms may affect the behaviour of drugs in the body. "This may explain why patients who are given the same drug with a similar dosage can have different reactions, with some showing side effects and others not showing any."

Pharmacogenetics, or the study of the genes responsible for the different responses to drugs, may be able to change this.

Goh has iniatiated an innovative translational research project in this field, together with co-investigators Dr Alex Chang, Oncology Programme Director at Johns Hopkins-NUH International Medical Centre (JH-NUH), Professor Lee How Sun from the National University of Singapore (NUS) and the Genome Institute of Singapore (GIS).

The study may uncover the differences between cancers in the East and the West. Cancer is the leading cause of death in Singapore and the rate is increasing every year. According to Chang, the rate of women diagnosed with breast cancer who did not undergo screening has increased by 4% every year in the last two decades in Singapore, compared to 2% in the United States where women were screened. "For breast cancer, our patients tend to be younger than patients in the United States. I suspect that the fundamental biology of breast cancer may be different between the East and the West," Chang says. By focusing on pharmacogenetics, the researchers will be able to look at the uniqueness of the disease in Singapore and the region so as to find a way to better treat cancer patients in the Asian population.

With the help of a high-throughput microarray system, Goh and his colleagues at the Genome Institute of Singapore NUH hope to build up the genetic profile of each cancer patient and use this information to decide which will be the best drug and dosage. The project is a collaborative effort with Johns Hopkins Singapore and the Genome Institute of Singapore.

Goh notes, "This approach would make drugs safer for clinical use and we can depend on existing drugs to achieve a very good response. The therapeutic implications are tremendous."

Patients will be less financially burdened since hospitalisation charges arising from side effects will be decreased. In addition, time and costs for drug development of new anti-cancer agents will be reduced by better patient selection.

Goh's laboratory won a five-year grant to conduct clinical trials. Initial investigations are on some of the more common cancers in Singapore, such as breast cancer, nasopharyngeal cancer, and colorectal cancer.

The researchers plan to collect tumour and gene samples from patients treated with chemotherapy, study the tumour tissue by microarray, and sequence relevant genes to find out why certain patients have toxic response, or no response.

Treatment Customised for Cancer Subgroups

Two patients with the same cancer may receive different diagnoses and treatments because they fall under different subgroups of the cancer.

Thanks to DNA microarrays, or what are often referred to as "genechips," researchers can now capture the "molecular portrait" of a particular cancer, from the levels of tens of thousands of genes simultaneously, so that subgroups of the cancer can be distinguished. In contrast, the traditional methods of characterising cancers using light microscopes rely more on visible gross changes.

The comparison is akin to looking at a target close-up, and from a distance, notes Dr Patrick Tan from the Division of Cellular and Molecular Research at the National Cancer Centre (NCC). "The molecular portraits give us such a close look at the target that what appears similar at a distance turns out to be different."

Using this modern molecular technology, Tan, together with pathologists at the Singapore General Hospital, has already identified groups of genes in breast cancer that are different from one another.

Based on these "subsets" of genes, they have developed genetic markers that can be used to facilitate the diagnosis and treatment of cancers (Figure 1).

From a profile of some 200 breast cancer samples, Tan, who is also a senior scientist with the Defence Medical Research Institute, discloses that his team has distinguished groups of genes, and designed two genetic identifiers. One marks out a cancerous breast from a healthy one, while the other distinguishes between a positive breast oestrogen receptor and a negative one. Both will have an impact on the type of treatment which will be carried out on a patient.

Tan and his team mates will continue to come up with more genetic identifiers as there are important clinical parameters that would affect the treatment. For instance, a useful genetic identifier would be one that differentiates between a metastasising (rapidly spreading) cancer and a local one.

"If it is a metastasising cancer, doctors may need to consider more radical treatments such as radiation and chemotherapy," he explains. Yet another genetic identifier can help doctors better predict or diagnose if a particular tumour is responsive to chemotherapy.

Tan and his NCC colleagues, Professor Kon Oi Lin and Dr Dennis Lim, have also profiled about 65 stomach cancer samples and found that the disease comprises at least two subgroups. They hypothesise that the subgroups arise from different progenital cells in the stomach. With this molecular knowledge, they hope to derive diagnostic and therapeutic tools.

A sensitive test which can diagnose stomach cancer at an early stage is especially critical. Too often, the cancer is detected too late, when it has grown and spread to other parts of the body.

In Japan, where stomach cancer represents the second-most-common cancer, doctors have resorted to screening men at risk by inserting an endoscope into their stomachs.

Tan intends to devise a less laborious test using DNA microarrays and molecular portraits where only "a few cells washed up from the stomach" are required from a patient.

Treatment for Mutated Tumour Suppressor Gene

Another approach is to customise treatment according to the patient's particular mutation of the tumour suppressor gene, p53, and his or her cancer type.

Associate Professor Kanaga Sabapathy, principal investigator at NCC's Laboratory of Molecular Carcinogenesis, is studying the signalling pathway that activates p53, in breast and lung cancer patients. P53 is the most important tumour suppressor gene and is mutated in more than half of all cancer cases. Hence, it is closely associated with the development of cancer.

The p53 mutation generally occurs in one of six "hotspots" in a cancer patient. However, it is still not known if a particular hotspot mutation predisposes a person to a certain type of cancer.

Sabapathy hopes to find out which drugs work best for a particular hotspot mutation with the help of "cell systems" or tumour cells taken from a patient and cultured in the laboratory. He plans to construct six cell systems, each featuring a different hotspot.

In addition, since p53 has been found to be an important tumour suppressor gene in mice, he will make p53 knock-in mouse models, each featuring a different hotspot mutation. Sabapathy says, "We can also test the various cancerous tissues from the mice to find which drugs work best on them."

This is important because the p53 mutation works in a tissue-specific manner. Hence, the properties of the mutation seen in lung cancer, for instance, are not the same as those seen in liver cancer, even if they may occur in the same hotspot.

For more information contact:
Dr Goh Boon Cher: gohbc@nuh.com.sg
Dr Patrick Tan: cmrtan@nccs.com.sg
Assoc Prof Kanaga Sabapathy: cmrksb@nccs.com.sg