Genomics advances against cancer

Gene sequencing helps identify cell molecular processes that lead to the development of different types of tumour.

By Diego Freire, in Barcelona

Agência FAPESP – Understanding the genetic and molecular factors that determine carcinogenesis, the process whereby normal cells are transformed into cancer cells, may lead to the development of new, more accurate therapeutic practices that take into account the specific characteristics of each tumour and how each organism reacts to the disease.

The last day of FAPESP Week Barcelona, co-hosted by FAPESP and Research Centres of Catalonia (CERCA) on May 28-29, featured a session on research in genomics and molecular biology that is making this “personalised” approach to treatment possible and bolstering efforts to combat cancer.

According to Anamaria Aranha Camargo from the Molecular Oncology Centre at São Paulo’s Syrian-Lebanese Hospital (Brazil), genomics could enable treatment of cancer to be personalised through knowledge of the genetic changes in each tumour, which may indicate the most effective approach for the case in question.

“Every tumour is different, even among tumours of the same type,” Camargo said. “Until recently they were all treated the same way. Treatment succeeded in some cases and failed in others. Then a new approach was tried: this is essentially empirical, based on trial and error. Initially it might not be effective. It starts with the treatment dispensed to most patients, and switches to a different treatment if the response is unsatisfactory.”

Molecular analysis technologies now enable the most suitable approach for each case to be identified before therapy begins. Hence the reference to “personalised” cancer treatment.

“Today the most widely used technique for this purpose is second-generation sequencing, i.e. sequencing the transcriptome or genome of the individual patient’s entire tumour, which always has specific alterations,” Camargo explained. “Once you’ve obtained this information on the typical behaviour of the specific tumour, you can use far better targeted drug therapy, for example.”

Translational research

An important dimension is the development of methods to ensure this knowledge is applied for the benefit of patients, Camargo stressed, especially those who respond well to the treatment but suffer a return of the disease, sometimes years later.

“In these cases the tumour acquires mutations that make it resistant,” she said. “Just as bacteria become resistant to antibiotics, tumour cells can become resistant to the drugs used in oncology. Researchers are now looking at patients who suffer from this resistance to treatment in order to understand the molecular processes that lead to it.”

Metastasis

For more than ten years Camargo has studied the Adam23 gene. Researchers have found that this surface molecule is often silenced in tumour cells, making them much more metastatic (capable of forming more tumours by invading nearby tissues). Camargo aims to develop an approach to block the silencing of genes that suppress metastasis.

“It’s a matter of basic biology but in a few years, when the mechanism is better known, it could lead to the development of a drug to block it. Not just in breast cancer, which is one of the areas we’re focusing on, but also in melanomas and glioblastomas, which are central nervous system tumours,” she said.

Camargo and her team have also gained a better understanding of rectal cancer, one of the most common forms of cancer in Brazil. The group compared patients who responded well to treatment with cases in which chemotherapy had no effect, identifying 27 genes with different patterns of expression.

“The idea is to try to predict whether a patient who comes to hospital will respond adequately to chemotherapy or radiotherapy,” she said. “If an inadequate response is predicted, this approach could be skipped and the patient would then be referred for surgery, avoiding a great deal of unnecessary physical, emotional and financial hardship.”

Flies

For Camargo, interaction with researchers from Catalonia during FAPESP Week could lead to collaborations that accelerate research in Brazil. “They’re at the frontier of genomics here, developing methodologies that will be used in other parts of the world within a few years,” she said.

At Barcelona’s Biomedical Research Institute (IRB), for example, researchers from several areas are working with fruit fly models to understand the cellular alterations that lead to the development and metastasis of human colon cancer. One of the most common forms of cancer worldwide, colon cancer (or colorectal cancer) involves tumours in the colon or rectum, both of which are part of the large intestine.

According to IRB Director Joan Guinovart, researchers at the institute have successfully generated the disease in the fruit fly Drosophila melanogaster as an alternative to mouse models, which are more time-consuming and costly.

“This model has allowed us to identify subtle interactions in the development of cancer that are practically impossible to detect in mice with the technology currently available,” Guinovart said.

Thanks to the ease with which genetic studies can be performed in Drosophila, the researchers were able to examine the effects of 250 genes that are altered in colorectal tumours and found that 30% influenced tumour growth.

They now plan to use the model to study new therapeutic target molecules, as an intermediate step between in vitro assays and testing in vertebrates.