en

How a scientific question led to cancer therapy

Interventions & Care
  • Claire Wyman

Many initiatives are born out of curiosity. For example, we know that DNA damage occurs a lot, but how does the repair mechanism work? Providing a fundamental answer to this question is leading to an effective therapy for many breast cancer patients.

It is also opening the way for the development of cancer-on-a-chip, making it possible to explore treatment options based on specific patient/tumour characteristics. And because students need the right competences to make all this happen, the original question has also led to the development of new degree programmes in Nanobiology.

Each human cell undergoes an estimated 100,000 DNA lesions per day. Atom groups easily fall off these giant molecules. How can it be that DNA, which is so vital to human cells, is also so unstable and vulnerable to damage in the watery cell environment? “Beautiful repair systems are in place to first recognise and then mend this damage,” says Roland Kanaar, Professor of Molecular Genetics at Erasmus MC Rotterdam. “These repair systems, some of which are based on the function of BRCA proteins and the PARP protein, work flawlessly most of the time. But unfortunately, they don't always work impeccably. Sometimes environmentally induced DNA damage escapes repair – and that is what can result in cancer.” In addition, says Kanaar, certain people are predisposed to developing cancer because of genetic defects that result in less effective DNA repair. “What’s more, DNA repair is also important for cancer therapies. Many therapies, such as radiotherapy, work because they induce an overload of DNA damage, resulting in cell death. Cellular DNA repair, however, can reduce the efficacy of the therapy.”

Functional test

An interesting follow-up question concerns how manipulation of the DNA repair process could influence cancer by strengthening the effect of therapy. “Currently one in eight women will develop breast cancer,” says Kanaar. “Approximately, 3% of these cases are associated with a tumour-specific defect in the BRCA proteins. This enables quicker mutation, which is vital for tumour cells. However, this defect creates therapeutic opportunities; inhibition of another DNA repair protein, PARP, results in DNA damage that requires BRCA proteins for repair. The tumour cells of such a patient, being defective in BRCA, therefore can’t tolerate PARP blockers, while the patient’s healthy cells can still employ BRCA proteins to repair the damage induced by the PARP blockers. During DNA repair, BRCA provides the transport system for the RAD51 protein that performs the actual repair of DNA damage. Without BRCA, RAD51 has no access to the damaged DNA, resulting in repair failure and cell death.”

For a small group of breast-cancer patients, about 3%, it should be possible to predict a favourable response to PARP blockers, based on family history or knowledge of germline BRCA mutation. “It turns out that in another 12% of patients, who don't have this mutation, it can work in the same way. RAD51 can’t reach the tumours damaged DNA when PARP blockers are administered,” says Kanaar. In the end, the PARP blocker-based therapy could work in approximately 15% of breast cancer cases. “The problem is, that the additional 12% of patients are a lot harder to find. There’s no hereditary component, so no prior knowledge. And as there’s no germline BRCA mutation, genetic screening won’t reveal these patients. And yet, they have the same tumour defect as the BRCA patients. However, a functional test on a biopsy could tell whether the treatment will work or not.”

What started off as a purely scientific question has now evolved into a treatment that’s approaching clinical application.

Although it will take time, a standard functional test could be carried out and a far larger patient group could benefit from the treatment with PARP blockers. “And preferably, a standard test would include more therapy options and would reveal much more information about the specific tumour, as well as the individual patient/tumour interaction,” says Kanaar.

Cancer-on-a-chip

This is necessary, because it is difficult to really beat cancer, due to its adaptability. “This is why we want to understand all possible pathways on a molecular level,” says Kanaar.  “A treatment for only one pathway is not enough. In many cases, for lasting success, you need to block several pathways at the same time. Our goal for the future would be that during surgery on a primary tumour or metastasis, tiny biopsies would be taken, and these would then be introduced to spots on a standard microfluidics chip, creating ‘cancer-on-a-chip’.”

This “molecular passport” of the cancer provides a diagnosis and prognosis for the patient. The PARP blocker therapy and other standard therapies will be tested on the chip to find out what works best for a particular patient. “The only problem is that knowledge of microfluidics and chips is not really the domain of medical biologists,” says Kanaar. “We need to connect technology to our biology.”

This is where the Delft team and industry come in, via Ronald Dekker and Lina Sarro, among others. “Delft physicists designed tools that enabled us to solve our questions with regard to mechanistic insight into RAD51’s function, for instance. Their optics and data opened the way for our study of single molecule behaviour. This collaboration has created a strong link between Medical Delta and the Human Disease Model Technology Institute (hDMT).”

Nanobiology

“We need a generation of scientists who understand the different methods and vocabulary of these fields, people with deep knowledge of mathematics who can describe and quantify biological processes using concepts and tools from physics. This is why TU Delft and Erasmus MC have set up a joint teaching programme, at both Bachelor’s and Master’s level, in Nanobiology,” says Kanaar.

The match between the disparate fields of engineers, biologists and doctors creates added value for society Prof. dr. Ronald Kanaar, Erasmus MC

The first Nanobiology graduates have already started to have an impact at both Delft and Rotterdam. “This bottom-up initiative by Medical Delta professor Claire Wyman, among others, has met with huge success,” says Kanaar. “In 2016, there were 130 enrollees, and next year we’ll be limiting admissions to ensure that the quality of the teaching programme remains high. The course make sure that the development towards cancer-on-a-chip will continue.”

Interview by: Leendert van der Ent