DNA Repair and Cancer
Cancer: cause and cure
"Around one in three people in the EU will be diagnosed with cancer during their lifetime," says CRUK, most commonly with bowel cancer. Breast cancer follows closely and lung cancer causes a fifth of total deaths in the EU. Yet, despite what we know about the evils of tobacco, almost a third of the EU population smoke. Perhaps they already know that only one in ten smokers will develop lung cancer. So if smoking isn't the major cause, then what is?
"This is difficult, because the damage comes mainly from inside of us," explains Jiri Bartek (Institute of Cancer Biology, Denmark). Every day there are tens of thousands of DNA injuries inside every normal body cell. Most of these result from chemicals produced during metabolism. Luckily, most of us come fitted with an insurance policy against such damage in the form of our DNA repair machinery. Jiri affirms that "we need to understand the pathways underlying the DNA damage response" in order to understand cancer.
His team of researchers is investigating how DNA lesions are detected and how cells then get sent to the recycle bin. "When you understand the pathway you can find a way to interrupt it." But why would we want to interrupt it? "Radiotherapy and chemotherapy work by causing damage," killing cancer cells, but a lot of our normal body cells too. If we could make cancer cells more sensitive to chemotherapeutics then we could lower the dosage, preserving healthy body cells and reducing the traumatic side-effects of chemotherapy.
The thinking behind the therapy
"We are trying to sensitize cancer cells towards irradiation," explains Jiri. "In most cancer cells, the G1 checkpoint is missing." The G1 stage in the life-cycle of a cell runs a safety check. With the help of checkpoint proteins like p53, the cell decides what to do next: divide or rest. The 'master watchman', p53, protects the cell from cancer by picking up on genetic damage, activating DNA repair pathways and stopping cell division if necessary.
"So, cancer cells differ from normal cells in that they mostly rely on the G2 checkpoint phase,” Jiri continues, which follows G1 and precedes cell division. “If you could somehow silence the G2 checkpoint, you would push them into cell division without repair to the damage,” they would divide with a mess of broken chromosomes and die. Knocking out G2 in normal cells wouldn’t be a problem, because they are protected by the G1 checkpoint. So inhibitors of this protein would specifically target cancer cells.
What kind of small molecules are we talking about? “CHK1 inhibitors, for example," says Jiri. CHK1 is an essential checkpoint protein for G2. Inhibitors of this protein are currently under trial, heralding a new wave in anti-cancer drugs. New strategies like G2-blocking represent a broader move towards improving treatment for cancer patients. "But we have to watch out for toxic side-effects," he warns, "and look for alternatives, like combination treatments that also target DNA repair mechanisms. Cancer cells are often defective in both signalling and repair pathways. "If we block faulty repair pathways in tumour cells, we increase damage in the tumour, but not normal cells."
"This all has implications for individualised cancer therapy and for family counselling," Jiri explains. Cancers result from defects in different DNA repair pathways. If you are born with a defect in these pathways you are more likely to develop cancer. "We could use markers to assess the DNA damage response status in every tumour," paving the way for personalised medicine. "With the current technology and the human genome as a yardstick, screening individuals for specific defects is a realistic goal. Coupled with an increased understanding of the DNA repair machinery and the consequences of specific repair defects, doctors will be in a better position to advise families on prognosis, but also to tailor treatments to their particular short-comings.
Joe Jiricny (Institute of Molecular Cancer Research, University of Zurich, Switzerland) agrees. "We can prevent colon cancer if we know who's at risk." Joe's team has studied families with mutations in the mismatch-repair (MMR) pathway. "We've identified 300 families in Switzerland and found 108 mutations that segregate from family to family." Colon cancer can be prevented by colonoscopy, regular internal screens for polyps that might turn cancerous. "Now that we can identify the mutation carriers, we can screen them," says Joe.
"And there's a double positive for the family," he adds. "At the moment a whole family is screened, yet only 50% of them inherit the mutation." Those with MMR mutations live with the risk of colon cancer, but the other half without mutations can be relieved of their fear; "they can just live a normal life. Those with mutations are assured that if they go through the screening programme, their chances of getting cancer are limited. So far, we have been able to prevent cancer in 90% of the males."
"In females, it's a bit more complicated, because they also have the tendency to get endometrial and ovarian cancer," Joe warns, "and this is not quite so easy to detect early with limited invasiveness. An endometrial endoscopy is a bit more unpleasant, and you can't look at ovaries in this way, so you have to use ultrasound, which is not as precise as colonoscopy. But even then, the prevention rate is 70% plus." So, for those who need anti-cancer treatment, how can this be improved? "We are trying to find a way of specifically targeting the MMR-deficient cells, to wipe them out with fewer side-effects, by a kind of gene-therapy approach," Joe explains.
Traditional methods are only 1.5-fold more effective at wiping out cancer cells than normal cells. Joe's method is 25-fold more effective at killing cancer cells than normal cells, at least in a model system. "Of course, we're trying to find the basic causes of colon cancer. When people inherit these mutations, are there environmental factors, you know: diet, nutrition and genetic factors that trigger the process of transformation in the epithelial cells in the colon and the endometrium?"
Looking at the bigger picture, Joe reveals that "13-15% of all colon cancers worldwide are MMR-deficient." Around 4% are inherited from our ancestors, but the majority, the remaining 9% are sporadic, caused by mutations we acquire as our cells divide. In some cases the MMR repair gene is completely switched off by a process of epigenetic silencing. Unlike mutation, this fault is reversible. Having the tools to decipher what has gone wrong in individual patients will pave the way for individualised treatment.
How can the DNA repair Integrated Project help? "The most important goal is trying to get the clinical link," Joe confirms. "The whole programme relies heavily on animal models; these are very useful but not always faithful to human pathology. We need to forge a link between the model system and the patient. To this end, we're using biochemistry to study the individual proteins involved in repair, how they work in human tissue and how relevant that is to human disease." The EU has awarded several million euros in support of DNA repair research. "Hopefully the programme in the long-term will benefit the patients."
Texts by Brona McVittie, Science Writer, London, UK.| Figure: Breast cancer cell viewed by lectron microscopy (source).
|
