Breakthrough information to be used in targeted cancer treatment has come via new research by scientists at the Institute of Molecular and Translation Medicine (IMTM) at the UP Faculty of Medicine and Dentistry in cooperation with the Danish Cancer Society in Copenhagen. The results contribute to a more thorough understanding of the DNA replication mechanism, a/k/a duplication of the genome during cell division. At the same time, the results point toward an entirely new concept in treatment strategy for tumours. The importance of the data has proven by the publication of a study in the prestigious international journal Nature.
Cell genome duplication, in which one of the parental DNA molecules creates two identical subsidiary molecules, is the fundamental condition for successful cell division and survival of an organism. This cellular “Xerox machine” however is not error-free, and mutations occur. Repairing these errors is very important for maintaining the integrity of the genome and ensuring its proper replication into the next generation. Poorly repaired or uncorrected errors in DNA copying can lead to mutations which increase the likelihood of normal cells transforming into tumour cells and in tumours increasing their aggressiveness and thereby their resistance to treatment and increasing their ability to metastasise.
DNA replication under control
“The DNA replication process must therefore be very carefully controlled, and this includes its tempo, which runs about one thousand letters of genetic code or bases per minute. To date, anticancer researchers have been aiming primarily at reducing the speed of replication – resulting in an incomplete reproduction process during the given time limit, which leads to cell death, or in further deepening of genome instability,” explained team leader Jiří Bártek, of the IMTM team and the Danish Cancer Society.
Scientists are making use of their findings regarding interruptions in DNA replication to explore the possibility of targeted introduction of “cell death” into tumour cells. In the just-published study, they looked at the drug olaparib, known under the trade name Lynparza, recently registered for treatment in ovarian and breast cancer. “We predicted that this drug would slow or even stop reproduction; nevertheless, the theory had not yet been proven by experiments,” said Pavel Moudrý of the IMTM, the first author of the publication in Nature.
Excessive speed damages cancer cells
The research team behind Jiří Bártek however came up with surprising findings. The drug olaparib can not only slow replication, but can also contribute to substantial acceleration of the process. “We have demonstrated that excessive reproduction speed in tumour cells leads to so many serious errors that the cells will then die,” explained Bártek. “The PARP enzyme is the important ‘brake’, and it is also the very same molecular target of the drug olaparib,” he added.
That in the end results in errors, and what is even more important, duplication errors occur not only during too slow DNA reproduction but also during increased DNA reproduction rates. Artificial introduction of increased reproduction speed is a completely new concept in cancer treatment strategy. “We can offer a certain analogy to automobile traffic: accidents occur when driving too slowly as well as when driving too fast. And because cancer cells generally have their imaginary autos in need of repair, the high-speed ride is deadly for them,” Bártek explained.
Hope for more perfectly-targeted therapy
Their findings have not only outlined a new concept in the fight against cancer, but also made possible a better understanding of the role of the PARP enzyme as a kind of regulator of reproductive speed. “The PARP enzyme is now the molecular goal of a whole group of promising substances called PARP inhibitors, including olaparib. These agents are used in treating tumours carrying mutations of the BRCA1 or BRCA2 gene, whether as the result of inherited mutation or mutations occurring in the tumour itself. Olaparib is now registered for treating breast and ovarian cancers with mutations of the aforementioned genes, and we believe that this effective treatment will soon be available to the majority of patients in Czechia. The new mechanism of the activity of PARP inhibitors thus will soon offer better-targeted treatment and development of more effective combinations of other drugs which would potentiate anticancer effects,” IMTM Director Marián Hajdúch emphasised.
Two Czechs played a key role in the study (the first author and a corresponding author) in which six researchers took part. This reflects the growing quality of UP scientific results, on a par with leading world cancer research workplaces.