Cancer cells can be deprived of immortality
Researchers at the Spanish National Cancer Research Center, working under the guidance of Dr. Maria Blasco, have developed a fundamentally new strategy for cancer treatment, which consists in using telomeres as a therapeutic target.
With each division, the cell must double its genetic material, but the DNA replication mechanism does not allow the entire chromosome to be completely copied, which leads to a gradual shortening of the protective end sections of chromosomes, known as telomeres. When the telomeres reach a critical length, the cell stops dividing and enters a phase of physiological aging or dies as a result of triggering the mechanism of programmed cell death (apopotosis).
The described phenomenon has been known to specialists for decades, as well as the ability of tumor cells to avoid this fate. Unlimited division of tumor cells is possible due to the activity of the enzyme telomerase, inactivated in the vast majority of healthy cells. The constant restoration of telomeres with the help of telomerase is one of the mechanisms that ensure the immortality of tumor cells.
Earlier attempts to influence tumors by inhibiting telomerase in malignant cells did not bring very encouraging results. Telomeres were shortened, but this led to cell death only after an indefinite number of divisions, which did not allow for a quick assessment of the effectiveness of such therapy.
The approach developed by the authors also affects telomeres, but does not require deactivation of telomerase.
Telomeres consist of multiple (hundreds of times) repeats of the same DNA sequence, and their integrity is maintained by a protective shell forming complex of six proteins known as shelterins. The strategy proposed by the authors is to suppress the activity of one of these proteins, namely shelterin TRF1, which leads to the destruction of the protective shell of telomeres.
Until now, researchers have not attempted to influence shelterins due to the fear of many potential side effects due to the fact that shelterins are present not only in tumor cells, but also in healthy cells. However, in experiments on mice, a very promising experimental therapy was accompanied by only minor manifestations of toxicity.
The authors worked with a mouse model of lung cancer, a disease that ranks first in mortality among cancer patients worldwide. At the same time, they chose the most aggressive type of lung cancer, which currently has no effective therapeutic targets. The cells of such tumors are characterized by the presence of an active oncogene K-Ras and the absence of a tumor suppressor protein p53.
The TRF1 protein was selected as a therapeutic target as the most studied representative of the shelterin family, expressed exclusively in telomeres. Moreover, it is known that inhibition of TRF1 affects the viability of so-called cancer stem cells, which are considered responsible for delayed recurrence of tumors.
To assess the toxicity of the approach, the researchers blocked the activity of TRF1 in the cells of healthy mice and animals with lung cancer using genetic methods. The subsequent rapid destruction of telomeres and the mass death of malignant cells or their entry into the phase of physiological aging ensured the cessation of tumor growth against the background of moderate manifestations of toxicity. Thus, shelterin TRF1 turned out to be the first therapeutic target effective against the most aggressive type of lung cancer.
After that, the authors analyzed the database of active molecules at their disposal and found two promising compounds inhibiting the activity of TRF1, which can act as a starting point for the development of a fundamentally new class of antitumor drugs. They are currently looking for partners in the pharmaceutical industry to take their research to the next level of the drug development process.
Article by Maria Garcia-Beccaria et al. Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage is published in the journal EMBO Molecular Medicine.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of the Spanish National Cancer Research Centre:
CNIO scientists are able to take immortality from cancer.
15.05.2015