Article Series: The Relationship Between Telomeres and Cancer 2. Telomere-Targeted Drugs in Cancer Treatment

Recently, telomeres have become increasingly popular in cancer treatment. According to researchers, cancer's weak point is the telomeres that ensure the orderly preservation of genetic information. Numerous experiments have demonstrated that removing telomere-protecting mechanisms causes cells to lose their viability.

In our previous article, we saw that telomere shortening causes cancer development by creating chromosomal irregularities and that the telomerase enzyme, which prevents telomere shortening,has high activity in cancer cells. Targeting telomerase in cancer treatment, that is, blocking its activity through certain genetic techniques, is therefore a highly promising approach for the future. This approach is expected to prevent telomerase enzymes from functioning, shorten telomeres in cancer cells, and activate the mechanism that initiates programmed cell death. Although these enzymes that lengthen telomeres hold promise for anticancer treatment, experts in this field have pointed out many risks. Some new studies, discussed in detail below, have identified other mechanisms that lengthen telomeres. These mechanisms generally operate independently of telomerase. Experiments in mouse models have revealed cancer cells resistant to telomerase inhibition. Similar results have also been observed in human cancer cells. New studies have shown ring-shaped structures called telomere loops at the chromosome ends of human cancer cells. These structures are thought to be one of the mechanisms that protect telomeres. There is also a risk that tumor cells may multiply without needing telomerase, that is, before telomere length reaches a critical level. This prevents telomerase-targeting drugs from fulfilling their function. Therefore, not only molecules that inhibit telomerase activity but also telomere-protecting proteins and drugs that break down telomeres should be developed.

Bone cancer (osteosarcoma), a type of brain cancer called GBM, and pancreatic cancer, are cancers with an unfavorable disease course that spread very quickly and for which current treatments are inadequate unless they are detected at a very early stage. According to a study published in the world-renowned journal Science, new treatments may be developed by targeting a cellular pathway responsible for these aggressive cancers' ability to multiply uncontrollably and without limit.

Particularly over the last 15 years, we have begun to understand cancer cells much better. This has changed the focus of cancer research. The observation that cancer cells and the communities they form (malignant tumors) exhibit behavior that could be called intelligent has led to new drugs targeting the vulnerabilities of cancer cells, becoming the focus of cancer research.

Whereas the telomere pathway was previously considered primarily responsible for cellular aging and death, studies in recent years have found that, in addition to the telomere pathway, the ALT pathwayis also responsible for cellular aging and death. Cancer cells were thus seen to need to secure both telomerase and the ALT pathway to bypass normal cellular aging and death processes. (ALT: Alternative lengthening of telomers)

The findings of the study published in Science offer hope for new treatments for ALT pathway-positive cancers (for example, bone, GBM, and pancreatic cancers).

Cancer cells divide much more frequently and uncontrollably than normal cells. They have developed mechanisms to overcome telomere shortening during each division that would lead to cell death. There are 2 main pathways for lengthening telomeres. The long-known pathway is telomere lengthening by telomerase. The newly discovered pathway, whose full mechanism has not yet been explained, is the ALT pathway. In this pathway, telomeres are lengthened using DNA sequences from other chromosomes.

A protein called ATR is a fundamental regulator of DNA repair and replication. This study demonstrated its critical role in the ALT pathway. The discovery of certain molecules that suppress ATR protein opens the door to new treatments for some ALT-positive diseases, such as bone, brain, and pancreatic cancer. These ATR-inhibiting molecules are being tested in scientific studies under the code names VE-821 and AZ20.

In conclusion, cancer research focusing on telomere pathways, holds great promise for cancer treatment, and we will continue to share developments in this field, which we follow closely.