Treatments targeting TELOMERASE, the key to cancer cell immortality

Telomerase enzymes are why cancer cells are called “immortal.” In earlier articles, we discussed telomeres and the telomerase enzyme and their importance in cancer development. As is known, structures called “telomeres” are found at the ends of our chromosomes, protecting genes as cells divide. In normal cells, telomeres continue to shorten with age. Telomerase enzyme activity is absent in our normal cells. In cancer cells, however, telomerase activity is very high, enabling them to multiply very rapidly and for a long time. These features indicate that telomerase has an important place in developing an effective treatment strategy.

Telomerase-targeted treatments involve 3 different approaches

1. Telomerase immunotherapy

The aim has been to use immunotherapies , which have produced successful results in cancer treatment in recent years, in telomerase-targeted treatments as well. The HTERT protein is necessary for effective telomerase enzyme function. The very high activity of HTERT in tumor cells has highlighted its potential as a target . For this reason, telomerase vaccines have been developed.

1. GRNVAC1: Dendritic cells, which activate T cells, are taken from the patient, modified to recognize the HTERT protein, and returned to the patient. The aim is to activate fighter T cells to attack tumor cells with active HTERT protein. This method is being tested for prostate cancer, and phase 1-2 clinical trials are ongoing.
2. GV1001: This is a peptide fragment containing part of the HTERT protein. Researchers have attempted to use this peptide to generate an immune response against tumors with high telomerase activity. Clinical trials are currently ongoing in liver, pancreatic and lung cancers. Phase-1 and phase-2 studies have shown telomerase-specific immune responses, with very low side effects. This vaccine is thought to be particularly effective against pancreatic cancers .

2. Telomerase gene therapy

To date, no gene therapy has been approved anywhere in the world. These treatments, still experimental, are approached in 2 ways.

• Telomerase gene therapy: Gene-silencing agents are delivered using specially designed viruses. These viruses enter only cells with high telomerase enzyme levels, namely tumors. The delivered gene-silencing agents thereby suppress telomerase activity and destroy the cancer cell.
• Suicide gene therapy: First, a gene segment enabling the cancer cell to produce a particular enzyme is delivered. This segment is designed to produce the enzyme only when the telomerase gene is active. A synthetic particle that the enzyme can break down is then designed, with a toxic substance attached. When the particle is broken down inside the tumor cell, the toxic substance is released and the cancer cell dies.
• Oncolytic virus therapy: Oncolytic viruses are special viruses that attack only cancer cells. Viruses designed for this purpose target only cancer cells with high telomerase activity and do not multiply in normal cells. However, there is concern that they could also affect stem cells with high telomerase activity, and research into this issue continues.

3. Telomerase inhibitors

The telomerase enzyme needs RNA fragments to add new telomeres to chromosome ends. It uses these RNA fragments as a kind of template. Researchers have therefore prepared “artificial RNA,” attempting to inhibit telomerase activity by causing the enzymes to bind to this RNA. Developed in 2014, Imetelstat is still undergoing clinical trials in various cancers. The FDA states that the drug’s liver toxicity is very high.

When will these studies translate into clinical use?

• Telomerase-targeted drugs are still experimental. Clinical trials have found very substantial side effects. Work continues on developing systems that target cancer cells more specifically.
• Very high telomerase activity in cancer cells offers an opportunity to develop an effective targeted therapy.
• CRISPR/Cas9 technology is expected to make treatments targeting the telomerase enzyme more effective.