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(TOP) Lung cancer cells treated with the TRF1 inhibitor developed by CNIO (TOP RIGHT) show less TRF1 bound to telomeres (GREEN). (BOTTOM, PINK) More telomeric DNA damage and therefore, more acute telomere uncapping, than non-treated cancer cells (BOTTOM LEFT). Image Credit: CNIO

Taking immortality out of cancer

Scientists have discovered a new strategy to fight cancer. They target telomeres — the structures at both ends of each chromosome. One group has found that blocking the TRF1 gene, essential to telomeres, creates dramatic improvements in mice with lung cancer.

"Telomere uncapping is emerging as a potential mechanism to develop new therapeutic targets for lung cancer," according to the Spanish National Cancer Research Centre (CNIO) Telomeres and Telomerase Group led by Maria Blasco. The work was published in EMBO Molecular Medicine.

Every time a cell divides, it must duplicate its DNA packaged inside its chromosomes. However, in DNA replication, the end of each chromosome cannot be completely replicated. As a result, telomeres shorten with each cell division. Excessively short telomeres are toxic to cells and force them to stop replicating. Eventually these cells are eliminated through senescence or apoptosis (cell death).

This process has been known for decades. However, cancer cells constantly divide, proliferating without any apparent limits as their telomeres do not shorten. The telomerase enzyme in cancer cells remains active, while in most healthy cells it is turned off. This constant repair of telomeres by telomerase allows tumor cells to be immortal and divide endlessly.

An obvious strategy to fight cancer then becomes inhibiting the telomerase enzyme in tumor cells. Previously tested, this approach doesn't take effect until after a varying number of cell divisions — so it is not an instant "cure" and the cancer continues spreading.

The new study uses a completely different approach than targeting telomerase.

Telomeres are made up of hundreds of repeating patterns of DNA sequences — a structure that shortens with each cell division. A six-protein complex, called "shelterin" from the term shelter or protection, forms a protective covering around Telomere DNA. The CNIO team blocked one of the shelterins, TRF1, destroying this telomere protective shield.

The idea of targeting the shelterins had not been tried for fear of igniting toxic effects as these proteins are present in both healthy as well as tumor cells.

"Nobody had explored the idea of using one of the shelterins as an anti-cancer target. It is difficult to find drugs that interfere with protein binding to DNA, and the possibility exists that drugs targeting telomere caps could be very toxic. For these reasons, no one had explored this option before, although it makes a lot of sense."

Maria Blasco PhD, leader, Spanish National Cancer Research Centre (CNIO) Telomeres and Telomerase Group

The present work revealed that blocking TRF1 only causes minor toxicities that are well tolerated by mice. And surprisingly "TRF1 removal induces acute telomere uncapping, which results in cellular senescence or cell death. We have seen that this strategy kills cancer cells efficiently, stops tumor growth and has bearable toxic effects. We've shown that we can find potential drugs able to inhibit TRF1 that have therapeutic effects when administered orally to mice," explains Blasco.

TRF1 was inhibited both genetically — in mice where the gene has been removed — and chemically using select compounds from CNIO's proprietary collection. These compounds, including the inhibitor ETP-470037 developed by the CNIO Experimental Therapeutics Program, may be a starting point for development of new drugs for cancer therapy.

CNIO scientists worked with mouse models for lung cancer, as it has the highest death rates worldwide. The studied mouse has a very aggressive type of lung cancer for which no drug targets had been found to date. Their tumors have an active K-Ras oncogene while missing the p53 tumor suppressor. TRF1 is the first target to be able to inhibit these tumors.

Now, having established the effectiveness and low toxicity of the TRF1 target, the researchers continue to look for chemical compounds to counter TRF1. Two types of compounds have been found to date. "We are now looking for partners in the pharmaceutical industry to bring this research into more advanced stages of drug development," adds Blasco.

Abstract
Telomeres are considered anti-cancer targets, as telomere maintenance above a minimum length is necessary for cancer growth. Telomerase abrogation in cancer-prone mouse models, however, only decreased tumor growth after several mouse generations when telomeres reach a critically short length, and this effect was lost upon p53 mutation. Here, we address whether induction of telomere uncapping by inhibition of the TRF1 shelterin protein can effectively block cancer growth independently of telomere length. We show that genetic Trf1 ablation impairs the growth of p53-null K-RasG12V-induced lung carcinomas and increases mouse survival independently of telomere length. This is accompanied by induction of telomeric DNA damage, apoptosis, decreased proliferation, and G2 arrest. Long-term whole-body Trf1 deletion in adult mice did not impact on mouse survival and viability, although some mice showed a moderately decreased cellularity in bone marrow and blood. Importantly, inhibition of TRF1 binding to telomeres by small molecules blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function. Thus, induction of acute telomere uncapping emerges as a potential new therapeutic target for lung cancer.

Synopsis
Activation of rapid telomere uncapping by inhibition of TRF1 can block growth of already established K-Ras-induced lung cancers independently of telomere length, and without seriously affecting mouse survival or tissue function.

Genetic Trf1 ablation impairs the growth of p53-null K-RasG12V-induced lung carcinomas and increases mouse survival independently of telomere length.

Inhibition of TRF1 binding to telomeres can be achieved in vivo by small molecules and blocks the growth of already established lung carcinomas without affecting mouse survival or tissue function.

Ubiquitous TRF1 downregulation allows tissue function with limited side effects.

The research has been funded by the Spanish Ministry of Economy and Competitiveness and the Botín Foundation and Banco Santander, through Santander Universities.

Maria Blasco's team was made up of Maria Garcia-Beccaria, Paula Martinez and Marinela Mendezwas and conducted in collaboration with the Experimental Therapeutics Program, the Experimental Oncology Group and the Histopathology, Molecular Imaging and Microscopy Units at CNIO, and the Animal Medicine and Surgery Department at the Universidad Complutense de Madrid.

Reference article: Therapeutic inhibition of TRF1 impairs the growth of p53-deficient K-RasG12V-induced lung cancer by induction of telomeric DNA damage. María García-Beccaria, Paula Martínez, Marinela Méndez-Pertuz, Sonia Martínez, Carmen Blanco-Aparicio, Marta Cañamero, Francisca Mulero, Chiara Ambrogio, Juana M. Flores, Diego Megias, Mariano Barbacid, Joaquín Pastor, Maria A. Blasco. EMBO Molecular Medicine (2015). doi: http://embomolmed.embopress.org/cgi/doi/10.15252/201404497

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