Tag: telomeres

Categories : CancerTags :

An Existing Cancer Drug Could Have a New Target: Cancer Cells’ ‘Fountain of Youth’

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A team of scientists has found that ponatinib, an existing cancer drug could be repurposed to target a subset of cancers that currently lack targeted treatment options and is often associated with poor outcomes. Their findings are published in Nature Communications.

Cancerous cells have a ‘fountain of youth’ by continually lengthening telomeres, but some use a different mechanism called the alternative lengthening of telomeres (ALT). This subset makes up 15% of all cancers and is especially prevalent in aggressive tumours such as osteosarcoma and glioblastoma. The team, led by Nanyang Technological University, Singapore (NTU Singapore), showed that ponatinib, a cancer drug approved by the US Food and Drug Administration, blocks key steps in the ALT mechanism that leads it to fail.

The scientists found that ponatinib helped to shrink bone tumours (a type of ALT cancer) without causing weight loss, a common side effect associated with cancer drugs. In mice with tumours treated with ponatinib, they found a reduction in a biomarker for ALT cancer as compared to untreated mice.

The researchers say that the findings move them a step closer to developing a targeted therapeutic option for ALT cancers, which lack clinically approved targeted treatments to date.

Dr Maya Jeitany and a team of researchers from the NTU School of Biological Sciences, together with collaborators are seeking to address this unmet need.

Dr Jeitany, study lead and senior research fellow at NTU’s School of Biological Sciences, said: “A prominent feature of cancer is its ability to evade cell death and acquire indefinite replication – to stay immortal, in other words – which it can do through the alternative lengthening of telomeres (ALT) mechanism. While a sizeable portion of cancer cells depend on this mechanism, there is no clinically approved targeted therapy available.

“Through our study, we identified a novel signalling pathway in the ALT mechanism and showed that the FDA-approved drug ponatinib inhibits this pathway and holds exceptional promise in stopping the growth of ALT cancer cells. Our findings may provide a new direction for the treatment of ALT cancers by repurposing an FDA-approved drug for these types of tumours.”

Commenting as an independent expert, Assistant Professor Valerie Yang, medical oncologist with the Department of Lymphoma and Sarcoma at the National Cancer Centre Singapore, said: “Sarcomas and glioblastomas are both highly complex cancers that are more prevalent in young people and currently have limited treatment options. The identification of a drug that is FDA-approved which can be repurposed to target ALT, an Achilles heel in these cancers, is very exciting.”

To date, there is no clinically approved targeted treatment for ALT cancers. Furthermore, many ALT cancers, such as osteosarcoma and glioblastoma, show resistance to chemotherapy, highlighting the need for a more targeted form of treatment.

Drug affects telomeres in ALT cancer cells

Through high-throughput drug screening and subsequent testing of shortlisted compounds, the scientists discovered that ponatinib, a drug approved by the FDA for a type of bone marrow cancer, can kill ALT cancer cells effectively.

When osteosarcoma and liposarcoma cells were treated with ponatinib, the scientists found that the drug led to DNA damage, dysfunctional telomeres, and triggered senescence. Importantly, the synthesis of telomeres in the cells also dropped after 18 to 20 hours of treatment with the drug.

Pre-clinical studies conducted on mice that had received transplants of human bone cancer cells further validated the potential of ponatinib. The drug reduced the tumour sizes without affecting the mice’s body weight, a common side effect associated with cancer treatments.

In mice with tumours treated with ponatinib, there was also a reduction in a biomarker for ALT cancer as compared to untreated mice – an indicator that the drug was effective in inhibiting ALT cancer growth.

The scientists ran further tests to identify ponatinib’s mode of action on telomeres in ALT cancer cells and identified a signalling pathway (a series of chemical reactions in which a group of molecules in a cell work together to control a cell function) that could be responsible for the drug’s effect on ALT.

The researchers are now studying further how ponatinib affects telomeres to understand in more detail the signalling pathway they have identified. They are also assessing potential ponatinib-based combinatorial drug treatments for ALT cancers.

Source: Nanyang Technological University

Categories : Ageing GeneticsTags :

Junk DNA Yields Insights into Ageing and Cancer

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Findings from a new study into ‘junk DNA’ have brought scientists one step closer to solving the mysteries of ageing and cancer.

Jiyue Zhu, a professor in the College of Pharmacy and Pharmaceutical Sciences, led a team which recently identified a DNA region known as VNTR2-1 which seems to drive activity of the telomerase gene, which has been shown to prevent ageing in certain types of cells. The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).

The telomerase gene controls the activity of the telomerase enzyme, which helps produce telomeres, the caps at the end of each strand of DNA that protect the chromosomes within our cells and which shorten over time until cells are no longer able to divide.

However, in certain cell types, such as reproductive cells and cancer cells, the telomerase gene’s activity ensures that telomeres are reset to the same length when DNA is copied. This is essentially what restarts the aging clock in new offspring but is also the reason why cancer cells can continue to multiply and form tumors.

Understanding how the telomerase gene is regulated and activated and why it is only active in certain types of cells could someday be the key to understanding how humans age, as well as how to stop the spread of cancer. That is why Prof Zhu has focused the past 20 years of his career as a scientist solely on the study of this gene.

Zhu said that VNTR2-1’s discovery is especially noteworthy due to the type of DNA sequence it represents.

“Almost 50% of our genome consists of repetitive DNA that does not code for protein,” noted Prof Zhu. “These DNA sequences tend to be considered as ‘junk DNA’ or dark matter in our genome, and they are difficult to study. Our study describes that one of those units actually has a function in that it enhances the activity of the telomerase gene.”

In previous work, deleting the DNA sequence from human and mouse cancer cells caused telomeres to shorten, cells to age, and tumours to stop growing. They conducted a subsequent study measuring the length of the sequence in DNA samples taken from Caucasian and African American centenarians and control participants in the Georgia Centenarian Study, a study that followed a group of people aged 100 or above between 1988 and 2008. The researchers found that the length of the sequence ranged from as short as 53 repeats of the DNA to as long as 160 repeats.

“It varies a lot, and our study actually shows that the telomerase gene is more active in people with a longer sequence,” Prof Zhu said.

Since very short sequences were found only in African American participants, they looked more closely at that group and found that there were relatively few centenarians with a short VNTR2-1 sequence as compared to control participants. However, Prof Zhu said that a shorter sequence does not necessarily translate to a shorter lifespan, since the telomerase gene is less active with possibly a shorter telomere length which could reduce cancer risk.

“Our findings are telling us that this VNTR2-1 sequence contributes to the genetic diversity of how we age and how we get cancer,” Prof Zhu said. “We know that oncogenes–or cancer genes–and tumor suppressor genes don’t account for all the reasons why we get cancer. Our research shows that the picture is a lot more complicated than a mutation of an oncogene and makes a strong case for expanding our research to look more closely at this so-called junk DNA.”

Prof Zhu observed that many African Americans in the United States for generations have Caucasian ancestry, which could have added this sequence. So he and his team hope to next be able to study the sequence in an African population.

Source: Washington State University

Journal information: Xu, T., et al. (2021) Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene. PNAS. doi.org/10.1073/pnas.2019043118.

Categories : Ageing PaediatricsTags :

Telomere Length May Be Set Early in Life

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Image source: Pixabay

Telomeres, the protective nucleotide end caps of chromosomes which shorten with every cell division, have been found by a new study to undergo great changes in length during the first years of life.

The length of telomeres is important in a number of age-related diseases and is also an important marker of biological age. When telomeres are completely shortened, cells become senescent and unable to divide any further to repair damage.

This study, one of the first to examine telomere length (TL) in childhood, found that the initial setting of TL during prenatal development and in the first years of life may determine one’s TL throughout childhood and potentially even into adulthood or older age. The study also finds that TL decreases most rapidly from birth to age 3, then remaining unchanged into the pre-puberty period, although on some occasions it was seen to lengthen.

Researchers at the Columbia Center for Children’s Environmental Health at Columbia University Mailman School of Public Health led the study, which followed 224 children from birth to age 9. Their findings were published in the journal Psychoneuroendocrinology.

The researchers discovered that a mother’s TL is predictive of newborn TL and tracks with her child’s TL through pre-adolescence. The reasons why some children have telomeres that shorten faster are unknown, though one explanation may be that telomeres are susceptible to environmental pollutants. It is also unknown why some children had telomeres that lengthened across the study period, a phenomenon seen in other studies.

“Given the importance of telomere length in cellular health and aging, it is critical to understand the dynamics of telomeres in childhood,” said senior author Julie Herbstman, PhD, director of CCCEH and associate professor of environmental health science at Columbia Mailman School. “The rapid rate of telomere attrition between birth and age 3 years may render telomeres particularly susceptible to environmental influences during this developmental window, potentially influencing life-long health and longevity.”

Researchers used polymerase chain reaction to measure TL in white blood cells isolated from cord blood and blood collected at ages 3, 5, 7, and 9, from 224 children. In a small group of mothers they also measured maternal TL at delivery.

The researchers said that further research is needed to understand the biological mechanisms behind the variance of TL shortening or lengthening rates in the first years of life, as well as modifiable environmental factors contributing to the shortening speed.

Source: Columbia Mailman School of Health

Categories : AgeingTags :

Telomere Lengthening May Treat Renal Fibrosis

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A new study has shown that it may be possible to treat renal fibrosis, an age-related disease, by lengthening telomeres.

Previous research had shown it was that lengthening telomeres successfully treated pulmonary fibrosis and infarctions in mice.

Renal fibrosis is the leading cause of kidney failure, treatable only with dialysis. Moderate renal fibrosis is present in some 11% of people over 65, and is a predictor of the severity of renal failure. Telomeres are proteins at the end of chromosomes that maintain genetic integrity during cellular division. They shorten over time, eventually to the point where they are too short for cells to divide, becoming senescent. Telomere lengthening, eg through hyperbaric oxygen therapy, has been suggested as a way to reverse many age-related declines.

While short telomeres were by themselves not enough to cause renal fibrosis, the researchers found that mice with short telomeres developed it when they were exposed to small amounts of toxin, mimicking the environmental toxins people are exposed to over their lives. Mice that also lacked a certain protein needed for telomere function, Trf1, developed renal fibrosis, showing that telomeres are indeed involved in proper kidney function.

Since genes involved in epithelial-to-mesenchymal transition are overexpressed in patients with kidney failure, the researchers looked for this in mice with short telomeres. And “we found that short telomeres induce changes in the expression of genes involved in EMT.”

As a final demonstration of the importance of telomeres in kidney fibrosis, the authors cultured kidney cells in which they expressed the gene for the telomerase enzyme, which elongates telomeres. In these cells with restored telomeres, the epithelial-to-mesenchymal transition program returned to normal, and the cells regained their healthy, pre-fibrosis appearance.

“As short telomeres accumulate with ageing in the organism, it is tempting to speculate that pathological EMT programmes associated with ageing, such as cancer and different types of tissue fibrosis, may be originated at least in part by the presence of short telomeres,” the authors conclude.

Source: News-Medical.Net

Categories : COVID LungTags :

Link Found Between Telomeres and COVID Lung Damage

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Researchers developing a therapy to regenerate lung tissue damaged by severe COVID have postulated that shortened telomeres are associated with the damage.

Telomeres are structures at the ends of chromosomes that maintain their integrity, and a small portion of them are lost with each cell division, such as when regenerating damaged tissue. As the telomere sections shorten, they eventually become unable to divide and are senescent. The team was already working on a way to regenerate lung tissue in pulmonary fibrosis, and adapted their research to the COVID pandemic. In pulmonary fibrosis, lung tissue becomes scarred and rigid, resulting in reduced lung capacity. In previous research, they had shown that telomere damage to the alveolar type II pneumocytes – which happen to be the same cells targeted by SARS-CoV-2.

Maria A Blasco, a researcher at CNIO said, “When I read that type II alveolar pneumocytes were involved in COVID-19, I immediately thought that telomeres might be involved.” The researchers believe short telomeres hinder tissue regeneration after severe COVID.

Blasco explained, “we know that the virus infects alveolar type II pneumocytes and that these cells are involved in lung regeneration; we also know that if they have telomeric damage they cannot regenerate, which induces fibrosis. This is what is seen in patients with lung lesions after COVID-19: we think they develop pulmonary fibrosis because they have shorter telomeres, which limits the regenerative capacity of their lungs.”

To support this, the team analysed the telomeres of 89 COVID patients. Although it might be expected that older patients had shorter telomeres, the researchers found that all of those with severe COVID had shorter telomeres – regardless of age.

The researchers wrote: “These findings demonstrate that molecular hallmarks of aging, such as the presence of short telomeres, can influence the severity of COVID-19 pathologies.”The involvement of shorter telomeres opens up the possibility of using telomerase to lengthen them again, as a potential treatment.The team will now move to an experimental mouse model, infecting mice with short telomeres and no telomerase with COVID, giving telomerase to some to see if the lung tissue can regenerate after severe COVID.

Source:News-Medical.Net

Journal information: Sanchez-Vazquez R, Guío-Carrión A, Zapatero-Gaviria A, Martínez P, Blasco M. Shorter telomere lengths in patients with severe COVID-19 disease. Aging (Albany NY). 2021. doi:10.18632/aging.202463