MSGID: 1:317/3 64acdb1b   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Existing cancer drug could be repurposed to fight certain aggressive   
   cancers    
      
     Date:   
         July 10, 2023   
     Source:   
         Nanyang Technological University   
     Summary:   
         A team of scientists has found that 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. This subset of cancers makes up 15 per cent of all   
         cancers and is especially prevalent in aggressive tumors such as   
         osteosarcoma (bone tumor) and glioblastoma (brain tumor).   
      
      
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   A team of scientists led by Nanyang Technological University, Singapore   
   (NTU Singapore) has found that 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.   
      
   This subset of cancers makes up 15 per cent of all cancers and is   
   especially prevalent in aggressive tumours such as osteosarcoma (bone   
   tumour) and glioblastoma (brain tumour).   
      
   These cancerous cells 'stay immortal' using a mechanism called   
   the alternative lengthening of telomeres (ALT), but the team has   
   demonstrated 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.   
      
   Reporting their findings based on laboratory experiments and preclinical   
   animal studies, 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 findings are published in the scientific journal Nature   
   Communications.   
      
   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 from the Cancer Science   
   Institute of Singapore and the Yong Loo Lin School of Medicine, both at   
   the National University of Singapore (NUS), and the Genome Institute of   
   Singapore at the Agency for Science, Technology and Research (A*STAR),   
   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."  The study aligns with NTU   
   2025, the University's five-year strategic plan, which aims to address   
   humanity's grand challenges by responding to the needs and challenges   
   of healthy living.   
      
   How cancer cells replicate and grow Telomeres are protective "caps"   
   at the tips of every chromosome, which carries our DNA. With each cell   
   division, a bit of the telomeres is naturally snipped off, until they   
   become too short, leading to cell death.   
      
   Most cancer cells bypass this process by activating an enzyme called   
   telomerase, which lengthens the telomeres so that the cells can   
   replicate indefinitely. However, about 15 per cent of cancers lengthen   
   their telomeres through alternative pathways, rather than activating   
   telomerase. This mechanism is known as the alternative lengthening of   
   telomeres (ALT).   
      
   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 -- a process of screening large numbers of relevant biological   
   or pharmacological compounds -- and subsequent testing of shortlisted   
   compounds, the scientists discovered that ponatinib, a drug approved by   
   the US Food and Drug Administration for a type of bone marrow cancer,   
   can kill ALT cancer cells effectively.   
      
   When osteosarcoma and liposarcoma (a tumour that grows in fatty tissues)   
   cells were treated with ponatinib, the scientists found that the drug   
   led to DNA damage, dysfunctional telomeres, and triggered senescence,   
   a process in which the cell stops dividing. 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.   
      
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   Journal Reference:   
      1. Frances Karla Kusuma, Aishvaryaa Prabhu, Galen Tieo, Syed Moiz   
      Ahmed,   
         Pushkar Dakle, Wai Khang Yong, Elina Pathak, Vikas Madan, Yan   
         Yi Jiang, Wai Leong Tam, Dennis Kappei, Peter Dro"ge, H. Phillip   
         Koeffler, Maya Jeitany. Signalling inhibition by ponatinib disrupts   
         productive alternative lengthening of telomeres (ALT). Nature   
         Communications, 2023; 14 (1) DOI: 10.1038/s41467-023-37633-3   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230710113634.htm   
      
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