The cancer accounts for 15 percent of all cancers and is especially common in aggressive tumors such as osteosarcoma and glioblastoma.
Post Date – 03:20 PM, Thursday – July 20
SINGAPORE: A cancer drug currently on the market could be modified to target a group of malignancies often associated with poor outcomes and lacking targeted treatment options, a team of researchers led by Nanyang Technological University, Singapore (NTU Singapore) has discovered.
These malignancies account for 15 percent of all cancers and are particularly common in malignancies such as brain-invasive osteosarcoma and glioblastoma.
These cancer cells are “remained immortal” using a mechanism called selective lengthening of telomeres (ALT), but the team has shown that the FDA-approved cancer drug ponatinib can block a key step in the ALT mechanism that causes it to fail.
Reporting their findings based on laboratory experiments and preclinical animal studies, the scientists found that ponatinib helped shrink bone tumors, a type of ALT cancer, without causing weight loss, a common side effect associated with cancer drugs. In mice with tumors treated with ponatinib, they found a reduction in the ALT cancer biomarker compared with untreated mice. The findings were published in the scientific journal Nature Communications.
The researchers say the findings bring them one step closer to developing targeted treatment options for ALT cancers, which so far lack clinically approved targeted therapies.
Dr. Maya Jeitany and a research team from Nanyang Technological University’s School of Biological Sciences, together with collaborators at the National University of Singapore’s (NUS) Institute of Cancer Science Singapore and Yeo Loo Lin School of Medicine, and the Agency for Science, Technology and Research’s (A*STAR) Genome Institute of Singapore, are seeking to address this unmet need.
Study leader Dr Jaitani, Senior Research Fellow at Nanyang Technological University’s School of Biological Sciences, said: “A remarkable feature of cancer is its ability to evade cell death and gain unlimited replication—in other words, remain immortal—and it does so through an alternative lengthening mechanism of telomeres (ALT). Although a significant proportion of cancer cells rely on this mechanism, there are currently no clinically approved targeted therapies.
“Through our study, we identified a novel signaling pathway in the ALT mechanism and showed that the FDA-approved drug ponatinib, which inhibits this pathway, holds particular promise in stopping the growth of ALT cancer cells. Our findings may provide new directions for the treatment of ALT cancers by repurposing FDA-approved drugs for this type of tumor.”
Valerie Yang, Assistant Professor of Medical Oncology, Division of Lymphoma and Sarcoma, National Cancer Center Singapore, commented as an independent expert: “Both sarcomas and glioblastomas are highly complex cancers that are more common in younger people and currently have limited treatment options.
The discovery of an FDA-approved drug that can be repurposed to target ALT, the Achilles’ heel of these cancers, is very exciting. The study is in line with Nanyang Technological University’s five-year strategic plan “NTU 2025”, which aims to address the great challenges facing humanity by addressing the needs and challenges of healthy living.
Telomeres are the protective “caps” on the ends of each chromosome that carry our DNA. With each cell division, some telomeres are naturally snipped off until they become too short, causing the cell to die.
Most cancer cells bypass this process by activating an enzyme called telomerase, which lengthens telomeres and allows cells to replicate indefinitely.
However, about 15 percent of cancers elongate telomeres by alternative pathways, rather than activating telomerase. This mechanism is called Alternative Lengthening of Telomeres (ALT).
To date, there are no clinically approved targeted therapies for ALT cancers. Furthermore, many ALT cancers, such as osteosarcoma and glioblastoma, exhibit resistance to chemotherapy, highlighting the need for more targeted forms of treatment.
Through high-throughput drug screening (the process of screening large numbers of relevant biological or pharmacological compounds) and subsequent testing of the shortlisted compounds, the scientists found that the FDA-approved drug ponatinib for the treatment of bone marrow cancer was effective in killing ALT cancer cells.
When osteosarcoma and liposarcoma (a type of tumor that grows in fatty tissue) cells were treated with ponatinib, the scientists found that the drug caused DNA damage, dysfunctional telomeres and triggered senescence (the process by which cells stop dividing).
Importantly, telomere synthesis in cells also decreased 18 to 20 hours after drug treatment.
The potential of ponatinib was further validated in preclinical studies in mice that received transplants of human bone cancer cells.
The drug shrunk tumor size without affecting the mice’s body weight, a common side effect associated with cancer treatments.
