Existing cancer drugs can fight aggressive cancers

A team of scientists led by Nanyang Technological University, Singapore (NTU Singapore) has found that existing cancer drugs can be reused to target a subset of cancers that currently lack targeted treatment options and are often associated with poor outcomes.

This subset of cancers accounts for 15% of all cancers and is particularly prevalent in aggressive tumors such as osteosarcoma (bone tumor) and glioblastoma (brain tumor).

These cancer cells are “immortalized” using a mechanism called alternative telomere elongation (ALT), but the team has shown that ponatinib, a cancer drug approved by the US Food and Drug Administration, blocks key steps in the ALT mechanism that lead 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 ponatinib-treated tumors, they found reduced biomarkers for ALT cancer compared to untreated mice. The findings are published in the scientific journal Nature Communications.

Developing therapeutic options

The researchers say the findings move them one step closer to developing targeted therapeutic options for ALT cancer, which to date has no clinically approved targeted treatments.

Maya Jeitany and a research team from the NTU School of Biological Sciences, along with collaborators from the Cancer Science Institute of Singapore and 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), strive to address this unmet need.

Jeitany, study lead and senior researcher at NTU’s School of Biological Sciences, said: “A salient feature of cancer is its ability to evade cell death and to achieve unrestricted replication – to remain immortal, in other words – which can be done through alternative mechanisms of elongation. telomeres (ALT). While most cancer cells rely on this mechanism, there are no clinically approved targeted therapies available.

“Through our research, we identified a novel signaling pathway in the mechanism of ALT and demonstrated that the FDA-approved drug ponatinib inhibits this pathway and holds tremendous promise in stopping the growth of ALT cancer cells. Our findings may provide new directions for the treatment of ALT cancer by reusing FDA-approved drugs for this tumor type.”

‘Achilles heel’ cancer

Assistant professor Valerie Yang, medical oncologist with the Department of Lymphoma and Sarcoma at the National Cancer Center Singapore, said: “Sarcoma and glioblastoma are very complex cancers that are more common in young people and currently have limited treatment options. Identification of an FDA-approved drug that can be reused to target ALT, a major weakness in this cancer, is very exciting.”

This study aligns with NTU 2025, the university’s five-year strategic plan, which aims to address humanitarian challenges by addressing the needs and challenges of healthy living.

How cancer cells replicate and grow

Telomeres are the protective “caps” at the ends of each chromosome, which carry our DNA. With each cell division, a small number of telomeres are naturally cut, until they become too short, causing cell death.

Most cancer cells bypass this process by activating an enzyme called telomerase, which lengthens telomeres so the cell can replicate indefinitely. However, about 15% of cancers lengthen their telomeres via alternative pathways, rather than activating telomerase. This mechanism is known as alternative telomere elongation (ALT).

To date, there are no clinically approved targeted treatments for ALT cancer. Additionally, many ALT cancers, such as osteosarcoma and glioblastoma, display resistance to chemotherapy, highlighting the need for more targeted forms of treatment.

Drug affects telomeres in ALT cancer cells

Through high-throughput drug screening – the process of screening a large number of biologically or pharmacologically relevant compounds – and subsequent testing of selected compounds, scientists found that ponatinib can kill ALT cancer cells effectively.

When osteosarcoma and liposarcoma cells (tumors that grow in fatty tissue) were treated with ponatinib, scientists found that the drug caused DNA damage, dysfunctional telomeres, and triggered senescence, a process in which cells stop dividing. Importantly, telomere synthesis in cells also decreased after 18 to 20 hours of treatment with the drug.

Pre-clinical studies conducted in mice that have received human bone cancer cell transplants further validate the potential of ponatinib. The drug reduced tumor size without affecting the mice’s weight, a common side effect associated with cancer treatment.

In mice with ponatinib-treated tumors, there were also reduced biomarkers for ALT cancer compared with untreated mice – an indicator that the drug is effective at inhibiting ALT cancer growth.

The scientists ran further tests to identify how ponatinib acts on telomeres in ALT cancer cells and identify signaling pathways (a series of chemical reactions in which groups of molecules in cells work together to control cell function) that could be responsible for the drug’s effect on ALT.

The researchers are now learning more about how ponatinib affects telomeres to understand, in more detail, the signaling pathway they have identified. They also assessed potential ponatinib-based combinatorial drug treatments for ALT cancer.