Finding effective treatments for cancer is one of the biggest challenges in medicine. A common malignant characteristic of cancer cells is their ability to achieve indefinite growth potential by maintaining and elongating telomeres – the end tips of chromosomes. A significant number of cancers use an Alternative Lengthening of Telomeres (ALT) mechanism to ensure their survival and proliferation. Therefore, targeting telomere maintenance mechanisms is a compelling area for cancer treatment development. Unfortunately, there are currently no clinically approved compounds for patients with ALT-dependent cancers.
A team of scientists from the NTU School of Biological Sciences have found that ponatinib, a drug approved by the US Food and Drug Administration (FDA) for the treatment of chronic myeloid leukaemia, has shown exceptional promise in stopping the growth of ALT-dependent cancerous cells.
From left to right: Galen Tieo, Dr. Maya Jeitany, and Professor Peter Dröge
What exactly are telomeres?
Telomeres are the structures at the ends of chromosomes that play a role in controlling the life span of cells. They also protect the rest of the chromosome from the loss of genetic information. Telomeres shorten when cells divide, and normal cells do not have a mechanism to prevent such shortening. Hence, when telomeres reach a critical short length, normal cells die.
On the bright side, telomeric shortening in normal cells acts as a safeguard against the formation of cancers by limiting the continuous propagation of cells.
ALT-dependent cancerous cells
Cancer cells, however, need to overcome telomeric shortening and achieve “cell immortality.” While most cancer cells re-activate the enzyme telomerase to elongate their telomeres, a subset of tumours rely on homology-directed repair (HDR) mechanisms known as ALT. ALT can be found in about 10 to 15 percent of all cancers and is especially prevalent in several cancer types such as osteosarcoma (bone cancer) and glioblastoma (brain cancer).
Telomeres of ALT cells are prone to heightened levels of replicative stress – difficulties or disruptions that hinder the DNA’s usual replication mechanisms. The breaks in their telomeres trigger the activation of DNA damage repair (DDR) pathways, which work to resolve the replication disruptions and preserve genomic integrity. These telomeres are primed for HDR mechanisms, which typically use another telomeric sequence to repair and maintain their length.
Ponatinib and a new use for the drug
Despite the high prevalence of cancers using ALT, there are zero drugs tailored for such cancers. However, in a recent study published in the journal Nature Communications, Dr. Maya Jeitany and her team in Associate Professor Peter Dröge’s unit at the NTU SBS found that ponatinib, an existing FDA-approved drug that is used to treat another type of cancer, chronic myeloid leukaemia, could be used to treat ALT-dependent cancer cells.
Ponatinib belongs to a class of drugs known as tyrosine kinase inhibitors (TKIs) and was designed to inhibit BCR-ABL1, a fusion protein that drives the proliferation and survival of cancer cells in chronic myeloid leukaemia. The drug works by blocking BCR-ABL1’s uncontrolled enzyme activities.
Dr Jeitany and her team discovered that ponatinib inhibited a signalling pathway identified in their study, ABL1-JNK-JUN, and interfered with telomere maintenance activities. This resulted in cancer cell death in vitro and in preclinical animal studies.
Where do we go from here?
Drug approvals by the FDA are costly and time-intensive to ensure that drugs are thoroughly evaluated and are safe for human usage. However, the work by Dr Jeitany and her team not only uncovered a new therapeutic avenue for scientists to work with when dealing with ALT-dependent cancers, but it also presents an opportunity to repurpose the use of an already clinically-approved anti-cancer drug to target another significant group of cancers. This allows for a more direct route to the Investigational New Drug (IND) application stage of the FDA-drug approval process.