Newly discovered activity of the leukemia drug, nilotinib, shows promise for being useful to treat certain types of cancer.
Hedgehog-dependent medulloblastoma is a deadly brain cancer that makes up about one-third of all childhood brain cancers. The Hedgehog (Hh) molecular signaling pathway and its specific component, Smoothened (SMO), is important for normal embryonic development. Abnormal activation of this Hh signaling pathway and overproduction of SMO has been implicated in this cancer, among many others. The Hh pathway is also involved in maintaining cancer stem cells, thus dysregulation of this pathway contributes to tumour resistance to chemotherapy and radiation therapy, ultimately leading to relapse.
Existing treatments for Hh-dependent cancers target the SMO component of the pathway. Unfortunately, these SMO-specific antagonists are not effective or become ineffective over time, as only a small portion of Hh-Medulloblastoma patients respond well to these SMO antagonist drugs and the rates of resistance or relapse is high. As a result, research has now focused on finding drugs with multiple targets, or mechanisms to target cancer cells of a particular cancer subtype.
In search of a new treatment
New data published in PLOS ONE from researchers in the United States describes nilotinib’s activity in targeting SMOs in the Hh pathway – a mechanism that was previously unknown. They first identified approved drugs with established anti-cancer activity that had similar properties of current SMO-antagonists. They used three-dimensional docking models to further screen the drugs for their ability to attach to SMOs in the Hh pathway. Nilotinib was found to be one of the top drug candidates predicted to have strong attachment potential to SMOs, similar to SMO-antagonist drugs used in Hh-dependent cancer treatments today.
Nilotinib reduced tumour growth in mice
Next, the research team investigated the effects of nilotinib in tumour growth. They conducted their experiments in mice models by injecting human medulloblastoma tumours into mice and then treating them with nilotinib. They found that treated mice with human medulloblastoma tumours had decreased tumour growth and no tumour resistance. Nilotinib was discovered to have anti-SMO activity in addition to its other known anti-cancer activity, meaning it had multiple mechanisms of activity against cancer cells. The multi-target action of nilotinib may make it a better agent to use against these Hh-dependent tumours than current SMO-antagonist drugs.
This discovery highlights the potential use of nilotinib in treating certain Hh-dependent cancers, such as Hh-medulloblastoma. Although nilotinib has not yet been studied in the context of Hh-dependent cancers, there is research underway studying the use of nilotinib in brain cancers. Nilotinib is already an FDA-approved drug with a well-known efficacy and safety profile and is well tolerated in long-term treatment. Based on the current findings, the researchers propose nilotinib as potentially an ideal candidate for treating certain cancers either alone or in combination with other anti-cancer therapies.
Written by Maggie Leung, PharmD.
Chahal, K. K., Li, J., Kufareva, I., Parle, M., Durden, D. L., Wechsler-Reya, R. J., … Abagyan, R. (2019). Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma. Plos One, 14(9). doi: 10.1371/journal.pone.0214901
Leukemia drug shows promise for treating a childhood brain cancer. (2019, September 20). Retrieved from https://www.eurekalert.org/pub_releases/2019-09/uoc–lds092019.php
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