Leukemia Drug Shows Promise for Treating a Childhood Brain Cancer
In mouse model, repurposed drug attacks medulloblastoma from two sides, reducing need for toxic combination therapies
A drug used to treat chronic myeloid leukemia appears to be more effective in stopping a type of medulloblastoma in mouse models than existing treatments for fatal brain tumor in children, reports a multi-institutional team led by researchers at the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California San Diego.
In the study, published on September 20, 2019 in PLOS One, the team demonstrated how the use of a single drug - nilotinib - specifically targets cancer cells that have abnormal activation of a cellular communication system, called the Hedgehog pathway, by two different mechanisms, making it more effective and less toxic than combination therapy.
"We have discovered a previously unknown activity of nilotinib that could be used to treat a large proportion of cases of medulloblastoma, a type of childhood brain cancer," said Ruben Abagyan, PhD, Professor at the Skaggs School of Pharmacy. "Although further research is needed, this drug could be used for several types of cancer with an overactive cell signalling pathway."
Several types of basal cell carcinoma, myeloid leukemia, rhabdomyosarcoma, pancreatic adenocarcinoma, glioblastoma and one-third of medulloblastoma cases have deficiencies in the Hedgehog signalling pathway - a key cellular system that regulates embryonic development and adult tissue regeneration. As a result of this deficiency, cancer cells overproduce a cell surface receptor called Smoothened. Malignant tumours with this anomaly account for a quarter of all cancer deaths, Abagyan said.
"Only a fraction of patients with this subtype of medulloblastoma respond well to current treatments that target only smoothed patients," said Abagyan. "Knowing that dysregulation of the Hedgehog pathway is important for the maintenance of cancer stem cells and plays a critical role in many cancers, we wanted to find a single drug that inhibits this pathway in addition to several other essential anti-cancer activities.
In this study, Abagyan and his team found that mice with human medulloblastoma tumours had their tumour growth reduced and that there was no drug resistance. Nilotinib simultaneously inhibits Smoothened kinases and several protein kinases essential for tumor growth.
Nilotinib is already a treatment approved by the U.S. Food and Drug Administration for chronic myeloid leukemia with a safety profile, making it a good therapeutic candidate alone or in combination with surgery, radiotherapy and chemotherapy, the authors wrote.
This project was a collaboration between several research laboratories including Clark C. Chen, MD, PhD, formerly of the UC San Diego Moores Cancer Center and now at the University of Minnesota Medical School.
