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Source: Thailand Medical News  Sep 23, 2019  4 years, 5 months, 5 days, 4 hours, 49 minutes ago

Nilotinib Can Be Repurposed As A Drug For Treating Pediatric Brain Cancer

Nilotinib Can Be Repurposed As A Drug For Treating Pediatric Brain Cancer
Source: Thailand Medical News  Sep 23, 2019  4 years, 5 months, 5 days, 4 hours, 49 minutes ago
Researchers at Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego have discovered that Nilotinib (Tasigna), a drug used to treat chronic myeloid leukemia (CML) appears to be more effective at stopping a type of brain cancer called medulloblastoma in animal models than existing treatments for the deadly pediatric brain tumor.
Nilotinib is a type of targeted cancer drug called a tyrosine kinase inhibitor (TKI). Tyrosine kinases are proteins that act as chemical messengers and can stimulate cancer cells to grow.
Nilotinib blocks a tyrosine kinase protein called Bcr-Abl. The protein is made by CML cells that have an abnormal chromosome called the Philadelphia chromosome. Blocking this protein stops the leukaemia cells that have the Philadelphia chromosome growing. Most people with CML have the Philadelphia chromosome.
The multinational research team demonstrated how use nilotinib specifically targets cancer cells that have an abnormal activation of a cell communication system, called the Hedgehog pathway, via two different mechanisms, making it more effective and less toxic than combining drugs.
Professor Ruben Abagyan, senior author of the study commented in an interview with Thailand Medical News "We discovered a previously unknown activity of nilotinib that may be leveraged to treat a large fraction of cases of medulloblastoma, a type of childhood brain cancer. While more research is needed, this pharmaceutical could potentially be used for several cancer types with an overactive cell-signaling pathway. It would make an excellent drug for repurposing"
Most variant types of basal cell carcinoma, myeloid leukemia, rhabdomyosarcoma, pancreatic adenocarcinoma, glioblastoma and one third of medulloblastoma cases have an impairment in the Hedgehog signaling pathway -- a key cellular system that regulates embryonic development and adult tissue regeneration. As a result of this impairment, the cancer cells overproduce a cell-surface receptor called Smoothened. Malignancies with this abnormality account for a more than 25 percent of all cancer deaths.
Only a fraction of patients with this subtype of medulloblastoma respond well to current therapies that only target Smoothened. Knowing that dysregulation of the Hedgehog pathway is important to the maintenance of cancer stem cells, and that it plays a critical role in several cancers, the research  team wanted to find a single drug that inhibits this pathway in addition to several other essential anti-cancer activities.
In the study, the research team discovered that animal models  bearing human medulloblastoma tumors saw tumor growth reduced and no drug resistance occurring. Nilotinib simultaneously inhibits Smoothened and several protein kinases critical for tumor growth.
Nilotinib is already a U.S. Food and Drug Administration approved therapy for chronic myeloid leukemia with a safety profile, making it a good therapeutic candidate alone or in combination with surgery, radiation therapy and chemotherapy. With further clinical trials, the drug could get repurposed by the US FDA for not treating pediatric medulloblastoma and also other cancers.
trong>Reference Kirti Kandhwal Chahal, Jie Li, Irina Kufareva, Milind Parle, Donald L. Durden, Robert J. Wechsler-Reya, Clark C. Chen, Ruben Abagyan. Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma. PLOS ONE, 2019; 14 (9): e0214901 DOI: 10.1371/journal.pone.0214901


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