Effect of Nilotinib on GBM

Glioblastoma multiforme (GBM) is the most common and the lethal brain tumor with very poor prognosis. GBM is relatively rare in children compared to adults and accounts for only 3-15% of central nervous system (CNS) tumors in children 1. Even with such rare occurrence pediatric glioblastoma has substantial morbidity and mortality with a median survival of 13-73 months. Pediatric glioblastoma is distinct from the adult glioblastoma in terms of molecular genetics, effectiveness of the adjuvant therapies and prognosis after treatment 1. In this article we provide a brief overview of the effects of a drug called Nilotinib on GBM.


Nilotinib is a medication sold under the brand name Tasigna. Nilotinib was developed by Novartis Pharmaceuticals and was approved by FDA in 2010. The development of Nilotinib was based on Abl-Imatinib complex. Imatinib was the first targeted tyrosine kinase inhibitor and was approved for treatment of cancer in 2002. Imatinib is a Bcr-Abl inhibitor and is used as first line therapy for Philadelphia chromosome/chronic myeloid leukemia (CML) and other malignancies for e.g. gastrointestinal stromal tumors (GIST). Imatinib works by binding to ATP-binding pocket of Bcr-Abl and as a result blocks kinase activity. Nilotinib is a, second-generation, receptor tyrosine kinase inhibitor used to treat Philadelphia chromosome/Bcr-Abl chronic myelogenous leukemia (CML). The target spectrum of Nilotinib is similar to that of Imatinib and is used for second-line treatment in cases of resistance or intolerance to Imatinib. The safety and toxicity profile of Nilotinib has been well-established. Besides Bcr-Abl tyrosine kinase, Nilotinib also plays a role in inhibiting the platelet-derived growth factor receptor-alpha (PDGFR-alpha) signaling. This article aims to outline efficacy of Nilotinib on GBM by a review of published research articles and clinical trials.


A preclinical study conducted by Au et.al. 3 used two independent pediatric GBM-derived cell lines with either high PDGFR-alpha or high PDGFR-beta expression to study the effects of Nilotinib treatment. The results of this preclinical study showed that Nilotinib inhibits activation of PDGFR-alpha and decrease cell proliferation as well. These results suggested that Nilotinib may be effective in managing PDGFR-alpha dependent group of pediatric gliomas 3.


The phase II clinical trial studied the efficacy of biomarker-selected patients of recurrent GBM enriched for PDGR-alpha activation 2. 34 patients with recurrent GBM with either amplification/overexpression of PDGR-alpha were enrolled in the study and Nilotinib was administered 400 mg twice a day. The results of the trial showed that Nilotinib had limited activity in recurrent GBM though there were a few durable responders. Additional research and molecular characterization are essential in order to find other biomarkers which in turn will help to select patients and study efficacy of Nilotinib in those patients and investigate whether Nilotinib will help those patients.


Contrary to the results and the findings of the above study and the clinical trial, Frolov et.al. has shown that treatment of GBM and patient-derived GBM stem cells with imatinib and Nilotinib results in increased tyrosine phosphorylation of multiple signaling proteins such as p130Cas, focal adhesion kinases (FAK) and paxillin (PAX). These signaling proteins are key to cell motility and hence result in enhanced tumor cell and stem cell migration and invasion 4. Even though clinical trials of Imatinib were encouraging for CML and GIST, Imatinib has lacked efficacy and failed clinical trials for glioblastoma.


Chahal et.al. has shown that Nilotinib is a direct inhibitor of the Hedgehog (Hh) signaling pathway in addition to its already known activity against multiple tyrosine-kinase-mediated proliferative pathways 5. Nilotinib directly binds Smoothened (SMO) and inhibits SMO signaling. Since dysregulation of SMO, a component of the Hh pathway, results in development of Medulloblastoma, which is the most common type of cancerous brain tumor and accounts for 33% of all pediatric brain tumors, the study has shown that Nilotinib holds promise to be used for the treatment of Hh-dependent cancers.


The results and the findings of the above-mentioned research studies and the clinical trial suggests that there is conflicting evidence regarding efficacy of Nilotinib for GBM. Although Nilotinib has shown promise for its use in certain studies, further research and clinical trials would be required to establish the usage of Nilotinib for GBM in pediatric patients.


Written by Pawan Patro, PhD


References:


1. Kanti Das, K. & Kumar, R. Pediatric Glioblastoma. in Glioblastoma (2017). doi:10.15586/codon.glioblastoma.2017.ch15.

2. Picconi, D., Juarez, T. & Kesari, S. ACTR-56. Phase II trial of Nilotinib in PDGFR-alpha enriched recurrent glioblastoma. Neuro. Oncol. 21, (2019).

3. Au, K. et al. A preclinical study demonstrating the efficacy of nilotinib in inhibiting the growth of pediatric high-grade glioma. J. Neurooncol. 122, (2015).

4. Frolov, A. et al. Imatinib and Nilotinib increase glioblastoma cell invasion via Abl-independent stimulation of p130Cas and FAK signalling. Sci. Rep. 6, (2016).

5. Chahal, K. K. et al. Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma. PLoS One 14, (2019).