Brigatinib and Its Combination with INK-128 as a Novel Treatment for NF2-Deficient Meningiomas
Abstract
Presently, an FDA-approved medical therapy for the treatment of NF2-deficient meningiomas is not available. In our continued efforts to identify novel targeted therapies for NF2-assoicated tumors, we, as members of the Synodos for NF2 Consortium in collaboration with the National Center for Advancing Translational Sciences (NCATS), have identified Brigatinib, a potent inhibitor of anaplastic lymphoma kinase (ALK) and other receptor tyrosine kinases (RTKs), to be effective as a single agent in inhibiting proliferation of NF2-deficient meningioma cells and suppressing tumor growth in an orthotopic, quantifiable meningioma animal model. Our additional studies showed that INK-128, a dual mTORC1/2 inhibitor, synergized with Brigatinib to potently suppress meningioma cell proliferation in vitro. Based on these data, we have proposed to further evaluate the Brigatinib/INK-128 combination as an effective treatment for NF2-deficient meningiomas and investigate their mechanisms of action. During this report period, we demonstrated that NF2-deficient meningiomas did not express ALK and that Brigatinib potently suppressed the growth of NF2-deficient tumors via inhibition of multiple RTKs and non-RTKs, such as focal adhesion kinase (FAK), which has previously been recognized as an oncoprotein in NF2-related tumors. We have also determined the maximal tolerable doses (MTDs) for the Brigatinib and INK-128 drug combination and are in the process of generating mice bearing intracranial sporadic meningioma xenografts for the efficacy study. In addition, we are developing another xenograft animal model using an NF2-associated meningioma.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2019
- Accession Number
- AD1097845
Entities
People
- Long-Sheng Chang