Brigatinib and Its Combination with INK-128 as a Novel Treatment for NF2-Deficient Meningiomas
Abstract
Accounting for over 30% of all primary brain tumors, meningiomas are the most common brain tumors. Despite their high prevalence, these tumors are severely understudied and, as a result, not well understood. Meningiomas can occur spontaneously in the general population or are frequently found in patients with neurofibromatosis type 2 (NF2), an extremely debilitating neurogenetic disorder that predisposes affected individuals to the development of bilateral vestibular schwannomas and multiple meningiomas. Previous studies have established that NF2 is caused by mutations in the NF2/merlin tumor suppressor gene. Interestingly, in addition to all NF2-related tumors, about 50% of sporadic meningiomas harbor NF2 mutations. Research over the last two decades has greatly enhanced our understanding of the complex molecular signaling changes associated with the loss of merlin, the NF2 gene product, in NF2-associated tumor cells. In recent years, a few agents that target merlin-regulated pathways have been evaluated in preclinical cell culture and animal models, and several of them that showed efficacy in preclinical models have advanced to clinical trials in NF2 and sporadic patients with progressive vestibular schwannomas and meningiomas. However, a Food and Drug Administration (FDA)-approved medical therapy for these tumors is still not available. Current treatment options for NF2-associated meningiomas are limited to surgery and radiation; however, these treatments could cause severe complications, such as seizure, intracranial bleeding, and stroke. As patients with NF2 often develop multiple meningiomas, surgery may not be possible due to too many tumors or locations that are difficult to operate on, such as the skull base. Furthermore, incomplete tumor resection is not uncommon and is a main cause of tumor recurrence. In addition, radiation therapy may induce malignant transformation of benign tumors and increase the risk for secondary malignancies. Together, these factors underscore the importance of developing an effective medical therapy that stops tumor growth or completely eradicates NF2-associated tumors. The overarching goal of our research is to identify a medical therapy that effectively eradicates NF2-deficient meningiomas. To achieve this goal, Dr. Chang at Nationwide Children’s Hospital has teamed with Dr. Ramesh at Massachusetts General Hospital. Together, they propose to evaluate a novel drug combination, Brigatinib and INK128, as a potential treatment for NF2-deficient meningiomas and to investigate their molecular mechanisms of action. Brigatinib is an inhibitor of anaplastic lymphoma kinase (ALK) and several other receptor tyrosine kinases (RTKs) that are frequently activated in NF2-associated tumors. Brigatinib, under the trade name ALUNBRIG™, has recently received FDA approval for the treatment of ALK-positive non-small cell lung carcinomas. INK128 is a highly potent inhibitor of both mTORC1 and mTORC2 kinases, which were previously shown to be aberrantly activated in NF2-deficient meningiomas by the Ramesh group. Using a quantifiable, intracranial, NF2-deficient meningioma animal model that we established, we found that, as a single agent, either Brigatinib or INK128 is well tolerated in mice and potently suppresses intracranial meningioma growth. Additional studies carried out in the Ramesh and Chang laboratories uncovered synergy in growth inhibition in cultured NF2-deficient meningioma cells when Brigatinib was combined with INK128. Based on these findings, we propose to define the mechanism of Brigatinib activity and understand the synergy between Brigatinib and INK128 in NF2-deficient meningioma cells. In addition, we plan to prove that the Brigatinib/INK128 combination is highly potent in both intracranial NF2-deficient sporadic and NF2-associated meningioma animal models. We believe that the results to be obtained from this study will potentially lead to an effective combinati
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810547
Entities
People
- Long-Sheng Chang
Organizations
- United States Army