Assessment of MEKK2 as a Novel Therapeutic Target in Neurofibromatosis
Abstract
Neurofibromatosis type 1 is a relatively common heritable disorder that has a major impact on nearly every organ in the body. In addition to the tumors of the nervous system that are the source of the name of this disorder, defects in the skeletal system are a major source of pain, disability, and even death in neurofibromatosis type 1 patients. These include deformity of the skeleton and fragility of the bones that makes them particularly easy to fracture. Compounding this problem, some patients with neurofibromatosis are simply unable to heal bone fractures, and these persistent fractures can be present even at birth. Studies in mice have shown that almost all of the defects in neurofibromatosis type 1 can be traced to over-activation of a protein called the extracellular response kinase (ERK). Accordingly, drugs that block ERK activation have had a promising effect to treat mouse models of neurofibromatosis. However, these drugs that block ERK have been used in the treatment of some forms of malignant melanoma, which has revealed that they have substantial side effects that may limit the ability of this approach to be applied to neurofibromatosis patients. These side effects likely arise as the ERK pathway is a very fundamental method for cells to respond to changes in their environment, and ERK activity is needed to maintain many of the organs in the body. To advance the treatment of patients with neurofibromatosis type 1, we must identify more specific ways to block the abnormal forms of ERK activation while still allowing the forms of ERK activation needed to keep organs happy to proceed unimpeded. We have recently conducted a screen to identify a drug target that contributes to the activation of ERK in cells of the skeleton, identifying a gene called MEKK2. Notably MEKK2 is of a class of genes called kinases that are well validated as drug targets. In our preliminary data, we present evidence that MEKK2 plays an important role to activate ERK in cells of the skeleton. Additionally, we present further evidence that MEKK2 mediates responses to the signals that are known to be altered in neurofibromatosis type 1. Taken together, these observations lead us to believe that MEKK2 is a key mediator of the over-activation of ERK seen in neufibromatosis type 1. In our first aim, we will directly test this and establish that MEKK2 is needed for the overactivation of ERK that occurs in cellular models of neurofibromatosis type 1. In Aim 2, we will test if inhibition of MEKK2 can treat both cellular and mouse models of neurofibromatosis type 1. If successful, this work would benefit patients with neurofibromatosis type 1 by identifying a new drug target, MEKK2 for the treatment of this disorder. Moreover, as drugs inhibiting MEKK2 may block the abnormal activation of ERK that occurs in neurofibromatosis while allowing some of the normal ERK signals that are required to maintain healthy organs to pass unimpeded, this approach may have fewer side effects than total inhibition of ERK. This would in turn increase the tolerability of this treatment and allow greater numbers of neurofibromatosis patients to benefit. If this project is successful, it would be used as justification to (1) develop better drugs targeting MEKK2 that are more specific than currently available options and screen these drugs for their ability to treat mouse models of neurofibromatosis and (2) study if drugs targeting MEKK2 can treat other aspects of neurofibromatosis type 1 in addition to the skeletal defects. Regarding drug development, we note that Weill Cornell has a core facility explicitly designed to allow for faculty initiated drug discovery projects, thus these efforts can begin quickly after the completion of this project.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610398
Entities
People
- Matthew B Greenblatt
Organizations
- United States Army
- Weill Cornell Medicine