Targeting AXL in Preclinical Models of Plexiform Neurofibroma and Malignant Peripheral Nerve Sheath Tumor Chemoprevention
Abstract
Neurofibromatosis type 1 (NF1) is one of the most common cancer predisposition syndromes worldwide. NF1 is caused by mutations in the NF1 gene, which codes for the protein called neurofibromin. Patients with NF1 suffer from tumors of the peripheral nerves, called plexiform neurofibromas (PNF), which can cause serious medical problems including disfigurement, paralysis, and chronic pain. The development of atypical neurofibroma (ANF) can be an early warning sign of tumor progression to a devastating form of sarcoma called malignant peripheral nerve sheath tumors (MPNST). MPNST is the leading cause of premature death in persons with NF1. There are no effective drug therapies to treat MPNST once it develops, or to delay or prevent existing PNF and ANF from progressing to MPNST. Currently, the frontline therapy is complete surgical resection, which is often associated with significant medical complications or infeasible entirely due to the size and location of these tumors near vital organs. Treatment options for both PNF and ANF remain limited with only one FDA-approved drug to date. Toxicities due to off-target effects have proven to be a limiting factor as well. The overarching goal of this translational research grant is to identify new agents with activity across a spectrum of tumors affecting NF1 patients to move forward in phase 2 clinical trials, both for treating existing PNF but also to delay or even prevent the development of MPNST from PNF/ANF precursors. Development of effective drug therapies for ANF has been hindered by incomplete understanding of the endogenous roles of key targets involved in tumor growth and progression, as well as the lack of preclinical models that mimic the evolution of these tumors in NF1 patients. Our laboratory recently generated new mouse models that accurately recapitulate the genetic and pathological changes in humans to fill this void. These mice develop PNF as well as a spectrum of progressive ANF and MPNSTs that share the same genetic mutations found in human patients. These models are well correlated with what is observed clinically in NF1 patients and make them ideally suited for understanding the disease processes and carrying out preclinical therapeutic studies. Using these mouse models, linked with a recent phase 2 clinical trial of the drug cabozantinib in adult NF1 patients with PNF, we have identified a signaling protein called AXL, which we believe to be a key target underlying treatment responses both in mice and in human NF1 patients with PNF. Studies proposed in this application will validate AXL as a drug target in a spectrum of NF1 related tumors and test a drug, bemcentinib, which potently and selectively blocks AXL signaling as a strategy to shrink existing PNF as well as to prevent progression of PNF/ANF to MPNST in mice. Bemcentinib is the first AXL specific drug to enter the clinic in 2014 and is now in six phase 2 clinical trials for other human cancers with promising results. It has demonstrated an excellent clinical safety profile in greater than 250 patients having received the drug to date. We anticipate that selectively targeting AXL will offer distinct advantages to patients for use both as a single agent or in combination with other agents, such as selumetinib (MEK inhibitor), by avoiding undesirable side effects associated with broader multi-targeted and less specific drugs. If the results are positive, these studies will provide the necessary preclinical data required to move this drug or other similar agents forward to early phase clinical trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110534
Entities
People
- David Clapp
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army