Cotargeting RAF and MEK kinases in NF1-Associated Malignant Peripheral Nerve Sheath Tumor
Abstract
The most common malignancy and a leading cause of death in patients with neurofibromatosis type 1 (NF1) is peripheral nerve sheath tumor (NF1-MPNST). NF1-MPNST is a type of highly aggressive soft-tissue sarcoma with very limited therapy options due to resistance to conventional therapies as well as metastatic propensity. There is an urgent need for novel and more effective therapies. The most common molecular characteristic of NF1-MPNST is loss-of-function alterations in the NF1 gene. This leads to uncontrolled activation of RAS oncoproteins and RAS- effector pathways, among which the RAF-MEK-ERK signaling cascade has proven an attractive therapeutic target. However, responses to MEK inhibitors have been limited and current efforts are focused on development of combinatorial strategies. Recent preclinical and clinical evaluation of a novel dual RAF/MEK inhibitor has been encouraging in RAS-driven cancers. Evaluation of such inhibitors in NF1-associated cancers, including MPNST, is still lacking. Our preliminary data indicated that such inhibitor could circumvent RAF-mediated resistance to traditional MEK inhibitors in NF1-MPNST cells. Moreover, when NF1-MPNST tumor xenografts were treated with dual RAF/MEK inhibitor, this led to tumor regression (as opposed to progressive disease upon treatment with conventional MEK inhibitors). Therefore dual RAF/MEK inhibitor could have clinical applications in NF1-MPNST. In addition, we found that RAF/MEK inhibition modulated DNA damage response pathways and can possibly sensitize NF1-MPNST to chemotherapy agents. These results are the basis of our proposal to (1) preclinically evaluate the activity of this inhibitor in NF1-MPNST and (2) design novel combinatorial approaches and evaluate effect on chemotherapy response. We will employ evaluation of patient-derived xenograft models, in vivo pharmacodynamic assays with clinically relevant drug exposures, and genomic and pharmacologic synthetic lethal screens. Accomplishment of our project has the potential to lead to design of much needed novel therapies for patients with NF1-MPNST.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310217
Entities
People
- Angelina Vaseva
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio