Malignant peripheral nerve sheath tumors (MPNSTs) are among the most devastating and intractable of the soft tissue sarcomas. MPNSTs are also the most common neurofibromatosis type 1 (NF1)-associated cancer and a leading cause of death in NF1 patients. Taking advantage of the expertise our team has built over the past five years testing single agent treatments in mouse models of MPNST, we propose a set of combination pre-clinical tests to support a next generation of clinical trials. The NF1 gene product, neurofibromin, is an off signal for Ras proteins, resulting in aberrant Ras-Raf-MEK signaling in MPNST cells. Our recent publication shows that a MEK inhibitor effectively delays MPNST growth. In addition we found that an Aurora kinase A (AURKA) inhibitor stops tumor growth. Preliminary data show that a small molecule in combination with an oncolytic virus actually shrinks tumors and induces some cures. This proposal leverages the complimentary expertise of two PIs.
In Aim 1 Dr. Cripe will lead the studies exploring small molecules combined with oncolytic viral therapy.
In Aim 2 Dr. Ratner will combine small molecules to either target G1/S with G2/M inhibition (horizontal inhibition) or enhance G2/M inhibition (vertical inhibition). Together the studies are anticipated to discover therapeutic combinations that cure MPNST in model systems, and can rapidly be moved into clinical trials.
Malignant Peripheral Nerve Sheath Tumors (MPNSTs) account for 5-10% of all soft tissue sarcomas. MPNSTs are one of the most common non-rhabdomyosarcoma soft-tissue sarcomas, and carry the greatest risk for death among soft tissue sarcoma types. MPNSTs are also the most common Neurofibromatosis type 1 (NF1) - associated malignancy and the leading cause of death in adults with NF1. Complete surgical removal is the only successful treatment of MPNSTs, and the outcome for unresectable, recurrent, or metastatic MPNST remains extremely poor. We focus on preclinical testing of combinations of small molecule compounds, and a biologic, to generate data supporting a next generation of clinical trials.
|Haworth, Kellie B; Arnold, Michael A; Pierson, Christopher R et al. (2017) Immune profiling of NF1-associated tumors reveals histologic subtype distinctions and heterogeneity: implications for immunotherapy. Oncotarget 8:82037-82048|
|Currier, Mark A; Sprague, Les; Rizvi, Tilat A et al. (2017) Aurora A kinase inhibition enhances oncolytic herpes virotherapy through cytotoxic synergy and innate cellular immune modulation. Oncotarget 8:17412-17427|
|Kendall, Jed J; Chaney, Katherine E; Patel, Ami V et al. (2016) CK2 blockade causes MPNST cell apoptosis and promotes degradation of ?-catenin. Oncotarget 7:53191-53203|
|Friedman, Gregory K; Beierle, Elizabeth A; Gillespie, George Yancey et al. (2015) Pediatric cancer gone viral. Part II: potential clinical application of oncolytic herpes simplex virus-1 in children. Mol Ther Oncolytics 2:|
|Cripe, Timothy P; Chen, Chun-Yu; Denton, Nicholas L et al. (2015) Pediatric cancer gone viral. Part I: strategies for utilizing oncolytic herpes simplex virus-1 in children. Mol Ther Oncolytics 2:|
|Haworth, Kellie B; Leddon, Jennifer L; Chen, Chun-Yu et al. (2015) Going back to class I: MHC and immunotherapies for childhood cancer. Pediatr Blood Cancer 62:571-6|