• MPNST – targeted therapies and adaptive and acquired resistance
• NF1 biospecimen repository
• MPNST genomics
• Development and characterization of novel MPNST patient derived xenografts
• Acquired resistance to RAF and MEK inhibitors in BRAF V600E high-grade gliomas
• RAS pathway targeted therapies for RAS-driven pediatric rhabdomyosarcoma

Deregulated ERK signaling in MPNST. ERK signaling output is activated in many human tumors, including those with BRAF and RAS mutations and those with loss of NF1.  Several pediatric solid tumors are known to express these mutations, including a subset of rhabdomyosarcoma, neuroblastoma, and MPNST.  Our research aims to investigate the ability of ERK pathway inhibition to produce anti-tumor responses in cancers with dysregulated RAS signaling.   A primary focus of this work is determining the adaptive signaling response to MEK inhibition and other targeted therapies in models of MPNST, to identify mechanisms by which tumors with loss of NF1 can evade MEK inhibition, and to identify targets for more effective and combination therapy.

Resistance to RAF/MEK targeted therapy and novel targeted therapy combinations in BRAF mutant high-grade gliomas. While molecularly targeted therapies are successful in some patients with high-grade glioma, they have limited success in other patients. We have identified several novel, and independent mechanisms of resistance to RAF-targeted therapy in glioma.  We are currently evaluating novel small-molecule targeted therapies to overcome resistance and produce more deep and durable responses. We are committed to understanding resistance and exploring novel mechanisms of overcoming resistance to targeted therapy for patients with BRAF-mutant glioma, as well as other ERK-dependent gliomas.

Effects of farnesyl transferase inhibition in pediatric solid tumors with oncogenic mutations in HRAS. Despite the minimal clinical efficacy seen with farnesyl transferase inhibition in previous pediatric clinical trials, the farnesyltransferase inhibitor (FTI) tipifarnib has now demonstrated preliminary activity when given to genomically selected populations.  Based upon this, we have investigated its effects in pediatric solid tumor models, and have demonstrated that farnesyl transferase inhibition is active in preclinical models of fusion-negative HRAS-mutated rhabdomyosarcoma.

• Targeting farnesylation as a novel therapeutic approach in HRAS-mutant rhabdomyosarcoma
  Odeniyide P, Yohe ME, Pollard K, Vaseva AV, Calizo A, Zhang L, Rodriguez FJ, Gross JM, Allen AN, Wan X, Somwar R, Schreck KC, Kessler L, Wang J, Pratilas CA.
• Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAF V600E-Mutant Human Glioma
  Schreck KC, Morin A, Zhao G, Allen AN, Flannery P, Glantz M, Green AL, Jones C, Jones KL, Kilburn LB, Nazemi KJ, Samuel D, Sanford B, Solomon DA, Wang J, Pratilas CA, Nicolaides T, Mulcahy Levy JM.
• Combination MEK and mTOR inhibitor therapy is active in models of glioblastoma
  Schreck KC, Allen AN, Wang J, Pratilas CA.
• Adaptive and Acquired Resistance to MEK Inhibition in Malignant Peripheral Nerve Sheath Tumors is Mediated by Activation of Receptor Tyrosine Kinases
  Wang J, Pollard K, Calizo A, Pratilas CA.
• Combined Inhibition of SHP2 and MEK is Effective in Models of NF1-deficient Malignant Peripheral Nerve Sheath Tumors
  Wang J, Pollard K, Allen AN, Tomar T, Pijnenburg D, Yao Z, Rodriguez FJ, Pratilas CA.
• A Clinically and Genomically Annotated Nerve Sheath Tumor Biospecimen Repository
  Pollard K, Banerjee J, Doan X, Wang J, Xindi G, Allaway R, Langmead S, Slobogean B, Meyer CF, Loeb, DM, Morris CD, Belzberg AJ, Blakeley JO, Rodriguez FJ, Guinney J, Gosline SJC, Pratilas CA.
• A Secondary Mutation in BRAF Confers Resistance to RAF Inhibition in a BRAF ^V600E-Mutant Brain Tumor
  Wang J, Yao Z, Jonsson P, Allen AN, Qin ACR, Uddin S, Dunkel IJ, Petriccione M, Manova K, Haque S, Rosenblum MK, Pisapia DJ, Rosen N, Taylor BS, Pratilas CA.

• BRAF Mutations and the Utility of RAF and MEK Inhibitors in Primary Brain Tumors.
• Schreck KC, Grossman SA, Pratilas CA.
• Telomere alterations in neurofibromatosis type 1-associated solid tumors.
  Rodriguez FJ, Graham MK, Brosnan-Cashman JA, Barber JR, Davis C, Vizcaino MA, Palsgrove DN, Giannini C, Pekmezci M, Dahiya S, Gokden M, Noë M, Wood LD, Pratilas CA, Morris CD, Belzberg A, Blakeley J, Heaphy CM.
• Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1 or ALK aberrations (STARTRK-NG).  Desai AV, Robinson GW, Gauvain K, Basu EM, Macy ME, Maese L, Whipple NS, Sabnis AJ, Foster JH, Shusterman S, Yoon J, Weiss BD, Abdelbaki MS, Armstrong AE, Cash T, Pratilas CA, Corradini N, Marshall LV, Farid-Kapadia M, Chohan S, Devlin C, Meneses-Lorente G, Cardenas A, Hutchinson KE, Bergthold G, Caron H, Chow Maneval E, Gajjar A, Fox E.
• Trends of lymph node sampling and metastasis in pediatric and young adult patients with clear cell, epithelioid, and synovial sarcomas.  Weller JH, Westermann C, Patel P, Beckman RM, Pratilas CA, Morris CD, Rhee DS. 
• Adult Wilms Tumor: Genetic Evidence of Origin of a Subset of Cases From Metanephric Adenoma.  Argani P, Tickoo SK, Matoso A, Pratilas CA, Mehra R, Tretiakova M, Sibony M, Meeker AK, Lin MT, Reuter VE, Epstein JI, Gagan J, Palsgrove DN.
• Novel patient-derived models of desmoplastic small round cell tumor confirm a targetable dependency on ERBB signaling.   Smith RS, Odintsov I, Liu Z, Lui AJ, Hayashi T, Vojnic M, Suehara Y, Delasos L, Mattar MS, Hmeljak J, Ramirez HA, Shaw M, Bui G, Hartono AB, Gladstone E, Kunte S, Magnan H, Khodos I, De Stanchina E, La Quaglia MP, Yao J, Laé M, Lee SB, Spraggon L, Pratilas CA, Ladanyi M, Somwar R.
• Predictors of Recurrence and Patterns of Initial Failure in Localized Ewing Sarcoma: A Contemporary 20-Year Experience.    Stachelek GC, Ligon JA, Vogel J, Levin AS, Llosa NJ, Ladle BH, Meyer CF, Terezakis SA, Morris CD, Ladra MM, Pratilas CA.
• Chromosome 8 gain is associated with high-grade transformation in MPNST.  Dehner C, Moon CI, Zhang X, Zhou Z, Miller C, Xu H, Wan X, Yang K, Mashl J, Gosline SJ, Wang Y, Zhang X, Godec A, Jones PA, Dahiya S, Bhatia H, Primeau T, Li S, Pollard K, Rodriguez FJ, Ding L, Pratilas CA, Shern JF, Hirbe AC.