Genetic Drivers of Pediatric and Young Adult High-Grade Glioma and DIPG

Our lab is studying the molecular mechanisms by which mutations in high-grade glioma (HGG,  including glioblastoma (GBM) and  diffuse intrinsic pontine glioma (DIPG),  affect response to therapy. As an example, we developed an animal model of ATRX-deficient GBM. ATRX is a histone chaperone protein that is mutated in a large number of adolescent GBMs. Data from the project demonstrated the role of ATRX in GBM tumor progression, treatment response and loss of tumor genetic stability.  This work provided a platform for future development of targeted therapy for patients with ATRX-deficient GBM.  Additionally,we have studied mechanisms of tumor progression, DNA damage repair, and epigenetic regulation in animal models of GBM. Through this work, we have developed a program of translational research to improve therapies for pediatric and young adult HGG and DIPG.

Selected publications:

  1. Koschmann C, Calinescu AA, Nunez FJ, Mckay A, Fazal Salom J, Thomas D, Mulpuri L, Kamran N, Mendez F, Dzaman M, Krasinkiewicz J, Doherty R, Lemons R, Brosnan-Cashman J, Li Y, Roh S, Zhao L, Ferguson D, Appelman H, Gorbunova V, Meeker A, Jones C, Lowenstein PR and Castro MC (2016).  ATRX loss promotes tumor growth and impairs non-homologous end joining DNA repair in glioma.  Science Transl Med. 8 (328), 328ra28.
  2. Kamran N, Calinescu C, Candolfi M, Mineharu Y, Assad A, Koschmann C, Nunez FJ, Lowenstein PR and Castro MG (2016).  Recent advances and future of immunotherapy for glioblastoma. Expert Opin Biol Ther.  2016 Oct;16(10):1245-64.
  3. Koschmann C, Lowenstein PR and Castro MC (2016).  ATRX Mutations and Glioblastoma: Impaired DNA Damage Repair, Alternative Lengthening of Telomeres, and Genetic Instability.  Molecular and Cellular Oncology. 2016 Apr 27;3(3):e1167158.
  4. Calinescu A, Aguillera Nunez F, Koschmann C, Kolb B, Lowenstein PR, and Castro MC (2015).  Transposon mediated integration of plasmid DNA into the subventricular zone of neonatal mice to generate novel models of glioblastoma.  J Vis Exp. 2015 Feb 22;(96).
  5. Koschmann C, Nunez FJ, Mendez F, Brosnan-Cashman J, Meeker A, Lowenstein PR and Castro MG (2017).  Mutated chromatin regulatory factors as tumor drivers in cancer.  Cancer Research. 2017 Jan 15;77(2):227-233.

Precision Medicine in Pediatric Neuro-Oncology

We are currently pursuing translational and clinical research projects in precision medicine in Pediatric Oncology and Neuro-Oncology. Along with clinicians and researchers at the University of Michigan, we have created a program in which pediatric and adult glioma samples are used to generate novel primary cell cultures. We use these cell cultures to study mechanisms of glioma growth and targeted treatment response. As a co-investigator in the MiOncoseq Research Program (PIs Chinnayain/Mody), we pair DNA/RNA sequencing of the patient’s tumor, germline and, primary tumor cell cultures with the development of targeted therapies. These results are presented in the multi-disciplinary and multi-institutional UM CNS Precision Medicine conference.  

In addition, we are developing a clinical phase 2 study trial that incorporates precision medicine with blood brain barrier optimization for children with high-grade glioma (including DIPG) at diagnosis and relapse, for which out lab will lead the biologic correlative research. 

Selected Publications:

  1. Koschmann C, Zamler D, MacKay A, Robinson D, Wu YM, Doherty R, Marini B, Tran D, Garton H, Muraszko K, Robertson P, Leonard M, Zhao L, Bixby D, Peterson L, Camelo-Piragua S, Jones C, Mody R, Lowenstein PR, Castro MG. Characterizing and targeting PDGFRA alterations in pediatric high-grade glioma. Oncotarget. 2016 Aug 25. 
  2. Bruzek A, Zureick, A, Mc Keever P, Garton, H, Robertson, P., Mody R, and Koschmann C (2016). Molecular characterization reveals NF1 loss and FGFR1 activating mutation in a pediatric spinal oligodendroglioma.  Pediatric Blood and Cancer.  2016 Nov 10. 
  3. Rogawski S, Vitanza N, Gauthier A, Ramaswamy V, and Koschmann C (2017). Integrating RNA sequencing into neuro-oncology practice.  Translational ResearchIn Press.
  4. Shao L, Miller S, Koschmann C, Camelo-Piragua S. Whole genome SNP array improves diagnosis and therapy in pediatric brain tumors.  International Journal of Surgical PathologyIn Press. 
  5. Marini B, Benitez L, Zureick A, Salloum R, Gauthier A, Brown J, Wu Y, Robinson D, Kumar C, Lonigro R, Vats P, Cao X, Kasaian K, Anderson B, Mullan B, Chandler B, Linzey J, Camelo-Piragua S, Venneti S; Mc Keever P, McFadden K, Lieberman A, Brown N, Shao L, Leonard M; Junck L, McKean E, Maher C, Garton H, Muraszko K, Hervey-Jumper S, Mulcahy-Levy J, Greem A, Hoffman L, Dorris K, Vitanza N, Wang J, Schwartz J, Lulla R, Pillay Smiley N, Bornhorst M, Haas-Kogan D, Robertson P, Chinnaiyan A, Mody R and Koschmann C. Blood brain barrier-adapted precision medicine therapy for pediatric brain tumors. Translational Research.  In Press.
  6. Linzey J, Marini B, McFadden K, Lorenzana A, Mody R, Robertson P and Koschmann C. Identification and targeting of a novel FGFR fusion in a pediatric thalamic “central oligodendroglioma.” npj Precision Oncology.  In Press.
  7. Koschmann C, Farooqui Z, Kasaian K, Cao X, Zamler D, Stallard S, Venneti S, Hervey-Jumper S, Garton H, Muraszko K, Franchi L, Robertson P, Leonard M, Opipari V, Castro M, Lowenstein P, Chinnaiyan A, and Mody R. Multi-focal sequencing of a diffuse intrinsic pontine glioma establishes PTEN loss as a driving event. npj Precision Oncology.  In Press.