Photo of Cigall Kadoch,  PhD

Cigall Kadoch, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute


cigall_kadoch@dfci.harvard.edu

Cigall Kadoch, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Assistant Professor, Pediatrics, Harvard Medical School
  • Assistant Professor, Pediatric Oncology, Dana-Farber Cancer Institute
  • Principal Investigator, Pediatric Oncology, Dana-Farber Cancer Institute
  • Institute, Chemical Biology, Broad Institute of MIT and Harvard

DF/HCC PROGRAM AFFILIATION

Research Abstract

Recent whole-genome sequencing studies of human cancers have heralded the discovery of several new, surprising classes of genes not previously known to play causal roles in cancer. One of the most significant findings unveiled in these genomic studies is the high mutation frequency in genes involved in epigenomic and chromatin biology-based processes. The most frequent and wide-spread among them are mutations in the genes encoding subunits of the mSWI/SNF (BAF) ATP-dependent chromatin remodeling complexes, which we recently determined to be broadly recurrent in >20% of all human cancers (Kadoch et al, Nature Genetics 2013). To investigate the underlying mechanism, we have studied a rare, genomically well-defined cancer type, human synovial sarcoma (SS) in which 100% of tumors have a precise translocation involving a specific subunit, SS18, indicating that the translocation is the initiating oncogenic event. The utility of this disease setting has provided us with a powerful foundation toward understanding the oncogenic mechanisms directed by altered chromatin remodeling complexes. We showed that perturbation via the SS18-SSX fusion usurps BAF complex protein subunit composition, and that this restructuring mistargets complexes to specific oncogenic loci to drive proliferation (Kadoch and Crabtree, Cell 2013). Excitingly, we demonstrate the dynamic reversibility of this process in this setting and extend these approaches and findings to other cancer types with BAF complex mutations.

The central focus of our laboratory is to understand BAF complex pathway-of-assembly, to determine the complex subunit and associated protein factor composition of oncogenic BAF complexes, and to define the mechanistic basis of locus-specific and genome-wide retargeting. These key goals build upon our unique expertise at the border of biochemistry and chromatin regulation, and create for a new synthesis of concepts and methodologies as novel strategies to target a broad range of human cancers.

 

Publications

Powered by Harvard Catalyst
  • Kadoch C, Li J, Wong VS, Chen L, Cha S, Munster PN, Lowell CA, Shuman MA, Rubenstein JL. Complement Activation and Intraventricular Rituximab Distribution in Recurrent Central Nervous System Lymphoma. Clin Cancer Res 2013. PubMed
  • Rubenstein JL, Wong VS, Kadoch C, Gao HX, Barajas R, Chen L, Josephson SA, Scott B, Douglas V, Maiti M, Kaplan LD, Treseler PA, Cha S, Hwang JH, Cinque P, Cyster JG, Lowell C. CXCL13 plus interleukin 10 is highly specific for the diagnosis of CNS lymphoma. Blood 2013; 121:4740-8. PubMed
  • Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, Crabtree GR. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet 2013; 45:592-601. PubMed
  • Kadoch C, Crabtree GR. Reversible disruption of mSWI/SNF (BAF) complexes by the SS18-SSX oncogenic fusion in synovial sarcoma. Cell 2013; 153:71-85. PubMed
  • Rubenstein JL, Li J, Chen L, Advani R, Drappatz J, Gerstner E, Batchelor T, Krouwer H, Hwang J, Auerback G, Kadoch C, Lowell C, Munster P, Cha S, Shuman MA, Damon LE. Multicenter phase 1 trial of intraventricular immunochemotherapy in recurrent CNS lymphoma. Blood 2013; 121:745-51. PubMed
  • Algazi AP, Kadoch C, Rubenstein JL. Biology and treatment of primary central nervous system lymphoma. 2009; 6:587-97. PubMed
  • Kadoch C, Dinca EB, Voicu R, Chen L, Nguyen D, Parikh S, Karrim J, Shuman MA, Lowell CA, Treseler PA, James CD, Rubenstein JL. Pathologic correlates of primary central nervous system lymphoma defined in an orthotopic xenograft model. Clin Cancer Res 2009; 15:1989-97. PubMed
  • Rubenstein JL,Shen A,Batchelor TT,Kadoch C,Treseler P,Shuman MA. Differential gene expression in central nervous system lymphoma. Blood 2009; 113:266-7; author reply 267-8. PubMed
  • Roy S, Josephson SA, Fridlyand J, Karch J, Kadoch C, Karrim J, Damon L, Treseler P, Kunwar S, Shuman MA, Jones T, Becker CH, Schulman H, Rubenstein JL. Protein biomarker identification in the CSF of patients with CNS lymphoma. J Clin Oncol 2007; 26:96-105. PubMed
  • Kadoch C, Treseler P, Rubenstein JL. Molecular pathogenesis of primary central nervous system lymphoma. Neurosurg Focus 2006; 21:E1. PubMed
  • Kadoch C, D'Amico AV, Matthews RH. When prostate brachytherapy fails: a case report and discussion. Oncologist 2005; 10:799-805. PubMed