Research Overview

Dr. George is a physician scientist with a major focus on two aspects of the pediatric solid tumor neuroblastoma, identifying molecular targets that can be translated into novel therapies and understanding the perturbations that occur during development to drive neuroblastoma initiation and progression. Following the identification of activating mutations in the ALK tyrosine kinase receptor in neuroblastoma by Dr George and colleagues, her laboratory is investigating mechanisms of ALK activation and regulation in neuroblastoma as well as strategies to inhibit ALK that can be used therapeutically. The second focus of Dr. George’s laboratory is to better understand the development of the sympathetic nervous system, with particular emphasis on the PHOX2B transcription factor, a master regulator of noradrenergic differentiation and a gene that is mutated in hereditary neuroblastomas. Thirdly, Dr George's group is interested in studying the resistance mechanisms that lead to relapsed neuroblastoma and in developing early phase clinical trials for these patients. The translational research program in Dr. George’s laboratory integrates basic developmental and cancer biology, pre-clinical drug development and clinical trials targeting molecular aberrations in neuroblastoma.

Research Background

Dr. George attended medical school at A.M. Dogliotti College of Medicine, University of Liberia. She trained in pediatrics and received her PhD in cancer biology from the University of Newcastle-upon-Tyne, UK. She completed a fellowship in Pediatric Hematology/Oncology at Children’s Hospital Boston/Dana-Farber Cancer Institute. Dr. George completed her residency as a member of the Boston Combined Residency Program in Pediatrics. Research in Dr George's laboratory is funded by the National Institutes of Health, The Sidney Kimmel Foundation and the American Cancer Society.

Education

Medical School

A.M. Dogliotti College of Medicine, University of Liberia
Monrovia Liberia

Internship

John F. Kennedy Memorial Medical Center
Indio CA

Residency

Pediatrics Boston Combined Residency Program (BCRP)
Boston MA

Residency

The Royal Victoria Infirmary
Newcastle-upon-Tyne England

Fellowship

Pediatric Hematology -Oncology Boston Children's Hospital/Dana-Farber Cancer Institute
Boston MA

Fellowship

Pathology Harvard Medical School
Boston MA

Publications

  1. Artificial intelligence-based morphologic classification and molecular characterization of neuroblastic tumors from digital histopathology. NPJ Precis Oncol. 2024 Nov 08; 8(1):255. View Abstract
  2. Novel miRNA-inducing drugs enable differentiation of retinoic acid-resistant neuroblastoma cells. bioRxiv. 2024 Jul 29. View Abstract
  3. Small-molecule inhibition of the METTL3/METTL14 complex suppresses neuroblastoma tumor growth and promotes differentiation. Cell Rep. 2024 05 28; 43(5):114165. View Abstract
  4. The MYCN 5' UTR as a therapeutic target in neuroblastoma. Cell Rep. 2024 05 28; 43(5):114134. View Abstract
  5. CKLF instigates a "cold" microenvironment to promote MYCN-mediated tumor aggressiveness. Sci Adv. 2024 Mar 15; 10(11):eadh9547. View Abstract
  6. Epigenetic modulation of neuroblastoma enhances T cell and NK cell immunogenicity by inducing a tumor-cell lineage switch. J Immunother Cancer. 2022 12; 10(12). View Abstract
  7. Mesenchymal and adrenergic cell lineage states in neuroblastoma possess distinct immunogenic phenotypes. Nat Cancer. 2022 10; 3(10):1228-1246. View Abstract
  8. Synergistic Anti-Tumor Effect of Combining Selective CDK7 and BRD4 Inhibition in Neuroblastoma. Front Oncol. 2021; 11:773186. View Abstract
  9. Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration. Cell Rep. 2021 07 13; 36(2):109363. View Abstract
  10. Giotto: a toolbox for integrative analysis and visualization of spatial expression data. Genome Biol. 2021 03 08; 22(1):78. View Abstract
  11. Accelerating drug development for neuroblastoma: Summary of the Second Neuroblastoma Drug Development Strategy forum from Innovative Therapies for Children with Cancer and International Society of Paediatric Oncology Europe Neuroblastoma. Eur J Cancer. 2020 09; 136:52-68. View Abstract
  12. Formation of Human Neuroblastoma in Mouse-Human Neural Crest Chimeras. Cell Stem Cell. 2020 04 02; 26(4):579-592.e6. View Abstract
  13. MYCN amplification and ATRX mutations are incompatible in neuroblastoma. Nat Commun. 2020 02 14; 11(1):913. View Abstract
  14. Forty-five patient-derived xenografts capture the clinical and biological heterogeneity of Wilms tumor. Nat Commun. 2019 12 20; 10(1):5806. View Abstract
  15. Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma. J Clin Invest. 2019 10 01; 129(10):4377-4392. View Abstract
  16. BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells. Nature. 2019 08; 572(7771):676-680. View Abstract
  17. JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma. Nat Commun. 2019 07 25; 10(1):3319. View Abstract
  18. CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation. Nat Commun. 2019 04 15; 10(1):1757. View Abstract
  19. mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature. 2018 09; 561(7724):556-560. View Abstract
  20. Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK). J Med Chem. 2018 05 10; 61(9):4249-4255. View Abstract
  21. Overcoming Resistance to the THZ Series of Covalent Transcriptional CDK Inhibitors. Cell Chem Biol. 2018 02 15; 25(2):135-142.e5. View Abstract
  22. Super-Enhancer-Driven Transcriptional Dependencies in Cancer. Trends Cancer. 2017 04; 3(4):269-281. View Abstract
  23. Cbx3/HP1? deficiency confers enhanced tumor-killing capacity on CD8+ T cells. Sci Rep. 2017 02 21; 7:42888. View Abstract
  24. Glutathione biosynthesis is upregulated at the initiation of MYCN-driven neuroblastoma tumorigenesis. Mol Oncol. 2016 06; 10(6):866-78. View Abstract
  25. Targeting ALK: The Ten Lives of a Tumor. Cancer Discov. 2016 Jan; 6(1):20-1. View Abstract
  26. Discovery of Inhibitors That Overcome the G1202R Anaplastic Lymphoma Kinase Resistance Mutation. J Med Chem. 2015 Dec 10; 58(23):9296-9308. View Abstract
  27. TERT rearrangements are frequent in neuroblastoma and identify aggressive tumors. Nat Genet. 2015 Dec; 47(12):1411-4. View Abstract
  28. Seek and Ye Shall Find: Subclonal Anaplastic Lymphoma Kinase Mutations. Clin Cancer Res. 2015 Nov 01; 21(21):4747-9. View Abstract
  29. A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 for children with relapsed or therapy-refractory neuroblastoma and sarcoma. Cancer Immunol Immunother. 2015 Oct; 64(10):1251-60. View Abstract
  30. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell. 2014 Dec 08; 26(6):909-922. View Abstract
  31. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell. 2014 Nov 20; 159(5):1126-1139. View Abstract
  32. Molecular rationale for the use of PI3K/AKT/mTOR pathway inhibitors in combination with crizotinib in ALK-mutated neuroblastoma. Oncotarget. 2014 Sep 30; 5(18):8737-49. View Abstract
  33. Intrinsic susceptibility MRI identifies tumors with ALKF1174L mutation in genetically-engineered murine models of high-risk neuroblastoma. PLoS One. 2014; 9(3):e92886. View Abstract
  34. Distinct neuroblastoma-associated alterations of PHOX2B impair sympathetic neuronal differentiation in zebrafish models. PLoS Genet. 2013 Jun; 9(6):e1003533. View Abstract
  35. The ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell. 2012 Jul 10; 22(1):117-30. View Abstract
  36. Promising therapeutic targets in neuroblastoma. Clin Cancer Res. 2012 May 15; 18(10):2740-53. View Abstract
  37. Activated ALK collaborates with MYCN in neuroblastoma pathogenesis. Cancer Cell. 2012 Mar 20; 21(3):362-73. View Abstract
  38. Tumor histology during induction therapy in patients with high-risk neuroblastoma. Pediatr Blood Cancer. 2012 Sep; 59(3):506-10. View Abstract
  39. Emerging importance of ALK in neuroblastoma. Semin Cancer Biol. 2011 Oct; 21(4):267-75. View Abstract
  40. Discovery of 3,5-Diamino-1,2,4-triazole Ureas as Potent Anaplastic Lymphoma Kinase Inhibitors. ACS Med Chem Lett. 2011 May 12; 2(5):379-384. View Abstract
  41. Expression of the neuron-specific protein CHD5 is an independent marker of outcome in neuroblastoma. Mol Cancer. 2010 Oct 15; 9:277. View Abstract
  42. Phase I study of decitabine with doxorubicin and cyclophosphamide in children with neuroblastoma and other solid tumors: a Children's Oncology Group study. Pediatr Blood Cancer. 2010 Oct; 55(4):629-38. View Abstract
  43. Pharmacotherapy of neuroblastoma. Expert Opin Pharmacother. 2010 Jun; 11(9):1467-78. View Abstract
  44. Comparison of primary neuroblastoma tumors and derivative early-passage cell lines using genome-wide single nucleotide polymorphism array analysis. Cancer Res. 2009 May 15; 69(10):4143-9. View Abstract
  45. Anaplastic lymphoma kinase: role in cancer pathogenesis and small-molecule inhibitor development for therapy. Expert Rev Anticancer Ther. 2009 Mar; 9(3):331-56. View Abstract
  46. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature. 2008 Oct 16; 455(7215):975-8. View Abstract
  47. The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev. 2008 Apr 01; 22(7):884-93. View Abstract
  48. Neuroblastoma cells isolated from bone marrow metastases contain a naturally enriched tumor-initiating cell. Cancer Res. 2007 Dec 01; 67(23):11234-43. View Abstract
  49. Genome-wide analysis of neuroblastomas using high-density single nucleotide polymorphism arrays. PLoS One. 2007 Feb 28; 2(2):e255. View Abstract
  50. Does MYCN amplification manifested as homogeneously staining regions at diagnosis predict a worse outcome in children with neuroblastoma? A Children's Oncology Group study. Clin Cancer Res. 2006 Oct 01; 12(19):5693-7. View Abstract
  51. High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update. J Clin Oncol. 2006 Jun 20; 24(18):2891-6. View Abstract
  52. Zebrafish foxd3 is selectively required for neural crest specification, migration and survival. Dev Biol. 2006 Apr 01; 292(1):174-88. View Abstract
  53. Hyperdiploidy plus nonamplified MYCN confers a favorable prognosis in children 12 to 18 months old with disseminated neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol. 2005 Sep 20; 23(27):6466-73. View Abstract
  54. Association between congenital cardiovascular malformations and neuroblastoma. J Pediatr. 2004 Apr; 144(4):444-8. View Abstract
  55. Development of a real-time polymerase chain reaction assay for prediction of the uptake of meta-[(131)I]iodobenzylguanidine by neuroblastoma tumors. Clin Cancer Res. 2003 Aug 15; 9(9):3338-44. View Abstract

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