In our lab, we seek to understand the mechanisms that are critical for maintaining the survival of the cancer stem-like cell population responsible for metastasis, treatment-resistance, and tumor recurrence in the most common malignant brain tumor of childhood, medulloblastoma. Overall, we hope to translate our findings to novel therapeutic strategies for this brain cancer.
Dr. MacDonald first reported the platelet-derived growth factor receptor (PDGFR)-RAS/MAPK signaling pathway in medulloblastoma metastasis in 2001, Nature Genetics. Since then, his lab has explored targeting PDGFR therapeutically, and subsequently discovered STAT3 as a critical downstream mediator of survival signaling in medulloblastoma cancer stem-like cells. A Phase I clinical trial with the STAT3 inhibitor WP1066, the first in children, will begin in early 2020 for relapsed pediatric brain cancers. In addition, in collaboration with scientists at Georgia Tech, the MacDonald lab: 1) developed a microfluidic system to rapidly screen drug efficacy in real-time using patient brain tumor biopsy specimens; 2) investigating nanoparticles and focused ultrasound to improve drug delivery to brain tumors; and 3) utilizing Cluster-ChipTM technology to study circulating tumor cells in medulloblastoma. Studies to determine the precise functions of STAT3 in medulloblastoma and optimal application of STAT3 inhibitors in combination with other agents to maximize therapeutic effects are ongoing.
Hongying Zhang, PhD
Education: PhD in Molecular Biology
Current projects: The effect of ONC201/206 on the signaling pathways in medulloblastoma (MB); Study on the Stat3 signaling in medulloblastoma
Fun fact: I enjoy music and travel.
Lianyping Yuan, MD, PhD
Current Project: My current major research projects are focusing on STAT3 signaling in medulloblastoma initiation and development, exploring the interaction between STAT3 and Shh signaling, trying to elucidate the roles and mechanisms of STAT3 in Shh medulloblastoma, as well as the effect of STAT3 inhibitors to treat medulloblastoma. The final goals are to better understand the formation and development of medulloblastoma, and to provide new clinical therapeutic strategies for medulloblastoma.
Fun fact: I like to spend my free time walking in parks and watching sports games.
Kishore Kumar Jella, MS, PhD
Current Project: I will be working on neurospheres, preclinical drug testing and generating patient-derived xenografts (PDXs) from brain tumor biopsies.
Fun fact: I enjoy chatting with friends.
Bing Yu, PhD
Education: PhD, Biological and Biomedical Sciences, Emory University, 2013; BS, Biological Sciences, China Agricultural University, 2007
Current Projects: Preclinical study of novel therapeutics for MB using ex vivo brain slice culture; evaluation of pSTAT3 inhibition in the WP1006 clinical study
Fun fact: I am the dad of 130lb Labrador retriever and two lovely daughters. I love reading on my kindle and taking strolls with my dog. Olympus MFT system fanboy. Spent a year in Heidelberg, Germany at the age of 13. My favorite places to vacation are Puerto Rico and Maui, Hawaii.
Jingbo Liu, MS, MPH
Education: MPH, Umea University, Sweden, 2001; MS, Molecular Epidemiology in cardiovascular disease, Shanghai Medical University, China,1999; BS, Medical Sciences, West China Medical University, China,1985
Current Projects: Preclinical study of WP1066, NOC206 for medulloblastoma using transgenic medulloblastoma mouse models SmoA1 as well as the Tamoxifen induced medulloblastoma mouse model Math-Cre-ER-PTC flox/flox; investigating nanoparticles and focused ultrasound to improve drug delivery to brain tumors
Fun fact: I love fine art and enjoy oil painting as well as traditional Chinese painting. In 2015, two of my oil paintings were chosen for an 8 week showing at the Gwinnett County Public Library.
James Felker, MD, Pediatric Hematology/Oncology Fellow, 07/2015-06/2017, Neuro-Oncology Fellow, 07/17-06/18, Children’s Healthcare of Atlanta/Emory University
Laura Katie Williamson, MD, Pediatric Hematology/Oncology Fellow, 07/2014-06/2016, Children’s Healthcare of Atlanta/Emory University
Nicole Schlesinger McKinney, MD, Pediatric Hematology/Oncology Fellow, 07/2010-06/2012, Children’s Healthcare of Atlanta/Emory University
William Peterson, MD, Pediatric Hematology-Oncology Fellow, 07/2010-05/2013, Children’s Healthcare of Atlanta/Emory University
John Crawford, MD, Neurology Post-Doctoral Fellow 07/2005-06/2009, (NSADA Award Mentor), Children’s National Medical Center
Javad Nazarian, PhD, Genetics Post-Doctoral Fellow, 07/2005-06/2009, Children’s National Medical Center
Tamara Abou-Antoun, PhD, Graduate student, 07/2003-06/2008, George Washington University and Children’s Research Institute
Mi Rim Choi, MD, Pediatric Hematology/Oncology Fellow, 07/2005-06/2008, Children’s National Medical Center
Allesandra Jales, PhD, Graduate student, 07/2006-06/2008, George Washington University and Children’s Research Institute
Halldora Thorarinsdottir, MD, Pediatric Hematology/Oncology Fellow, 07/2004-06/2006, Children’s National Medical Center
Oren Becher, MD, Pediatric Resident, 07/2001-06/2003, Children’s National Medical Center, Washington, DC
Arun Chopra, MD, Pediatric Resident, 07/2001-06/2003, Children’s National Medical Center, Washington, DC
Soumen Khatua, MD, Pediatric Hematology/Oncology Fellow, 07/2001-06/2003, Children’s National Medical Center
Ross JL, Chen Z, Herting CJ, Grabovska Y, Szulzewsky F, Puigdelloses M, Monterroza L, Switchenko J, Wadhwani NR, Cimino PJ, Mackay A, Jones C, Read RD, MacDonald TJ, Schniederjan M, Becher OJ, Hambardzumyan D. Platelet-derived growth factor beta is a potent inflammatory driver in paediatric high-grade glioma. Brain. 2021 Feb 12;144(1):53-69. doi: 10.1093/brain/awaa382. PMID: 33300045.
Packer RJ, MacDonald TJ. Integrated analysis of pediatric low-grade glioma: clinical implications and the path forward. Neuro Oncol. 2020 Oct 14;22(10):1413-1414. doi: 10.1093/neuonc/noaa187.PMID: 32770203.
Kim J, Dey A, Malhotra A, Liu J, Ahn SI, Sei YJ, Kenney AM, MacDonald TJ, Kim Y. Engineered biomimetic nanoparticle for dual targeting of the cancer stem-like cell population in sonic hedgehog medulloblastoma. Proc Natl Acad Sci U S A. 2020 Sep 29;117(39):24205-24212. doi: 10.1073/pnas.1911229117. Epub 2020 Sep 15. PMID: 32934143.
Huang D, Liu J, Eldridge RC, Gaul DA, Paine MRL, Uppal K, MacDonald TJ, Fernández FM. Lipidome signatures of metastasis in a transgenic mouse model of sonic hedgehog medulloblastoma. Anal Bioanal Chem. 2020 Oct;412(25):7017-7027. doi: 10.1007/s00216-020-02837-9. Epub 2020 Aug 14. PMID: 32794007.
Robinson MH, Vasquez J, Kaushal A, MacDonald TJ, Velázquez Vega JE, Schniederjan M, Dhodapkar K. Subtype and grade-dependent spatial heterogeneity of T-cell infiltration in pediatric glioma. J Immunother Cancer. 2020 Aug;8(2):e001066. doi: 10.1136/jitc-2020-001066. PMID: 32788236.
Clarke M, Mackay A, Ismer B, Pickles JC, Tatevossian RG, Newman S, Bale TA, Stoler I, Izquierdo E, Temelso S, Carvalho DM, Molinari V, Burford A, Howell L, Virasami A, Fairchild AR, Avery A, Chalker J, Kristiansen M, Haupfear K, Dalton JD, Orisme W, Wen J, Hubank M, Kurian KM, Rowe C, Maybury M, Crosier S, Knipstein J, Schüller U, Kordes U, Kram DE, Snuderl M, Bridges L, Martin AJ, Doey LJ, Al-Sarraj S, Chandler C, Zebian B, Cairns C, Natrajan R, Boult JKR, Robinson SP, Sill M, Dunkel IJ, Gilheeney SW, Rosenblum MK, Hughes D, Proszek PZ, Macdonald TJ, Preusser M, Haberler C, Slavc I, Packer R, Ng HK, Caspi S, Popović M, Faganel Kotnik B, Wood MD, Baird L, Davare MA, Solomon DA, Olsen TK, Brandal P, Farrell M, Cryan JB, Capra M, Karremann M, Schittenhelm J, Schuhmann MU, Ebinger M, Dinjens WNM, Kerl K, Hettmer S, Pietsch T, Andreiuolo F, Driever PH, Korshunov A, Hiddingh L, Worst BC, Sturm D, Zuckermann M, Witt O, Bloom T, Mitchell C, Miele E, Colafati GS, Diomedi-Camassei F, Bailey S, Moore AS, Hassall TEG, Lowis SP, Tsoli M, Cowley MJ, Ziegler DS, Karajannis MA, Aquilina K, Hargrave DR, Carceller F, Marshall LV, von Deimling A, Kramm CM, Pfister SM, Sahm F, Baker SJ, Mastronuzzi A, Carai A, Vinci M, Capper D, Popov S, Ellison DW, Jacques TS, Jones DTW, Jones C. Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes. Cancer Discov. 2020 Jul;10(7):942-963. doi: 10.1158/2159-8290.CD-19-1030. Epub 2020 Apr 1. PMID: 32238360.
Erker C, Tamrazi B, Poussaint TY, Mueller S, Mata-Mbemba D, Franceschi E, Brandes AA, Rao A, Haworth KB, Wen PY, Goldman S, Vezina G, MacDonald TJ, Dunkel IJ, Morgan PS, Jaspan T, Prados MD, Warren KE. Response assessment in paediatric high-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group. Lancet Oncol. 2020 Jun;21(6):e317-e329. doi: 10.1016/S1470-2045(20)30173-X. PMID: 32502458.
Qayed, M., et al., A phase I study of sirolimus in combination with metronomic therapy (CHOAnome) in children with recurrent or refractory solid and brain tumors. Pediatr Blood Cancer, 2020. 67(4): p. e28134, 31876107.
Packer, R.J., et al., Implications of New Understandings of Gliomas in Children and Adults with NF1: Report of a Consensus Conference. Neuro Oncol, 2020, 32055852.
Kautiainen, R.J., et al., GSTP1 polymorphisms sex-specific association with verbal intelligence in survivors of pediatric medulloblastoma tumors. Child Neuropsychol, 2020: p. 1-15, 32054423.
Ahn, S.I., et al., Microengineered human blood-brain barrier platform for understanding nanoparticle transport mechanisms. Nat Commun, 2020. 11(1): p. 175, PMC6954233.
Siegel, B.I., et al., Host Genome Variation is Associated with Neurocognitive Outcome in Survivors of Pediatric Medulloblastoma. Transl Oncol, 2019. 12(7): p. 908-916, PMC6515414.
Paine, M.R.L., et al., Three-Dimensional Mass Spectrometry Imaging Identifies Lipid Markers of Medulloblastoma Metastasis. Sci Rep, 2019. 9(1): p. 2205, PMC6379434.
Dobson, T.H.W., et al., Transcriptional repressor REST drives lineage stage-specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma. Sci Signal, 2019. 12(565), 30670636.
Maximov V, Chen Z, Wei Y, Robinson MH, Herting CJ, Shanmugam NS, Rudneva VA, Goldsmith KC, MacDonald TJ, Northcott PA, Hambardzumyan D, Kenney AM. Tumour-associated macrophages exhibit anti-tumoural properties in Sonic Hedgehog medulloblastoma. Nat Commun. 2019 Jun 3;10(1):2410. doi: 10.1038/s41467-019-10458-9.PMID: 31160587.
V Foundation for Cancer Research - Circulating Tumor Cell Clusters as a Novel Biomarker for Medulloblastoma Treatment
Goals: To molecularly characterize captured circulating tumor cell clusters (CTCCs) in blood and CSF and correlate CTCC detection with clinical outcomes in medulloblastoma patients
Pediatric Brain Tumor Foundation - Optimizing Outcomes in Pediatric Low Grade Glioma
Goals: To identify genomic predispositions associated with long-term neurocognitive outcomes in children with low-grade gliomas
National Institutes of Health/Georgia Cancer Center - Augusta University - Chemo-Radio-Immunotherapy for Pediatric Brain Tumors
Goals: To conduct a Phase 2 trial of IDO-inhibitor drug indoximod in combination with chemotherapy and radiation in pediatric patients with relapsed brain tumors
Children’s Healthcare of Atlanta - Lassiter Family Innovation Fund for Brain Tumor Research
Goals: To preclinically test and develop novel therapeutics for clinical investigation for pediatric brain tumor patients
CURE Childhood Cancer - Combined CSF-1R and STAT3 Inhibition as a Novel Immunotherapeutic Strategy for Medulloblastoma
Goals: To test the effect of STAT3 inhibition on tumor associated macrophages in medulloblastoma
CURE Childhood Cancer - Employing Focused Ultrasound to Aid Therapeutic Delivery to Pediatric Brain Tumors
Goals: To determine whether focused ultrasound can facilitate transport of oncolytic virus across the blood-brain-barrier to tumor in a murine model of medulloblastoma
CURE Childhood Cancer - Phase I Trial of WP1066 for Children with Recurrent or Refractory and Progressive Malignant Brain Tumors (Clinical)
Goals: To determine the maximum tolerated dose of WP1066 that can be safely given to children
CURE Childhood Cancer - Aflac Cancer Center Precision Medicine Program
Goals: The goal is to identify and test targetable alterations in relapsed medulloblastoma
Peach Bowl LegACy Fund - Phase I Trial of WP1066 for children with recurrent or refractory and progressive malignant brain tumors (Biology)
Goals: To determine the PKs, immune and biological correlates of treatment with WP1066