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Dennis Patrick Meehan Hughes, M.D., Ph.D.

Present Title & Affiliation

Primary Appointment

Associate Professor, Department of Pediatrics - Research, Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX

Dual/Joint/Adjunct Appointment

Graduate Faculty, The University of Texas Graduate School of Biomedical Sciences, Houston, TX

Bio Statement

Dennis Hughes, MD, PhD, a graduate of the MD/PhD (MSTP) Program at Yale University, is Associate Professor of Pediatrics at MD Anderson Cancer Center. He has received numerous awards as a clinician and researcher, including being named to the Best Doctors in America, America’s Top Oncologists and America’s Top Pediatricians. He is the national PI for a first-in-children phase I evaluation of panitumumab in pediatrics, and is a member of the Bone Tumor Biology Sub-committee for the Children’s Oncology Group.  As a physician-scientist, he focuses on osteosarcoma, both in the clinic and the laboratory. He is a pediatric oncologist with the Children’s Cancer Hospital at MD Anderson Cancer Center, and his clinical practice is limited to children with bone tumors such as osteosarcoma and to children with melanoma. His laboratory investigates mechanisms of metastasis and therapy resistance in osteosarcoma, focusing particularly on cell signaling and pathways that may be targets of small molecule medicines, especially the Notch and ERBB signaling pathways. Since Notch is difficult to target with inhibitory therapies, his laboratory is exploring the regulation of this pathway in sarcoma, both upstream and downstream of Notch itself, seeking better therapeutic targets.  Building on their success in these investigations in osteosarcoma, the laboratory now is evaluating these same targets in other solid tumors such as Ewing sarcoma, Neuroblastoma and GIST. In the laboratory, Dr. Hughes has supervised four graduate students, 5 postdoctoral fellows, 4 medical student researchers and 6 undergraduate researchers. He is a frequent lecturer in graduate student courses, especially the Cancer Cell Signaling Course of the GSBS, and has served on 11 graduate student advisory, examining and supervisory committees, including 5 for MD/PhD students.  He also lectures at other institutions, both about his laboratory research and about pediatric melanoma, prevention and sun safety for children and teens.

Research Interests

 

My laboratory investigates mechanisms of metastasis and therapy resistance in osteosarcoma, focusing particularly on cell signaling and pathways that may be targets of small molecule medicines, especially the Notch and ERBB signaling pathways. Within the ERBB pathway, we are evaluating the hypothesis that pan-ERBB inhibition will be more effective therapeutically for osteosarcoma than would selective inhibitors, due to redundant signaling mechanisms and unique functions of Her-4 in this disease. With the focus on Her-4, we are exploring its unique contributions to chemotherapy resistance and the specific relationship Her-4 has to anchorage-independent growth and anoikis resistance.   

 

We also maintain a focus on the role of notch in sarcoma. Our published work demonstrates a role for Notch pathway expression in promoting invasion and metastasis in osteosarcoma, and we currently are extending these studies to other sarcomas. Since Notch is difficult to target with inhibitory therapies, we are exploring the regulation of this pathway in sarcoma, both upstream and downstream of Notch itself, seeking better therapeutic targets. Our latest data suggests that Metadherin is essential for osteosarcoma invasion and metastasis and may be an outstanding candidate for novel therapies. Our overall goal for these studies, both with ERBB and Notch, is to identify new approaches for osteosarcoma therapy that exploit unique aspects of sarcoma biology.

 

Clinical Interests

Osteosarcoma, Pediatric Melanoma, Pediatric GIST, Desmoid tumor, other solid tumors of childhood.

Education & Training

Postgraduate Training

2/2003-8/2004 Lecturer/Research Fellow, Sarcoma Correlative Sciences Laboratories, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI
7/2000-1/2003 Research Fellow, Retroviral/Genetic Immunotherapy, Tumor Immunity Program, University of Michigan, Ann Arbor, MI
7/1999-6/2002 Fellowship, Pediatric Hematology/Oncology, University of Michigan Medical Center, Ann Arbor, MI
7/1997-6/1999 Residency, Pediatrics, University of Vermont - Fletcher Allen, Burlington, VT
6/1996-6/1997 Internship, Pediatrics, University of Vermont - Fletcher Allen, Burlington, VT

Experience/Service

Academic Appointments

Assistant Professor, Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX, 9/2004-8/2011

Administrative Appointments/Responsibilities

Co-Director, MD-PhD Program, University of Texas Health Science Center at Houston, Houston, TX, 7/2007-present

Institutional Committee Activities

Member, Institutional Research Grants Study Section, 2007-2010
Member, Advisory Board, The Jori Zemel Children's Bone Cancer Foundation, Clear Lake, Texas, 1/2005-9/2011

Honors and Awards

2010-present America's Top Pediatricians
2010 Nöllenburg Prize - Basic Science Award, 42nd Congress of the International Society of Paediatric Oncology Meeting
2007-2010 Physicians Scientist Award, University of Texas MD Anderson Cancer Center
1984-1988 University of Notre Dame Scholar

Professional Memberships

American Association for Cancer Research
Member, 2003-present
American Society of Clinical Oncology
Member, 2001-present
American Society of Pediatric Hematology/Oncology
Member, 2002-present
Children's Oncology Group
Associate Member, 2002-present
Connective Tissue Oncology Society
Member, 2004-present

Selected Publications

Peer-Reviewed Original Research Articles

1. Hu J, Liu X, Hughes D, Esteva FJ, Liu B, Chandra J, Li S. Herceptin conjugates linked by EDC boost direct tumor cell death via programmed tumor cell necrosis. PLoS One 6(8):223270.doi:10.1371/journal.pone.0023270, 2011. e-Pub 8/2011. PMCID: PMC3154407.
2. Richards KN, Zweidler-McKay PA, Van Roy N, Speleman F, Trevino J, Zage PE, Hughes DP. Signaling of ERBB Receptor Tyrosine Kinases Promotes Neuroblastoma Growth in vitro and in vivo. Cancer 116(13):3233-43, 7/2010. PMCID: PMC2923448.
3. Geryk-Hall M, Yang Y, Hughes DP. Driven to Death: Inhibition of Farnesylation Increases Ras Activity in Osteosarcoma and Promotes Growth Arrest and Cell Death. Mol Cancer Ther 9(5):1111-9, 5/2010. e-Pub 4/2010. PMCID: PMC2868119.
4. Zhang P, Yang Y, Nolo R, Zweidler-McKay PA, Hughes DP. Regulation of NOTCH signaling by reciprocal inhibition of HES1 and DTX1 and its role in osteosarcoma invasiveness. Oncogene 29(20):2916-26, 5/2010. e-Pub 3/2010. PMCID: PMC2874642.
5. Hughes DP. Strategies for the targeted delivery of therapeutics for Osteosarcoma. Expert Opin Drug Deliv 6(12):1311-21, 12/2009. PMID: 19761419.
6. Geryk-Hall M, Hughes DP. Critical signaling pathways in bone sarcoma: candidates for therapeutic interventions. Curr Oncol Rep 11(6):446-53, 11/2009. PMID: 19840522.
7. Hughes DP. Novel agents in development for pediatric sarcomas. Curr Opin Oncol 21(4):332-7, 7/2009. PMID: 19444103.
8. Nikolova DA, Asangani IA, Nelson LD, Hughes DP, Siwak DR, Mills GB, Harms A, Buchholz E, Pilz LR, Manegold C, Allgayer H. Cetuximab attenuates invasion, metastasis, and u-PAR gene expression in non small-cell lung cancer (NSCLC), and u-PAR, besides E-cadherin, is a novel biomarker of Cetuximab sensitivity. Cancer Res 69(6)(6):2461-70, 3/2009. e-Pub 3/2009. PMID: 19276367.
9. Zhu L, Zhang P, Yang Y, Buford AS, Wang WL, Thomas DG, Hughes, DPM. How the NOTCH Pathway contributes to the Ability of Osteosarcoma Cells to Metastasize. Cancer treat res 152:479-96, 1/2009. PMID: 20213410.
10. Anderson P, Kornguth D, Ahrar K, Hughes D, Phan P, Huh W, Cornelius K, Mahajan A. Recurrent, Refractory, Metastatic, and/or Unresectable Pediatric Sarcomas: Treatment Options for Young People that are "Off the Roadmap". Pediatric Health 2(5):605-615, 10/2008.
11. Zhang P, Yang Y, Zweidler-McKay PA, Hughes DP. A critical role of Notch signaling in osteosarcoma invasion and metastasis. Clin Cancer Res 14(10):2962-2969, 5/2008. PMCID: PMC2830718.
12. Mahajan A, Woo SY, Kornguth DG, Hughes D, Huh W, Chang EL, Herzog CE, Pelloski CE, Anderson P. Multimodality treatment of osteosarcoma: radiation in a high-risk cohort. Pediatr Blood Cancer 50(5):976-982, 5/2008. PMID: 18213710.
13. Li S, Yang J, Urban FA, MacGregor JN, Hughes DP, Chang AE, McDonagh KT, Li Q. Genetically engineered T cells expressing a HER2-specific chimeric receptor mediate antigen-specific tumor regression. Cancer Gene Ther 15(6):382-392, 2008. PMID: 18292797.
14. Lemme SD, Kevin Raymond A, Cannon CP, Normand AN, Smith KC, Hughes DP. Primary tuberculosis of bone mimicking a lytic bone tumor. J Pediatr Hematol Oncol 29(3)(3):198-202, 3/2007. PMID: 17356403.
15. Mensah-Osman EJ, Thomas DG, Tabb MM, Larios JM, Hughes DP, Giordano TJ, Lizyness ML, Rae JM, Blumberg B, Hollenberg PF, Baker LH. Expression levels and activation of a PXR variant are directly related to drug resistance in osteosarcoma cell lines. Cancer 109:957-65, 2007. PMID: 17279585.
16. Hughes DPM, Thomas DG, Giordano TJ, McDonagh KT, Baker LH. Essential erbB family phosphorylation in osteosarcoma as a target for CI-1033 inhibition. Pediatr Blood Cancer 46:614-623 2006 Published Online: 8 Jul 2005, 2006. PMID: 16007579.
17. Macgregor JN, Li Q, Chang AE, Braun TM, Hughes DPM, McDonagh KT. Ex vivo culture with interleukin (IL)-12 improves CD8(+) T-cell adoptive immunotherapy for murine leukemia independent of IL-18 or IFN-gamma but requires perforin. Cancer Res 66:4913-4921, 2006. PMID: 16651448.
18. Hughes DPM. Protein Lysate array assessment of therapeutic targets in sarcoma. European Journal of Cancer 4(6):24, 2006.
19. Hughes DPM, Baskar D, Urban FF, Friedman MS, Braun TM, McDonagh KT. Fate and function of anti-CD3/CD28-activated T cells following adoptive transfer: IL-2 promotes development of anti-tumor memory T cells in vivo. Cytotherapy 7(5):396-407, 2005. PMID: 16236629.
20. Hughes DPM, Thomas DG, Giordano TJ, Baker LH, McDonagh KT. Cell surface expression of epidermal growth factor receptor and Her-2 with nuclear expression of Her-4 in primary osteosarcoma. Cancer Res 64(6):2047-2053, 2004. PMID: 15026342.
21. Li SP, Urban FA, Macgregor JN, Hughes DP, McDonagh KT. Chimeric T cell receptor N29gamma redirect T lymphocytes response specific to p185HER2 in A murine model of metastatic breast cancer]. Ai Zheng 23(11 Suppl):1370-5, 2004. PMID: 15566639.
22. Hong R, Shen V, Rooney C, Hughes DPM, Smith C, Comoli P, Zhang L. Correction of DiGeorge anomaly with EBV-induced lymphoma by transplantation of organ-cultured thymus and Epstein-Barr-specific cytotoxic T lymphocytes. Clin Immunol 98(1):54-61, 2001. PMID: 11141327.
23. Peng SL, Madaio MP, Hughes DPM, Crispe IN, Owen MJ, Wen L, Hayday AC, Craft J. Murine lupus in the absence of alpha beta T cells. J Immunol 156:4041-4049, 1996. PMID: 8621947.
24. Hughes DPM, Crispe IN. A naturally occurring soluble isoform of murine Fas generated by alternative splicing. J Exp Med 182(5):1395-1401, 1995. PMCID: PMC2192224.
25. Hughes DPM, Hayday A, Craft JE, Owen MJ, Crispe IN. T cells with gamma/delta T cell receptors (TCR) of intestinal type are preferentially expanded in TCR-alpha-deficient lpr mice. J Exp Med 182(1):233-241, 1995. PMCID: PMC2192080.

Invited Articles

1. Anderson P, Kopp L, Anderson N, Cornelius K, Herzog C, Hughes D, Huh W. Novel Bone Cancer Drugs: Investigational Agents and Control Paradigms for Bone Sarcomas. Expert Opinion on Investigational Drugs 17(11):1703-15, 2008. PMID: 18922107.

Book Chapters

1. Hughes DPM, Levine J. Immunotherapeutic approaches to the HSCT patient. In: Pediatric Bone Marrow Transplantation Kline RM (ed). Marcel Dekker, Inc. New York, 2005.
2. Hughes DPM, Levine J. Immunotherapy options for relapse after BMT. In: Pediatric Stem Cell Transplantation. Mehta P (ed), Janes and Bartlett Publishers, Inc. Sudbury, MA, 2003.

Grant & Contract Support

Title: Her-4 mediates tumor cell survival and chemoresistence
Funding Source: NIH/NCI
Role: Principal Investigator
Duration: 4/1/2012 - 3/31/2017
 
Title: Her-4 mediates tumor cell survival and chemoresistance
Funding Source: Cancer Prevention & Research Institute of Texas (CPRIT)
Role: Principal Investigator
Duration: 12/1/2011 - 11/30/2014
 
Title: Regulation of osteosarcoma metastasis by Notch and Hes1 Pathway Signaling
Funding Source: NIH/NCI
Role: Principal Investigator
Duration: 9/13/2011 - 7/31/2016
 
Title: Preclinical evaluation of erbb family members as therapeutic targets of osteosarcoma
Funding Source: National Cancer Institute (DHHS-NIH)
Role: Principal Investigator
Duration: 9/1/2010 - 2/28/2015
 
Title: Pharmacological and Genetic Blockade of Hes1 in Osteosarcoma Suppresses Invasiveness and Metastasis In Vitro and In Vivo
Funding Source: Hope Street Kids Fellowship
Role: Principal Investigator
Duration: 7/1/2007 - 6/30/2009
 
Title: Physicians Scientist Award
Funding Source: University of Texas MD Anderson Cancer Center
Role: Principal Investigator
Duration: 4/1/2007 - 5/31/2010
 
Title: Ras-mediated erbB Signaling in Osteosarcoma
Funding Source: NIH/NCI
Role: Principal Investigator
Duration: 9/24/2006 - 5/31/2011
 
Funding Source: Jori Zemel Children's Bone Cancer Foundation: Zemel Scholar Award
Role: Mentor of Scholars
Duration: 12/1/2005 - 6/30/2009
 
Funding Source: Mike Doiron Legends of Friendswood Foundation
Role: Principal Investigator
Duration: 10/1/2005 - 9/30/2006
 
Title: Antigenic threshold for a Her-2-specific chimeric TCR
Funding Source: Children's Health Research Center Grant, University of Michigan, Department of Pediatric,
Role: Principal Investigator
Duration: 9/1/2003 - 8/31/2004
 
Title: Adoptive Immunotherapy for GD2-expressing Osteosarcoma
Funding Source: Translational Research Program of the Group Chair's Development Fund
Role: Principal Investigator
Duration: 2/1/2003 - 11/30/2003
 
Title: Adoptive Immunotherapy for GD2-expressing Osteosarcoma
Funding Source: John and Suzanne Munn Research Grant
Role: Principal Investigator
Duration: 1/1/2003 - 1/1/2004
 
Title: Research Award, Evan Shapiro Fund to Combat Pediatric Cancer, Her-2 and EGFR family member expression in pediatric sarcomas
Funding Source: University of Michigan Comprehensive Cancer Center
Role: Co-Investigator
Principal Investigator: Gregory Yanik
Duration: 7/1/2002 - 8/31/2004
 
Title: Genetic immunotherapy for malignancy: murine modeling
Funding Source: National Institutes of Health, Individual NRSA Training Award National Institutes of Health
Role: Principal Investigator
Duration: 7/1/2002 - 6/30/2004

Last updated: 5/15/2014