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David C. Fajgenbaum, MD, MBA, MSc

David C. Fajgenbaum, MD, MBA, MSc Researcher

Assistant Professor of Medicine

Dr. Fajgenbaum is employed by Penn Medicine.

Clinical Specialties

Specialty:

  • Medical Genetics

Programs & Centers:

Memberships

ACCELERATE Steering Committee: a collaborative partnership between University of Pennsylvania, Castleman Disease Collaborative Network, and Janssen Pharmaceuticals, International American Society of Hematology, National Castleman Disease Collaborative Network, International Heal Grief, International Medici Oncology Initiative Advisory Council, International Medidata Strategic Advisory Board, International NIH, NCATS Office for Rare Diseases Research, Toolkit Project, National Rare Disease Diagnostic Consortium, National

Hospital Affiliation

Dr. Fajgenbaum is employed by Penn Medicine.

Research

Description of Research Expertise:

Research interests:
Elucidating the etiology, dysregulated cell types, signaling pathways, and effector cytokines in idiopathic multicentric Castleman disease (iMCD) and related cytokine storm disorders; identifying effective treatments for iMCD patients; PI3K/Akt/mTOR signaling in iMCD; role of stromal cells and chemokines in iMCD

Keywords:
IL-6, cytokine storm, stromal cells; chemokines, PI3K/Akt/mTOR

Research summary:
1) Elucidating the etiology, dysregulated cell types, signaling pathways, and effector cytokines in idiopathic multicentric Castleman disease (iMCD) and related cytokine storm disorders
iMCD is a poorly-understood and deadly hematologic disorder. A proinflammatory cytokine storm and reactive lymphoproliferation occur for an unknown etiology. The poor understanding of etiology and pathogenesis has limited the development of effective treatments and contributed to the significant morbidity and mortality associated with iMCD (55-77% 5-year overall survival). Currently, we leverage a variety of techniques to study the etiology and pathogenesis of iMCD. In addition, we leverage a biobank (CastleBank) to collect samples to fuel our translational research.

2) Identifying effective treatments for iMCD patients
The poor understanding of iMCD pathogenesis has slowed the development of treatment approaches. Currently, there is only one FDA-approved treatment for iMCD, which is effective in approximately one-third or patients. We run an international Natural History Study of Castleman Disease (ACCELERATE) to collect in-depth data on patients around the world to identify effective treatment approaches currently being used off-label.

3) PI3K/Akt/mTOR signaling in iMCD
Proteomic, flow cytometric, and immunostaining studies revealed upregulation of Vascular Endothelial Growth Factor (VEGF), activated CD8+ T cells, and uncontrolled PI3K/Akt/mTOR signaling in iMCD. Whole genome sequencing of an iMCD patient and both parents revealed rare compound heterozygous missense mutations in both alleles of a negative regulator of T cell activation and a candidate etiological mechanism. These novel findings led to the first-ever use of sirolimus in iMCD and a prolonged remission for a refractory patient (manuscript in submission). Drawing upon the world’s largest collection of iMCD patients and their biospecimens in ACCELERATE, we are employing whole genome sequencing, transcriptomics, proteomics, flow cytometry and phospho-flow, and cellular signaling assays to continue to elucidate the role of PI3K/Akt/mTOR signaling in iMCD. As there are no animal models, we are also performing extensive correlative studies to quantify changes in VEGF, T cell activation, PI3K/Akt/mTOR signaling, and other immunological markers following in vivo sirolimus administration to patients and documenting treatment efficacy.

4) Investigating the role of stromal cells and chemokines in iMCD
Quantification of 1,129 plasma proteins in iMCD revealed highly up-regulated acute phase reactants and chemokines. The chemokines that were most upregulated are essential for normal lymph node morphology/function and typically produced by lymph node stromal cells. The most up-regulated chemokine, CXCL13, is responsible for homing B cells into the germinal center. This is interesting, because the pathological hallmark of iMCD is dysmorphic lymph node germinal centers with either too few (atrophic) or too many B cells (hyperplastic). Immunohistochemistry confirmed significantly increased germinal center expression of CXCL13. We are exploring the mechanisms of lymph node stromal cell activation and chemokine signaling.

Rotation Projects are available in all areas

Lab personnel:
Dustin Shilling, PhD, Associate Director
Sheila Pierson, MS, Biostatistician
Rozena Rasheed, Biobank Coordinator
Katherine Floess, Data Analyst
Johnson Khor, Data Analyst
Jasira Ziglar, Data Analyst
Dale Kobrin, Biomedical Leadership Fellow
Curran Reilly, Biomedical Leadership Fellow
Ruth-Anne Langan, PhD student

Selected Publications:

Sheila K. Pierson, Aaron J. Stonestrom, Dustin Shilling, Jason Ruth, Christopher S. Nabel, Amrit Singh, Yue Ren, Katie Stone, Hongzhe Li, Frits van Rhee, David C. Fajgenbaum: Plasma proteomics identifies a 'chemokine storm' in idiopathic multicentric Castleman disease American Journal of Hematology. 93 (7): 902-912,2018.

David C. Fajgenbaum & Dustin Shilling: Castleman Disease Pathogenesis Chapter in: Hematology/Oncology Clinics of North America: Castleman’s Disease. 32 (1): 11-21,2018.

Eric Oksenhendler, David Boutboul, David C. Fajgenbaum, Adrien Mirouse, Claire Fieschi, Marion Malphettes, Laetitia Vercellino, Véronique Meignin, Laurence Gérard, Lionel Galicier: The full spectrum of Castleman Disease: 273 patients studied over 20 years British Journal of Hematology. 180 (2): 206-216,2018.

David C. Fajgenbaum, Thomas S. Uldrick, Adam Bagg, Dale Frank, David Wu, Gordan Srkalovic, David Simpson, Amy Y. Liu, David Menke, Shanmuganathan Chandrakasan, Mary Jo Lechowicz, Raymond S.M. Wong, Sheila Pierson, Michele Paessler, Jean-François Rossi, Makoto Ide, Jason Ruth, Michael Croglio, Alexander Suarez, Vera Krymskaya, Amy Chadburn, Gisele Colleoni, Sunita Nasta, Raj Jayanthan, Christopher S. Nabel, Corey Casper, Angela Dispenzieri, Alexander Fosså, Dermot Kelleher, Razelle Kurzrock, Ahmet Dogan: International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease Blood. 129 (12): 1646-1657,2017.

Li Yu, Meifeng Tu, Jorge Cortes, Zijun Y. Xu-Monette, Roberto N. Miranda, Jun Zhang, Robert Z. Orlowski, Sattva Neelapu, Prajwal C. Boddu, Mary A. Akosile, Thomas S. Uldrick, Robert Yarchoan, L. Jeffrey Medeiros, Yong Li, David C. Fajgenbaum, Ken H. Young: Clinical and pathological characteristics of HIV- and HHV8- negative Castleman disease Blood. 129 (12): 1658-1668,2017.

Céline Louis, Sandrine Vijgen, Kaveh Samii, Yves Chalandon, Louis Terriou, David Launay, David C. Fajgenbaum, Jörg D. Seebach, Yannick D. Muller: TAFRO Syndrome in Caucasians: A Case Report and Review of the Literature Frontiers in Medicine. 4 : 149,2017.

David C. Fajgenbaum, Jason R. Ruth, Dermot P. Kelleher, Arthur H. Rubenstein: The Collaborative Network Approach: A New Framework to Accelerate Castleman Disease and Other Rare Disease Research The Lancet Haematology. 3 (4): 150-152,2016.

Noriko Iwaki, David C. Fajgenbaum, Christopher S. Nabel, Yuka Gion, Eisei Kondo, Mitsuhiro Kawano, Taro Masunari, Isao Yoshida, Hiroshi Moro, Koji Nikkuni, Kazue Takai, Kosei Matsue, Mitsutoshi Kurosawa, Masao Hagihara, Akio Saito, Masataka Okamoto, Kenji Yokota, Shinichiro Hiraiwa, Naoya Nakamura, Shinji Nakao, Tadashi Yoshino, Yasuharu Sato: Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease American Journal of Hematology. 91 (2): 220-226,2016.

Amy Y. Liu, Christopher S. Nabel, Brian S. Finkelman, Jason R. Ruth, Razelle Kurzrock, Frits van Rhee, Vera P. Krymskaya, Dermot P. Kelleher, Arthur H. Rubenstein, David C. Fajgenbaum: Idiopathic Multicentric Castleman's Disease: A Systematic Literature Review The Lancet Haematology. 3 (4): 163-175,2016.

David C. Fajgenbaum, Frits van Rhee, Chris Nabel: HHV-8-negative, idiopathic multicentric Castleman disease: novel insights into biology, pathogenesis, and therapy Blood. 123 : 2924-2933,2014.

View all publications

Academic Contact Info

Hospital of the University of Pennsylvania (HUP)
Division of Medical Genetics
5th Floor Silverstein, Suite S05094
3400 Spruce Street

Philadelphia, PA 19104