Biomedical Graduate Studies

Description of Other Expertise

David Fajgenbaum, MD, MBA, MSc, FCPP, is an Associate Professor of Medicine in Translational Medicine & Human Genetics at the University of Pennsylvania, Founding Director of the Center for Cytokine Storm Treatment & Laboratory (CSTL), Co-Founder and President of Every Cure, and Co-Founder and President of the Castleman Disease Collaborative Network (CDCN). He is also the national bestselling author of 'Chasing My Cure: A Doctor's Race to Turn Hope Into Action' and a patient battling idiopathic multicentric Castleman disease (iMCD). Dr. Fajgenbaum discovered a repurposed treatment that saved his own life and others—a story he chronicled in his national bestselling memoir ‘Chasing My Cure‘, which is being adapted into a film by Forrest Gump producer Wendy Finerman. Dr. Fajgenbaum has transformed the treatment and survival of patients with Castleman disease and other diseases, advancing a total of 14 repurposed treatments for cancers and rare diseases.

He co-founded Every Cure to unlock more hidden cures from existing medicines and is pioneering a novel approach called “computational pharmacophenomics” that utilizes AI to predict the most promising drug repurposing opportunities and validates them in clinical trials. Dr. Fajgenbaum also serves on the Board of Directors for the Reagan-Udall Foundation for the FDA.

One of the youngest recipients of multiple top NIH and FDA grants, Dr. Fajgenbaum has authored over 100 scientific papers in leading journals, including The New England Journal of Medicine, The Lancet, and The Journal of Clinical Investigation. He has been profiled by The New York Times, Good Morning America, TODAY, and Forbes 30 Under 30 and has received numerous honors, including the 2016 Atlas Award alongside then VP Joe Biden, 2022 NDRI Service to Science Award alongside Nobel Laureates Katalin Kariko and Drew Weissman, 2023 Philadelphia Citizen of the Year Award, and selection to the 2025 TIME100 Health list of the world’s most influential people in health. Dr. Fajgenbaum earned a BS from Georgetown University, MSc from the University of Oxford, MD from the University of Pennsylvania, and MBA from The Wharton School.

Description of Research Expertise

See https://www.med.upenn.edu/CSTL/ for more information.

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; methods for accelerating drug development and drug repurposing

Keywords:
IL-6, cytokine storm, stromal cells; chemokines, PI3K/Akt/mTOR, JAK/STAT3

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 and JAK/STAT 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