Presidential Professor of Medicinal Chemistry and
Research Professor of Biochemistry
B.S. California Institute of Technology
Ph.D. Stanford University
Glenn Prestwich's Lab Page
Glenn Prestwich's Pubmed Literature Search
Molecular Biology Program
Biological Chemistry Program
The research in my laboratories is highly translational and includes prominent interactions with physicians and with companies tasked with developing new therapies. We are currently developing therapeutic applications of anti-cancer lysophospholipids, anti-inflammatory sulfated polysaccharides, and hyaluronan (HA)-derived synthetic extracellular matrices (sECMs) for 3-D cell culture and regenerative medicine. In addition, I mentor students and faculty to help them realize the promise of translational research in order to move innovative technology to the marketplace.
1. Signal Transduction Modifying Drugs
Isoform-selective agonists and antagonists of the lysophosphatidic acid (LPA) G-protein coupled receptors (GPCRs) regulate cancer cell proliferation, invasion, and angiogenesis. LPA also is a feedback inhibitor of the enzyme lysophospholipase D (lysoPLD, a.k.a., autotaxin, ATX), a central regulator of invasion and metastasis. An optimal therapeutic profile for cancer treatment would be a metabolically-stabilized, pan-LPA receptor antagonist that also inhibited lysoPLD. One dual activity analog, BrP-LPA, is a long-lived receptor-specific pan-antagonist for LPA receptors and also inhibits ATX.
2. Sulfated Polysaccharide Drugs
The semi-synthetic glycosaminoglycan ethers, or SAGEs. constitute a novel class of inflammation-modulatory therapeutic agents that have three main modes of action: (1) inhibition of cationic proteases, (2) inhibition of P- and L-selectin binding, and (3) antagonism of the receptor for advanced glycation end-products (RAGE). RAGE acts as a biological rheostat, amplifying immune and inflammatory responses in conditions that include diabetic retinopathy and nephropathy, age-related macular degeneration, cystic fibrosis, Alzheimer's disease, metastatic cancer, and periodontal disease. Our lead SAGE dramatically reduces erythema and neutrophil iniltration in a mouse model for rosacea, shows no adverse effects at injected doses 100 times above those planned therapeutic levels, and reduces of cancer metastasis mediated by RAGE.
3. Synthetic Extracellular Matrices for Regenerative Medicine
We developed injectable and biocompatible vehicles for delivery, retention, growth, and differentiation of stem cells for clinical use in regenerative medicine. This sECM platform is based on in situ crosslinkable HA-based hydrogels. The composition and stiffness of the sECM can be customized for use with progenitor and mature cell populations. The sECM materials are marketed as products for veterinary wound care and bone repair, and as research tools for 3-D culture of stem cells, primary human cells, and orthotopic tumor xenografts. For example, orthotopic, "patient-like" breast, lung, colon, pancreatic, and ovarian tumors were created and then treated with a novel pan-lysophosphatidic acid receptor antagonist that has dual activity as a low nanomolar inhibitor of ATX.
Selected Recent Publications
- W. Y. Lee, J. Savage, A. Pulsipher, N. Rao, T. Kennedy, G. D. Prestwich, and M. Ryan, A modified glycosaminoglycan, GM-0111, inhibits molecular signaling involved in periodontitis, PLoS ONE, 11(6) e0157310 (2016).
- C. B. Highley, G. D. Prestwich, and J. A. Burdick, Recent advances in hyaluronic acid hydrogels for biomedical applications, Curr. Opin. Biotech, 40, 35-40 (2016).
- M-A. Mouratis, N. Oikonomou, C. Magkrioti, G. D. Prestwich, E. Kaffe, and V. Aidinis, Autotaxin-and endotoxin-induced acute lung injury, PLOS One, 10(7):e0133619 (2015).
- B. Wirostko, B. K. Mann, and G. D. Prestwich, “Clinical Development of Hyaluronan-Based Semisynthetic Extracellular Matrices,” Adv. Wound Care, 3, 708-716 (2014).
- G. D. Prestwich and Kevin Healy, “Why Cell Therapy Needs an ECM Mimetic,” invited editorial, Expert Opinion in Biological Therapy, 15, 3-7 (2015).
- A. Chopra, M. E. Murray, D. Raz-Ben Aroush, M. Mendez, R. Halleluyan, D. Restle, P. A. Galie, F. Byfield, R. Bucki, C. Marcinkiewicz, G. D. Prestwich, T. I. Zarembinski, C. S. Chen, E. Puré, J. Y. Kresh, and P. A. Janmey, “Augmentation of integrin-mediated mechanotransduction by hyaluronic acid,” Biomaterials, 35, 71-82 (2014).
- W. Y. Lee, J. R. Savage, J. Zhang, W. Jia, S. Oottamasathien, and G. D. Prestwich, Prevention of anti-microbial peptide LL-37 induced ATP release in the urinary bladder by a modified glycosaminoglycan, PLoS ONE, 8(10) e77854 (2013).
- D. Madan, C. G. Ferguson, W. Y. Lee, G. D. Prestwich, and C. A. Testa, Non-invasive imaging of autotaxin-expressing tumors using an enzyme-activated near-infrared fluorogenic substrate, PLoS ONE, 8(11): e79065 (2013).
- I. Nikitopoulou, E. Kaffe, I. Sevastou, I. Sirioti, M. Samiotaki, D. Madan, G. D. Prestwich, and V. Aidinis, Metabolically-stabilized phosphonate analog of lysophosphatidic acid attenuates collagen-induced arthritis, PLoS ONE, 8(7): e70941 (2013).
- G. D. Prestwich, “Culture of impact: faculty as mentors for student entrepreneurs,” Science Translational Medicine 5, 169ed2 (2013).
- G. D. Prestwich, I. Erickson, T. I. Zarembinski, M. West, and W. P. Tew, “The Translational Imperative: Making Cell Therapy Simple and Effective,” Acta Biomaterialia, 8, 4200-4207 (2012).
- R. Turner, E. Wauthier, O. Lozoya, R. McClelland, J. E. Bowsher, C. Barbier, D. Gerber, G. D. Prestwich, E. Hsu, D. A Gerber and L. M. Reid, Successful Transplantation of Human Hepatic Stem Cells and with Restricted Localization to Liver Using Hyaluronan Grafts, Hepatology, 57, 775-785 (2013).
- K. Cheng, A. Blusztajn, D. Shen, T-S. Li, B. Sun, G. Galang, T. Zarembinski, G. D. Prestwich, E. Marban, R. Ruckdeschel Smith, and L. Marban, “Enhanced Engraftment and Therapeutic Benefit of Human Cardiosphere-derived Cells Delivered in an In Situ Polymerizable Hydrogel”, Biomaterials 33, 5317-5324 (2012).
- A. Astashkina, B. K. Mann, G. D. Prestwich, and D. W. Grainger, “Comparing predictive drug nephrotoxicity in kidney 3-D primary organoid culture and immortalized cell lines,” Biomaterials, 33, 4712-4721(2012).
- G. D. Prestwich, “Clinical Biomaterials Derived from Hyaluronic Acid for Use in Cell and Molecule Delivery in Regenerative Medicine,” J. Controlled Release, 155, 193-199 (2011).