Presidential Professor of Medicinal Chemistry and
Research Professor of Biochemistry
B.S. California Institute of Technology
Ph.D. Stanford University
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.
- Rao NV, Argyle B, Xu X, Reynolds PR, Walenga JM, Prechel M, Prestwich GD, MacArthur RB, Walters BB, Hoidal JR, Kennedy TP (2010) Low Anticoagulant Heparin Targets Multiple Sites of Inflammation, Suppresses Heparin-Induced Thrombocytopenia and Inhibits Interaction of RAGE with its Ligands. Am J Physiol Cell Physiol, In Press
- Skardal A, Zhang J, McCoard L, Xu X, Oottamasathien S, Prestwich GD (2010) "Photocrosslinkable hyaluronan-gelatin hydrogels for two-step bioprinting. Tissue Engineering, In Press
- Elia R, Fuegy PW, VanDelden A, Firpo MA, Prestwich GD, Peattie RA (2010) Stimulation of in vivo angiogenesis by in situ crosslinked, dual growth factor-loaded, glycosaminoglycan hydrogels. Biomaterials 31:4630-4638
- Yang G, Espandar L, Mamalis N, Prestwich GD (2010) Accelerated Repair of Corneal Epithelial Abrasion and Alkali Burn Injuries in Rabbits with a Crosslinked Hyaluronan Derivative. Vet Ophthalmology 13:144-150
- Xu X, Prestwich GD (2010) Inhibition of Tumor Growth and Angiogenesis by a Lysophosphatidic Acid Antagonist in an Engineered Three-Dimensional Lung Cancer Xenograft Model. Cancer 116:1739-1750
- Zhang H, He J, Kutateladze TG, Sakai T, Sasaki T, Markadieu N, Erneux C, Prestwich GD (2010) 5-Stabilized Phosphatidylinositol 3,4,5-Trisphosphate Analogues Bind Grp1 PH and Inhibit Neutrophil Migration. ChemBioChem 11:388-395
- Zhang H, Xu X, Gajewiak J, Tsukarara R, Liu J, Fells J, Perygin D, Parrill A, Tigyi G, Prestwich GD (2009) Dual Activity Lysophosphatidic Acid Receptor Pan-Antagonist/Lysophospholipase D Inhibitor Suppresses Breast Cancer Cell Migration and Invasion in vitro and causes Tumor Regression in vivo. Cancer Res 69:5441-5449
- Prestwich GD (2008) Engineering a clinically-useful matrix for cell therapy. Organogenesis 4:42-47
- Prestwich GD (2008) Evaluating drug toxicity and efficacy in three dimensions: using synthetic extracellular matrices in drug discovery. Acc Chem Res 41:139-148