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.
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.
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.
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.