$7 million NCI grant renewal supports cancer drug discovery research based on compounds found in nature
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) and the Ohio State College of Pharmacy have been awarded a five-year, $7 million competitive Program Project Grant (PPG) renewal from the National Cancer Institute (NCI).
This multidisciplinary project grant represents the only PPG funded by the NCI in the nation led by a pharmacy investigator and will allow teams at Ohio State, the University of Illinois – Chicago and University of North Carolina – Greensboro to continue investigating potential anticancer drug leads based on compounds from tropical plants, coastal lichens, cultured cyanobacteria and filamentous fungi.
The grant renewal extends through 2025 and is led by principal investigator A. Douglas Kinghorn, PhD, DSc, professor and Jack L. Beal Chair of the Division of Medicinal Chemistry and Pharmacognosy at the College of Pharmacy. He is also a member of the OSUCCC – James Molecular Carcinogenesis and Chemoprevention Program.
“We are so appreciative of this renewed funding. It will enable us to continue our momentum of discovery in the lab, including further investigation of natural products identified as having potential for anticancer activity,” says Kinghorn, noting that, since the grant’s initial funding in 2007, more than 180 peer-reviewed research and review articles have been published based on findings from the three collaborating institutions.
The grant is organized around three projects and three cores:
Project 1 – Isolation Chemistry of Tropical Plants and Biological Evaluation
(Ohio State; Project Leader, Dr. A. Douglas Kinghorn)
Project 1 involves the isolation chemistry of bioactive tropical plants to be collected by Project 2 (see below), inclusive of extraction, dereplication, compound purification, structure elucidation and scale-up isolation stages. More recently, work has begun in screening U.S. coastal lichens and their fungal mycobionts (Dr. H. Liva Rakotondraibe). Biological screening is offered for Projects 1-3 using a selection of secondary cell-based and mechanism-based assays (Drs. Esperanza J. Carcache de Blanco and Jack C. Yalowich)
Project 2 – Isolation Chemistry of Cultured Cyanobacteria and Plant Acquisition
(UIC; Project Leader, Dr. Jimmy Orjala)
Project 2 entails cyanobacterial collection, culturing, genomic evaluation (Dr. Alessandra Eustaquio), extraction and dereplication, as well as plant collections from tropical rainforests (Dr. Djaja D. Soejarto). Extracts from the plants are further investigated in Project 1.
Project 3 – Isolation Chemistry of Filamentous Fungi and Biological Evaluation
(UNCG; Project Leader, Dr. Nicholas H. Oberlies)
Project 3 works on new lead compounds from fungi obtained from Mycosynthetix, Inc. (Hillsborough, NC; CEO/CSO Dr. Cedric J. Pearce), and comprises culturing, extraction, dereplication, compound purification, structure elucidation, scale-up isolation/yield optimization and biosynthetic manipulation. Some biological testing is carried out at Columbia University as part of Project 3 (Dr. Brent R. Stockwell).
Core A – Administrative and Biostatistics Core
(Ohio State; Core Director, Dr. A. Douglas Kinghorn)
Core A carries out overall administrative functions (aided by Dr. Amanda S. MacFarlane) and offers biostatistics support (directed by Dr. Xiaoli Zhang) to Projects 1-3 and Cores A, 1 and 2.
Core 1 – Biological Correlation and Analysis Core
(UIC; Core Director, Dr. Joanna E. Burdette, assisted by Dr. Leslie Aldrich)
Core 1 provides in vitro testing (screening assays using a small cancer cell line panel; HDAC and proteasome inhibition assays) for samples submitted by Projects 1-3. Promising compounds are evaluated mechanistically and evaluated in mouse hollow fiber and xenograft bioassays
Core 2 – Medicinal Chemistry and Pharmacokinetics Core
(Ohio State; Core Director, Dr. James R. Fuchs)
Core 2 conducts medicinal chemistry (synthesis/analogue development, SAR evaluation) and pharmacokinetic-related functions (e.g., solubility, stability, formulation, metabolism, protein binding; supervised by Dr. Mitch A. Phelps and aided by Dr. Chris Coss) for selected compounds of promise from Projects 1-3.
“Our faculty are working tirelessly to advance drug discovery for some of the most pressing medical problems. The work that Dr. Kinghorn and his team have done for the past 13 years is representative of this,” says Henry Mann, PharmD, FCCP, FCCM, FASHP, dean and professor of the College of Pharmacy.
“In addition, this grant provides a tremendous continued opportunity to train a future generation of scientists,” says Cynthia Carnes, PharmD, PhD, senior associate dean of research and graduate studies at the College of Pharmacy.
Co-investigators from the Ohio State College of Pharmacy include: Esperanza Carcache de Blanco, PhD; Christopher Coss, PhD; James Fuchs, PhD; Mitch Phelps, PhD; H. Liva Rakotondraibe, PhD; and Jack Yalowich, PhD.