Dr. A. Douglas Kinghorn leads $7 million NCI grant renewal for cancer drug discovery research
The Ohio State University College of Pharmacy and Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) have been awarded a five-year, $7 million competitive Program Project Grant (PPG) renewal from the National Cancer Institute (NCI).
The grant renewal is led by Contact Principal Investigator A. Douglas Kinghorn, PhD, BS Pharm, DSc, FRPharmS, professor and Jack L. Beal Chair of the Division of Medicinal Chemistry and Pharmacognosy at the College of Pharmacy. He is a member of the OSUCCC – James Molecular Carcinogenesis and Chemoprevention Program and received the permanent, honorific title of Distinguished University Professor in 2022.
"Our grant renewal is very much the result of teamwork at all levels and is undergirded by the efforts of several highly talented colleagues working in the laboratories of the three universities involved,” Dr. Kinghorn said. “We consider ourselves extremely fortunate to have been funded by the NCI for a fourth five-year term for this program project on natural products drug discovery."
The renewal for years 16-20 will allow teams at Ohio State, University of Illinois – Chicago and University of North Carolina – Greensboro to continue investigating potential anticancer drug leads based on compounds from tropical plants, U.S. coastal lichens, cultured terrestrial cyanobacteria and filamentous fungi.
“The renewal of this major Program Project Grant showcases the national leadership of our College of Pharmacy in the discovery of anticancer agents,” said Blake Peterson, PhD, chair and professor in the Division of Medicinal Chemistry and Pharmacognosy. “It highlights our ability to bring together experts from multiple institutions to discover new anticancer compounds from natural sources. With advanced laboratories, experienced researchers and strong collaborations across universities and federal agencies, the college continues to demonstrate its strength as a hub for cutting-edge drug discovery.”
This renewal will continue to support the college’s longest-funded research project and its only active P01 grant. It remains the only NCI-funded PPG in the nation led by a pharmacy investigator.
“Pharmacist-scientists bring a unique knowledge base and perspective to pharmacological research,” said Deanna Kroetz, PhD, BS Pharm ’85, dean and professor at the College of Pharmacy. “The deep clinical knowledge of disease and drug action that pharmacist-scientists like Dr. Kinghorn have informs research that is clearly focused on improving human health. Pharmaceutical sciences would benefit from more scientists with pharmacy backgrounds.”
Since its inception in 2007, members of the interdisciplinary group have generated more than 250 published research and review articles, delivered nearly 200 invited lectures and seminars, and given more than 320 contributed presentations at national and regional scientific meetings. The project has served as the foundation for 42 doctoral dissertations and 13 master’s theses.
“Discovering and developing new medicines typically takes years of discovery, testing, optimization and collaboration,” Dr. Peterson said. “Long-term grants like this provide the stability and resources needed to move promising discoveries from the lab toward potential new treatments.”
This new award is the sixth time since 1995 that Dr. Kinghorn has been named Principal Investigator of a funded collaborative program-type grant award (P01, U01 or U19) from NCI.
“Dr. Kinghorn has set the standard for success for the tenure-track faculty in the college, demonstrating excellence in all three pillars of academia–research, teaching and service,” Dean Kroetz said. “Among his many contributions are significant discoveries from this research, mentoring numerous students and fellows, and service to the college and university through leadership of key committees and advisory groups. The renewal of this P01 for years 16-20 is just one more example of his contributions to the college and his achievements in the pharmacognosy field.”
The continuing research funding 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 collected by Project 2, inclusive of extraction, dereplication, compound purification, structure elucidation and scale-up isolation stages. Work has continued in screening U.S. coastal lichens and their fungal mycobionts (Dr. H. Liva Rakotondraibe). To enhance compound structure elucidation and scale up, a synthesis component has been introduced (Dr. James R. Fuchs). Biological screening is offered for Projects 1-3 using a selection of secondary cell-based and mechanism-based assays (Dr. Esperanza J. Carcache de Blanco).
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 expert taxonomic advice on previous plant collections obtained from tropical rainforests (Dr. Djaja D. Soejarto). Extracts from these 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. Biological testing to investigate effects on ferroptosis 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 by Dr. Junan Li to Projects 1-3 and Cores A, 1 and 2.
Core 1 – Biological Correlation and Analysis Core
(UIC; Core Director, Dr. Joanna E. Burdette)
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 in mouse hollow fiber and xenograft bioassays, with mechanistic input involving proteomics.
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 by Dr. Mitch A. Phelps and aided by Dr. Chris Coss) for selected compounds of promise from Projects 1-3. In vivo assays using zebrafish are provided by Dr. Esperanza Carcache de Blanco.
Co-investigators from the Ohio State College of Pharmacy include Esperanza Carcache de Blanco, PhD; Christopher Coss, PhD ’03; Junan Li, PhD; Mitch Phelps, PhD ’05; and H. Liva Rakotondraibe, PhD. James Fuchs, PhD, professor and Associate Dean for Research and Graduate Studies, is serving as one of two Multiple Principal Investigators for the PPG.