Congratulations to Dustyn Barnette who successfully defended his Ph.D. dissertation entitled “Determining Metabolic Pathways to Liver Toxicity for Multiple Drug Classes Through Integrated Computational and Experimental Techniques” on September 10th. Dustyn was a student in the laboratory of Dr. Grover Paul Miller and is now a post-doctoral fellow at the National Center for Toxicological Research under the direction of Dr. Qiang Shi. A summary of his work is below.

Idiosyncratic adverse drug reactions (IADRs) present a challenge for drugs during development and after marketing. Drug bioactivation by liver xenobiotic enzymes is a prominent mechanism behind IADRs, often resulting in drug-induced liver injury.  Avoidance of structural alerts is the common practice used in drug design to minimize bioactivation, but the strategy is prone to false predictions.  A deeper mechanistic knowledge of drug bioactivation mechanisms, though requiring more resource-intensive strategies, can lead to safer drug design and clinical use. Herein, I used a strategic combination of investigative methodologies to study and elucidate bioactivation and detoxification pathways of drugs on and off the market. Multiple deep-learning neural network models provided high-throughput and efficient predictions of drug metabolism and analysis of patient data.  These were complemented with in vitro experiments using enzyme systems to conduct kinetics analysis and phenotyping for targeted study of metabolism for specific drugs. My application of these techniques focused on two types of drug bioactivation.  First, a study of the antifungal terbinafine identified a multi-pathway and multi-step series of N-dealkylations leading to formation of a reactive aldehyde.  The complex pathway was catalyzed by seven different P450s, possibly explaining the difficulty of predicting liver injury in patients.  Second, a comparative study of thiazole epoxidation for the never-marketed sudoxicam and its safer marketed derivative meloxicam identified multiple mechanisms by which thiazole substituents can determine toxicity risks, affecting both bioactivation and detoxifications pathways.  Varied enzyme specificity for the different pathways implied a major role for enzyme affinity in determining bioactivation outcomes. Overall, newly gained mechanistic knowledge for specific drug bioactivation was achieved by leveraging the strengths of two different investigational approaches, each of which informed and improved the other.  These findings deepen our understanding of how structural alerts translate to risks of liver injury.  Newly discovered promising targets for identifying toxicity predictive factors in patient data offer exciting opportunities for future studies of clinical outcomes for these and similar drugs.

A shout-out to MD/PhD student L. Clai Morehead, a student in Isabelle Miousse’s and Alan Tackett’s labs, who has been selected to present a talk at the annual MD/PhD National Student Conference this week. Clai also received a Diversity Award to support her participation in the virtual conference. Her talk, “Caloric restriction mimetics as an adjuvant to immune checkpoint inhibitors for treatment of melanoma,” is one of only six in the conference’s general medicine category, and Clai is among just 24 MD/PhD students chosen to present at the conference. Clai’s talk tied for best student talk. We’re proud of you Clai!

A $1.9 million grant from the National Institute of General Medical Studies (NIGMS) will allow a scientist at the University of Arkansas for Medical Sciences (UAMS) to advance his research of DNA damage response (DDR) in cancer and genetic disorders.

Justin Leung, Ph.D., received the five-year grant for his project titled “Deciphering the Chromatin-based DNA Damage Response Pathway.” NIGMS, a part of the National Institutes of Health, supports basic research that improves understanding of biological processes and lays the foundation for advances in disease diagnosis, treatment and prevention. ​

“DNA damage is a constant threat to our genetic material, so our bodies evolved a surveillance system called the DDR pathway. This pathway maintains our genome integrity by protecting our cells from damage to the genetic information that results in mutations and cell malignancies,” said Leung, assistant professor in the UAMS College of Medicine Department of Radiation Oncology and researcher in the UAMS Winthrop P. Rockefeller Cancer Institute.

An intact DDR pathway and network of DNA-repair proteins are essential for maintaining genome stability. When any component of the DDR pathway is compromised, DNA mutations will accumulate in cells, which potentially lead to diseases including cancer and genetic disorders.

“Our lab aims to understand how cells precisely repair DNA damage at the right place and right time. We investigate how the DDR is initiated and the mechanism by which DNA repair proteins are brought to the DNA breaks,” Leung said.

Leung’s grant, known as an R35 Maximizing Investigators’ Research Award, will be used to build a roadmap of the chromatin-based DDR pathway. The study will potentially provide insight into the causes of cancer and DDR-related genetic diseases. It will also help to develop therapeutic strategies for cancer treatment.

Research Findings Published

Findings from a collaborative project on DNA damage response conducted by Leung and Michael Huen, Ph.D., of the University of Hong Kong, was published July 1 in the scientific journal PNAS (Proceedings of the National Academy of Sciences of the United States of America).

The article titled “Screen identifies DYRK1B network as mediator of transcription repression on damaged chromatin,” outlines the team’s identification of a protein called DYRK1B and its functional network as a new branch of the DNA damage response to protect our genetic materials.

“Our work explains how DYRK1B dysregulation may fuel cancer progression. It also guides the development of a therapeutic strategy for the treatment of cancer and several rare genome instability-associated diseases,” Leung said.

The study uses a comprehensive proteomics approach supported by the IDeA (Institutional Development Award) National Resource for Quantitative Proteomics at UAMS to build an atlas for DYRK1B functions through profiling the potential biological pathways in which DYRK1B is involved.

“This study will open up new avenues for scientific discovery to study not only DNA repair but also a wide range of protein modifications in diverse cellular functions,” Leung said.

Postdoctoral fellow Kirk West, Ph.D., is the UAMS author of the study.

Genome-wide Cas9 binding specificity in Saccharomyces cerevisiae.

Waldrip ZJ, Jenjaroenpun P, DeYoung O, Nookaew I, Taverna SD, Raney KD, Tackett AJ.

PeerJ.

Frequent expression of activation induced cytidine deaminase in diffuse large B-cell lymphoma tissues from persons living with HIV.

Shponka V, Reveles CY, Alam S, Jaramillo M, Maguire A, Rimsza LM, Kendrick S.

AIDS.

Metabolism, CB1 cannabinoid receptor binding and in vivo activity of synthetic cannabinoid 5F-AKB48: Implications for toxicity.

Congratulations to Aaron Storey and his co-authors on their publication featured on the August 2020 cover of Molecular Omics.  The project was a collaboration between multiple labs and the proteomics and bioinformatics core facilities lead by Stephanie Byrum.

A $10.6 million grant from the National Institutes of Health (NIH) will allow the University of Arkansas for Medical Sciences (UAMS) to greatly expand its proteomics resource. This grant will establish the IDeA National Resource for Quantitative Proteomics as the first NIH National Resource in Arkansas, which will serve biomedical researchers across the nation.

Proteomics is the large-scale study of proteins that can lead to the development of new therapies and screening approaches for many diseases, including cancer.

The five-year grant was awarded to Alan Tackett, Ph.D., professor in the Department of Biochemistry and Molecular Biology and associate director for basic science at the UAMS Winthrop P. Rockefeller Cancer Institute. Tackett serves as an administrative director of this new national resource.

Other key contributors at UAMS are Rick Edmondson, Ph.D.; Samuel Mackintosh, Ph.D.; and Stephanie Byrum, Ph.D.; as well as Michael Kinter, Ph.D., at the Oklahoma Medical Research Foundation who serves as a co-administrative director.

The national resource was initially created through the Arkansas INBRE (IDeA Network of Biomedical Research Excellence) — an NIH program that promotes biomedical research for undergraduate students and faculty. Lawrence Cornett, Ph.D., professor in the UAMS College of Medicine Department of Physiology and Biophysics, serves as principal investigator and director of Arkansas INBRE.

“With this new funding, we will transition our proteomics resource to an NIH National Resource and expand our ability to provide highly advanced research support to scientists in underfunded areas throughout the United States,” said Tackett, who holds the Scharlau Family Endowed Chair for Cancer Research at UAMS.

Certain regions of the United States, designated as the IDeA Network, have historically received low levels of research funding from NIH. Scientists in these regions face challenges for accessing state-of-the-art proteomics resources.

The IDeA National Resource for Quantitative Proteomics at UAMS was established to address these gaps in services.

“Due to a lack of federal funding, it is often difficult for scientists in the IDeA Network to access the advanced instruments and trained personnel needed to analyze and interpret their research data. With this new funding, we will now be able to serve a diverse group of IDeA investigators for their research, which ranges from studies on model organisms to diseases such as cancer,” said Tackett, professor of biochemistry and molecular biology in the UAMS College of Medicine.

The expanded national resource will support researchers by providing highly advanced data analysis, outreach opportunities and education to scientists across the nation.

“Our goal is to increase the ability for scientists in the 23 IDeA states and Puerto Rico, as well as other NIH-supported investigators across the nation, to perform innovative research by providing unmatched access to advanced quantitative proteomics platforms and staff skilled in interpreting and analyzing complex biological data,” Tackett said.

The educational opportunities offered by the national resource include workshops that are designed to help faculty and student researchers across the nation better utilize proteomics in their research.

This federal grant will bolster the Cancer Institute’s ongoing efforts to receive National Cancer Institute Designation. To achieve designation, cancer centers undergo a highly competitive assessment process that demonstrates an outstanding depth and breadth of research in three areas: basic laboratory, patient/clinical and population-based. The designation brings with it many benefits, including expanded access to federal funding for researchers and improved access to clinical trials for patients.

Dr. Alan Tackett, Professor of Biochemistry and Molecular Biology, has been invited to serve as a standing member of the NIH Mechanisms of Cancer Therapeutics-1 (MCT1) Study Section, one of the major review boards for evaluation of cancer research by the Center for Scientific Review. The four-year appointment recognizes Dr. Tackett, who also serves as the Scharlau Family Endowed Chair in Cancer Research at UAMS, as a leader in this field. Congratulations to Dr. Tackett.

Neonatal Diet Impacts Circulatory miRNA Profile in a Porcine Model.

Carr LE, Bowlin AK, Elolimy AA, Byrum SD, Washam CL, Randolph CE, MacLeod SL, Yeruva L.

Front Immunol. 2020

Novel advances in biotransformation and bioactivation research-2019 year in review.

Khojasteh SC, Driscoll JP, Jackson KD, Miller GP, Mitra K, Rietjens IMCM, Zhang D.

Drug Metab Rev. 2020