May 14, 2019

by Susan Van Dusen

Alan Tackett, Ph.D.

Professor of Biochemistry and Molecular Biology, UAMS College of Medicine
Associate Director of Basic Research, UAMS Winthrop P. Rockefeller Cancer Institute

Dr. Tackett’s research focuses on the identification of biomarkers and drug targets to treat melanoma. Specifically, he focuses on the identification of molecular and epigenetic pathways dysregulated in metastatic melanoma patients who are non-responsive to immune checkpoint therapy. Immune checkpoint therapy has revolutionized the treatment of metastatic melanoma, but only approximately half of patients show responsiveness to treatment. Dr. Tackett’s laboratory uses state-of-the-art proteomics and epigenomics to uncover the molecular differences between patient tumors that are either responsive or non-responsive to therapy. Targets and molecular pathways identified from these studies are biologically validated in melanoma cell culture and in vivo models.

Furthermore, Dr. Tackett is interested in how dysregulation of epigenetics, namely histone posttranslational modifications, reprograms certain melanomas to drive cancer progression and therapy responsiveness.

All of Dr. Tackett’s research is highly collaborative and translational as his team works closely with UAMS clinicians in the Department of Surgery, Division of Medical Oncology and Department of Pathology to obtain tissue samples for his studies. In addition to the ongoing cancer research in his laboratory, Dr. Tackett received funding from the National Institutes of Health in 2017 to create a Center of Biomedical Research Excellence (COBRE) focused on systems biology, which provides training for young scientists and core facility infrastructure development. In 2016, Dr. Tackett leveraged funding from the National Institutes of Health to develop a National Resource for Proteomics at UAMS, which provides a biomarker discovery platform to UAMS investigators as well as 23 other states and Puerto Rico.

Dr. Tackett’s Grants

NIGMS – 5 P20 GM121293-02
Center for Translational Pediatric Research
07/11/2017-06/30/2022
$1,618,994* (not all projects are cancer-related)
Role: PI

NIGMS – 5 R01 GM118760-03
Epigenetic Profiling and Enzymatic Regulation of H3K23ME3 During Cellular Differentiation
03/01/2017-01/31/2021
$37,500*
Role: PI

NIGMS – 5 P20 GM103429-18
Partnerships for Biomedical Research in Arkansas
Director of Research Technology Core
05/01/2015–04/30/2020
$193,619**
Role: PI

NCI – Awaiting NOA (Notice of Award) for specific project dates and budget figures.
Identification of Druggable Targets to Complement Melanoma Therapy
Role: PI

In addition to leading his own Centers of Biomedical Research Excellent (COBRE) grant (5 P20 GM121293-02), Dr. Tackett serves as a project mentor for two other UAMS COBRE grants: Center for Musculoskeletal Disease Research (PI: Charles O’Brien: 5 P20 GM125503-02) and Center for Studies of Host Response to Cancer Therapy (PI: Martin Hauer-Jensen: 5 P20 GM109005-05).

*cancer-related annual direct costs
**annual direct costs, not cancer-related, relevant to facilitation of campuswide research

Dr. Tackett’s Collaborators

Dr. Tackett has worked with dozens of researchers across numerous institutions and countries. Some of the collaborators for his most recent melanoma-focused studies include:

• Juan Barreto, M.D., UAMS
• Stephanie Byrum, Ph.D., UAMS
• Rick Edmondson, Ph.D., UAMS
• Laura Hutchins, M.D., UAMS
• Sam Mackintosh, Ph.D., UAMS
• Issam Makhoul, M.D., UAMS
• Sara Shalin, M.D., Ph.D., UAMS
• Sean Taverna, Ph.D., Johns Hopkins School of Medicine

Opportunities for Collaboration

I am always looking for opportunities to collaborate with colleagues at UAMS. I have an open-door policy for discussing new ideas, projects and collaborations. My scientific expertise is in systems biology technologies, which can often drive new collaborations.

You Might Not Know That …

I enjoy fishing, boating and spending time on the lakes in Hot Springs. That city has so much to offer and it is an easy drive from Little Rock. I may be biased because I was born there.

Cancer-Related Publications

1: Shields BD, Koss B, Taylor EM, Storey AJ, West KL, Byrum SD, Mackintosh SG, Edmondson R, Mahmoud F, Shalin SC, Tackett AJ. Loss of E-Cadherin Inhibits CD103 Antitumor Activity and Reduces Checkpoint Blockade Responsiveness in Melanoma. Cancer Res. 2019 Mar 15;79(6):1113-1123. doi: 10.1158/0008-5472.CAN-18-1722. Epub 2019 Jan 23. PubMed PMID: 30674537; PubMed Central PMCID: PMC6420873.

2: Mahmoud F, Shields B, Makhoul I, Avaritt N, Wong HK, Hutchins LF, Shalin S, Tackett AJ. Immune surveillance in melanoma: From immune attack to melanoma escape and even counterattack. Cancer Biol Ther. 2017 Jul 3;18(7):451-469. doi: 10.1080/15384047.2017.1323596. Epub 2017 May 17. Review. PubMed PMID: 28513269; PubMed Central PMCID: PMC5639850.

3: Shields BD, Mahmoud F, Taylor EM, Byrum SD, Sengupta D, Koss B, Baldini G, Ransom S, Cline K, Mackintosh SG, Edmondson RD, Shalin S, Tackett AJ. Indicators of responsiveness to immune checkpoint inhibitors. Sci Rep. 2017 Apr 11;7(1):807. doi: 10.1038/s41598-017-01000-2. PubMed PMID: 28400597; PubMed Central PMCID: PMC5429745.

4: Sengupta D, Tackett AJ. Proteomic Findings in Melanoma. J Proteomics Bioinform. 2016 Apr;9(4). pii: e29. Epub 2016 Apr 27. PubMed PMID: 27274624; PubMed Central PMCID: PMC4888906.

5: Mahmoud F, Shields B, Makhoul I, Hutchins LF, Shalin SC, Tackett AJ. Role of EZH2 histone methyltrasferase in melanoma progression and metastasis. Cancer Biol Ther. 2016 Jun 2;17(6):579-91. doi: 10.1080/15384047.2016.1167291. Epub 2016 Apr 22 Review. PubMed PMID: 27105109; PubMed Central PMCID: PMC4990393.

CYP2C19 and 3A4 Dominate Metabolic Clearance and Bioactivation of Terbinafine Based on Computational and Experimental Approaches.

 

 

 

LC8/DYNLL1 is a 53BP1 effector and regulates checkpoint activation.

Congratulations to Anthonya Cooper who  successfully defended her dissertation entitled “Communication between Insulin and Serotonin Signaling Pathways in Placenta”.

Associate Professor
Department of Biochemistry & Molecular Biology
College of Medicine
Biochemistry Track Leader for the Graduate Program in Interdisciplinary Biomedical Sciences

Research Interest Statement

DNA replication is a complex and perilous undertaking for the cell because the risk of incurring insults to the genome is greatest when the double-helix is unwound for copying. My research team studies what happens when DNA damage is not repaired in a timely manner and ends up blocking the replication machinery. In other words, we study how cells “tolerate” damage for a time in order for the genome to be copied faithfully. These events shape evolutionary processes, influence the emergence of antibiotic resistance in bacteria, promote treatment resistance in cancer patients, and mutations in DNA damage tolerance-related genes underlie a wide range of human diseases.

A long-term goal of my research program is to uncover new mechanistic features of replication stress and DNA damage tolerance by studying these processes at the atomic, molecular and cellular level using a variety of techniques, including biochemical and biophysical approaches, methods related to cellular and molecular biology, and systems level approaches, such as proteomics. We also seek to deepen our understanding of how DNA damage tolerance impacts genome stability, patient response to treatment and tumor recurrence in certain cancers.

Partnering with Peter Crooks, M.Sc., Ph.D., D.Sc., (Pharmaceutical Sciences, UAMS) and Analiz Rodriguez, M.D., Ph.D., (Neurosurgery, UAMS), we are working to develop small-molecules targeting key elements of the aberrant replication stress response in gliomas and other types of cancer so that we might potentiate the therapeutic effects of standard-of-care drugs like Temodar.

Dr. Eoff’s Grants

National Cancer Institute
Translesion DNA polymerase kappa activity in gliomas
04/04/2014 – 02/28/2020*
$207,500*

UAMS Foundation/Medical Research Endowment
DNA polymerase kappa inhibitors
01/01/2019 – 12/31/2019
$15,000*

UAMS Seeds of Science
DNA polymerase kappa inhibitors
02/01/2019 – 1/31/2020
$15,000*

UAMS Arkansas Breast Cancer Research Program
Investigating Mechanisms of Treatment Resistance in Breast Cancer Stem Cells
02/01/2019 – 1/31/2020
$248,699*

UAMS COM Barton Bridging Grant
DNA polymerase kappa regulation and activity in gliomas
01/01/2019 – 1/01/2020
$45,000*
*cancer-related annual direct costs

Dr. Eoff’s UAMS Collaborators

• Analiz Rodriguez, M.D., Ph.D.
• Justin Leung, Ph.D.
• Kevin Raney, Ph.D.
• Alan Tackett, Ph.D.
• Peter Crooks, M.Sc., Ph.D., D.Sc.
• Michael Borrelli, Ph.D.
• Grover P. Miller, Ph.D.

Dr. Eoff’s External Collaborators

• Michelle Hamm, Ph.D. (University of Richmond)
• Julie Gunderson, Ph.D. (Hendrix College)
• Shana Sturla, Ph.D. (ETH, Zürich, Switzerland)
• Jeong-Yun Choi, M.D., Ph.D. (Sungkyunkwan University School of Medicine, South Korea)

Opportunities for Collaboration

My group has expertise in structural enzymology and molecular biology. While we are primarily interested in genomic maintenance, I’m curious about many scientific areas and welcome conversations about collaborating on a wide range of topics.

You Might Not Know That …

I’ve been a volunteer youth soccer coach for over a decade. I enjoy mixed martial arts training, and I like to combine my love of science with my passion for illustration. Also, one of my favorite ways to relax is by spending time with my family in the great outdoors.

Cancer-related Publications

• LC8/DYNLL1 is a 53BP1 effector and regulates checkpoint activation. West KL, Kelliher JL, Xu Z, An L, Reed MR, Eoff RL, Wang J, Huen MSY, Leung JWC. Nucleic Acids Res. 2019 Apr 15. pii: gkz263. doi: 10.1093/nar/gkz263. [Epub ahead of print] PMID:30982887
• A Small-Molecule Inhibitor of Human DNA Polymerase η Potentiates the Effects of Cisplatin in Tumor Cells. Zafar MK, Maddukuri L, Ketkar A, Penthala NR, Reed MR, Eddy S, Crooks PA, Eoff RL. Biochemistry. 2018 Feb 20;57(7):1262-1273. doi: 10.1021/acs.biochem.7b01176. Epub 2018 Jan 30. PMID:29345908
• Translesion DNA Synthesis in Cancer: Molecular Mechanisms and Therapeutic Opportunities. Zafar MK, Eoff RL. Chem Res Toxicol. 2017 Nov 20;30(11):1942-1955. doi: 10.1021/acs.chemrestox.7b00157. Epub 2017 Sep 28. Review. PMID:28841374
• Synthesis and Evaluation of 2-Naphthaleno trans-Stilbenes and Cyanostilbenes as Anticancer Agents. Madadi NR, Penthala NR, Ketkar A, Eoff RL, Trujullo-Alonso V, Guzman ML, Crooks PA. Anticancer Agents Med Chem. 2018;18(4):556-564. doi: 10.2174/1871521409666170412115703. PMID:28403783.

April 25, 2019 | LITTLE ROCK – You are invited to learn about the latest advances in cancer research, treatment and prevention at a free event at 11:30 a.m. May 16 in Hot Springs Village featuring a researcher from the University of Arkansas for Medical Sciences (UAMS).

The program will be at Diamante Country Club, 2000 Country Club Drive. Featured speaker will be Samantha Kendrick, Ph.D., assistant professor in the UAMS College of Medicine Department of Biochemistry and Molecular Biology. Kendrick’s research focuses on developing new therapies for aggressive forms of non-Hodgkin’s lymphoma that have the potential to reduce drug resistance and lead to better patient outcomes.

There is no charge to attend, and lunch is provided. To make a reservation, email mmgarcia@uams.edu or call (501) 526-6990, Ext. 8157 by May 10.

Kendrick was co-recipient of the UAMS Cancer Institute’s 2019 Seeds of Science grant award, which totaled $50,000 and was funded by proceeds from the Village Walk for Cancer Research. Since 2002, the walk has raised about $500,000 for research programs at the UAMS Cancer Institute. The 2019 walk is scheduled for Sept. 28 at Balboa Pavilion in Hot Springs Village.

This event is presented by the UAMS Winthrop P. Rockefeller Cancer Institute in conjunction with the Hot Springs Village Walk for Cancer Research. It is sponsored by the Envoys, an advocacy group of the Winthrop P. Rockefeller Cancer Institute Foundation.

Congratulations to first author, Kirk West, and other members of Alan Tackett‘s lab on their manuscript, Proteomic characterization of the arsenic response locus in S. cerevisiae, that is featured on the cover of Epigenetics.

Congratulations to Magdalena Delgado who successfully defended her dissertation entitled “Characterization of cell death induced by microtubule targeting agents in primary acute lymphoblastic leukemia cells” on April 24th.  Magdalena is a student in Timothy Chamber’s lab.

Congratulations to first author, Jun Gao, and other members of Kevin Raney‘s lab on their manuscript, DEAD-box RNA helicases Dbp2, Ded1 and Mss116 bind to G-quadruplex nucleic acids and destabilize G-quadruplex RNA, that is featured on the cover of Chemical Communications.