The Arkansas Research Alliance (ARA) inducted two of the Cancer Institute’s best and brightest into their Academy of Fellows and Scholars at the organization’s 2021 annual meeting. ARA is a unique assembly of the state’s top researchers, comprised of more than 20 scientists from Arkansas’ six research campuses. 

Cancer Institute Deputy Director Alan Tackett, Ph.D., was inducted as a fellow into the academy. Tackett is a pioneering researcher in the field of proteomics and established the country’s only National Proteomic Center at the Cancer Institute with funding from the National Institutes of Health (NIH). His research has been continuously funded by the NIH throughout his career, and his research endeavors have resulted in more than 80 peer-reviewed manuscripts. He has written multiple book chapters, been awarded four U.S. patents, acted as a scientific journal editor-in-chief, and served on more than 35 NIH extramural-funding review panels. 

Tackett oversees three biomedical research laboratories on the UAMS campus and one at the Arkansas Children’s Research Institute. He is also a professor in the Department of Biochemistry and Molecular Biology, UAMS College of Medicine, and the Scharlau Family Endowed Chair in Cancer Research. 

Renowned cardiologist, Edward Yeh, M.D., FACC, was inducted into the academy as a scholar. Yeh joined UAMS in 2020 as chair of the Department of Internal Medicine and the Nolan Family Distinguished Chair in Internal Medicine after serving for 16 years as the chair of the Department of Cardiology at the University of Texas MD Anderson Cancer Center. Yeh is a leading expert in the field of onco-cardiology. He discovered the molecular basis of chemo-induced cardiotoxicity, which opened a new field of cancer research to find better treatments that minimize the risk of heart complications. 

Asking and finding answers to the most complex scientific questions has never been a problem for researchers at the world-renowned Myeloma Center at the UAMS Winthrop P. Rockefeller Cancer Institute. It’s practically a way
of life when you’re dealing with one of the deadliest and often drug resistant blood cancers. 

In 1989, the institute’s myeloma researchers led the way in using the Total Therapy treatment approach that combines novel drugs with tandem autologous stem cell transplantation in a treatment sequence of induction, transplantation, consolidation and maintenance. Today, clinicians all over the world use this treatment approach. 

Although highly successful, many patients are not eligible for this approach and do not enjoy the long-term benefit of this intensive total therapy.
The therapy also comes with toxicities and affects quality of life. 

Armed with $5 million in funding, Myeloma Center Research Director Fenghuang “Frank” Zhan, M.D., Ph.D., is leading the center’s research team in a bold new direction. In five years, his team intends to cure myeloma using a total immunotherapy approach with little to no chemotherapy.

“Our plan is to develop novel targeted therapies that will include immunotherapeutic approaches to reduce the need for intensive toxic chemotherapy and stem cell transplant,” said Zhan.

“The broad vision is to target myeloma using combinations of highly effective immunotherapeutics, which we aim to develop, and eventually cure myeloma.”

With previous roles at the Utah Blood and Marrow Transplant and Myeloma Program at the University of Utah’s Huntsman Cancer Institute and the Holden Comprehensive Cancer Center at the University of Iowa Health Care, Zhan is an expert in molecular genetics and drug-resistant multiple myeloma.

Zhan’s funding includes a $1.3 million from the U.S. Department of Defense (DOD) and $1.74 million from the National Institutes of Health (NIH).

“Once the biology of myeloma stem cells is better understood, more novel therapeutic targets can be created and tested, with the ultimate goal being to develop a novel therapy and prevent myeloma relapses,” said Zhan.

His lab is using the DOD grant to study the biology of specific myeloma cancer cells that can survive chemotherapy, working to find a potential cure to eradicate these cells.

These drug-resistant cells often cause relapses of myeloma and other types of cancers. Zhan believes the protein, CD24, may serve as a reliable indicator of the presence of these drug-resistant cells. and the therapeutic antibody, SWA11, may be used to target them.

“We are working to develop a specific CAR-T cell therapy for this population of patients,” Zhan said, adding that the research is still in early stages.

The NIH-funded study focuses on the NEK2 and PD-L1 genes, striving to uncover how they work and how they may fuel myeloma. The disease of patients who have these genes is difficult to cure, and the patients are at high risk for relapse.

Therapies targeting PD-L1 have been successful in treating many cancers, but attempts to demonstrate their effectiveness for myeloma have not met with the same success. Zhan believes this is probably because this gene is most common in patients who have a subtype of myeloma called hyperdiploid, and PD-L1 studies have not targeted these patients.

As for other subtypes of myeloma where PD-L1 levels are low, such as in high-risk and relapsed myelomas, Zhan believes that a combination of a NEK2 treatment and PD-1/PD-L1 treatment could be effective.

Zhan’s lab of a dozen members, including five faculty members, five post-doctorates and two senior scientists, are working to test these theories at the molecular level using a couple of different methods.

“We have made a lot of progress in this study,” Zhan said of the study that focuses on patients with high-risk myeloma with cancer cells that are drug resistant. “We have made some major advancements and increased immune response.”

“Chemotherapies, stem cell transplants and immunotherapies don’t work with them so we need to reduce the number of NEK2 genes and increase the PD-L1 levels.”
The Myeloma Center’s patient database containing over 24,000 samples with attendant microarray and clinical data from healthy donors, and patients with Plasma Cell Dyscrasia greatly assists in the Myeloma Center researchers work.

“Our database is unique, and no one has this huge of a database,” Zhan said. “Within it, we find these markers and are able to move forward to develop this therapy.”

He believes the results of the studies could reach far beyond myeloma to assist in treating many other solid tumor and blood-related cancers.

“Dr. Zhan’s ability to identify and target myeloma stem cells and the genomic classification of the disease is an immense asset to UAMS,” said Frits van Rhee, M.D., Ph.D., clinical director of the Myeloma Center. “He is greatly helping us to further the innovative treatment we have offered for more than 30 years now.” 

Donald L. Johann Jr., M.D., an associate professor in the UAMS departments of Biomedical Informatics and Internal Medicine and principal investigator of an FDA clinical trial to develop an advanced method for diagnosing and monitoring lung cancer with a simple blood test, reported Nov. 30 in Oncology Live that investigators at the Winthrop P. Rockefeller Cancer Institute have made big strides in so-called liquid biopsies over the last five years. Johann and other researchers around the world earlier reported their validation of the processes for using the technique to detect cancer. They noted that the less invasive approach, compared to tissue biopsies, can detect large tumors and metastatic cancers with about 100% accuracy.

“We can find circulating DNA (ctDNA), which are nucleic acid biomolecules shed by a tumor into the blood and detected by next-generation sequencing,” he said in the November article. “Investigators at UAMS are now working to translate foundational work into cutting-edge care for patients with cancer at all stages of disease and across tumor types and eventually for screening assays.”

When DNA is damaged, the human body has a built-in repair shop known as the DNA damage response pathway that maintains the integrity of our genetic material. 

“DNA is damaged millions of times a day, either from internal or external sources. The DNA damage response pathway is the body’s natural process of maintaining genome stability,” said Justin Leung, Ph.D., assistant professor and director for Translational Research in the UAMS Department of Radiation Oncology. 

A prominent member of the Winthrop P. Rockefeller Cancer Institute, Leung leads one of the institute’s most promising research teams focused on learning more about the DNA repair process in cancer. 

In cancer patients, DNA mutates and becomes defective, essentially dysregulating the repair process. Leung believes the study of this defective DNA and its molecular environment can uncover new therapeutic targets that attack cancer cells in the DNA damage and response pathway. 

“In a normal cell, DNA will repair just fine, but if it mutates, it won’t
be able to do its job,” said Leung.

“The more DNA breaks, the more vulnerable it becomes and more sensitive to radiation. If we target the DNA damage response pathway in cancer cells, they are more likely to die and die quickly. With the right radiation dose, mutated cells should be highly responsive to treatment.” 

Funded by more than $5 million in research grants, Leung and his team are undertaking a comprehensive study of the molecular mechanisms of genome stability and the translational aspects of targeting the DNA damage response pathway as a therapeutic strategy. 

“My team’s expertise lies in an integrated workflow of molecular biology, gene editing, cell-based assays, biochemical assays, proteomics, live-cell microscopy and data analysis. They are the pillars of the science and the magic happens in the lab.” Leung said

Similar to the BRCA 1 gene discovery in breast cancer, Leung hopes to identify new DNA repair genes involved in cancer development. Both breast and ovarian cancers are well characterized for DNA repair pathway deficiency. 

“Translationally, if we identify new genes that are druggable, we can translate that to the clinic with good therapeutic interventions in the future,” Leung said.

By broadening his research to the entire molecular environment in which DNA repair takes place, Leung hopes to identify specific molecules that can target DNA repair genes and proteins and sensitize cancer cells to radiation. 

“We are just beginning to understand what molecules control damaged DNA in most cancers,” said Leung. “We hope our findings contribute to a better understanding of DNA repair in cancer and new approaches to treatment.” 

A native of Hong Kong, Leung came to cancer research by chance. He was studying diabetes and stroke for his Ph.D. at the University of Hong Kong when a Yale scientist, who later became his first postdoctoral mentor, inspired him to pursue cancer research. Leung received his comprehensive postdoctoral training at Yale, M.D. Anderson Cancer Center and the University of Texas at Austin. 

Ready to focus on his own research interests, Leung joined UAMS in 2018 with the National Cancer Institute’s (NCI) Transition Career Development Award. In four years, his lab has received six extramural awards from NCI, the National Institute of General Medical Sciences (NIGMS) and the American Cancer Society (ACS). He is the first early stage investigator to receive NIGMS’s R35 Maximizing Investigators’ Research Award and the only current ACS Research Scholar in Arkansas. 

Including a postdoctoral fellowship awarded to Kirk West, Ph.D., Leung and his team have three active ACS grants for different projects. Leung is a two-time recipient of the Arkansas Breast Cancer Research Program research grant. 

Recently, Leung received the highly competitive TheoryLab Collaborative (TLC) grant from ACS, eligible only to ACS research scholars. The TLC award exclusively funds innovative and high-impact ideas for cancer research and will go toward a new collaboration with Wenqi Wang, Ph.D., at the University of California, Irvine to study the role of the Hippo pathway in DNA repair. 

In all, Leung’s laboratory studies:

• Chromatin biology
• Histone functions 
• Molecular genetics 
• Epigenetics 
• Cancer evolution 
• Therapeutic resistance
• Radiation response