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.”