Miami CFAR, ISCI and Sylvester Researchers Receive Grant to Study Stem Cell Role in Kaposi’s Sarcoma
An interdisciplinary team of Miller School of Medicine researchers has received a $1.8 million grant from the National Cancer Institute to study the role of stem cells in Kaposi’s sarcoma oncogenesis and therapy.
“Kaposi’s sarcoma (KS) is the main type of cancer that affects people with HIV/AIDS,” said Enrique A. Mesri, Ph.D., associate professor and Graduate Program Director of Microbiology and Immunology, Director of the AIDS-Malignancies Program of the Miami Center for AIDS Research, and a member of the Viral Oncology Program of the Sylvester Comprehensive Cancer Center, who is one of the study’s principal investigators. “In the beginning of the AIDS epidemic, KS was rampant in the U.S. and the Western world. Since the implementation of anti-retroviral therapy, and the subsequent control and reduction of HIV viremia, KS incidence has been reduced.
“Cases remain, however, that resist anti-retroviral therapy. As with many KS cases in Africa that are diagnosed in a very advanced form, they often are also resistant to chemotherapy. Rational design and identification of new drugs, based on the knowledge of KS mechanisms of pathogenesis, is still a critical need.”
Mesri’s co-principal investigator in this study and a related prior study has been Pascal J. Goldschmidt, M.D., Senior Vice President for Medical Affairs and Dean of the Miller School and CEO of UHealth.
KS is an enigmatic tumor, characterized by proliferation of blood vessels and of spindle shaped cells of debated cellular origin. It is caused by infection with a type of human herpesvirus — the human herpesvirus-8, also called Kaposi’s sarcoma herpesvirus or KSHV.
To gain a deeper understanding of KS tumor formation, Mesri and Goldschmidt will be seeking the answers to two questions:
1.) What cell type/s become malignant when infected by this cancer-causing virus?
2.) What is the mechanism whereby infection with the KS virus induces malignant transformation?
The second question also involves identifying the virally encoded proteins that are essential for tumor formation and, since viruses always work in the context of interactions with the infected host, how these viral proteins recruit host proteins to cause cancer. Understanding these questions is essential to developing new methods to prevent and cure KS, particularly in patients with HIV/AIDS.
“Our laboratory has a long tradition of pursuing answers to these questions,” said Mesri. “We were able to identify a key viral gene called vGPCR that not only can transform normal cells into KS cells, but also induce the secretion of the most important host factor involved in angiogenesis induction, VEGF. Our insight on potential tissues of origin of the KS cell led us to the design of mouse animal models in which KS tumors are formed by KSHV-infected cells.”
Mesri and Goldschmidt employed a combination of these tools and novel insights into the role of the protein Rac1 and oxidative stress in these processes in the prior NCI-supported study to understand how KSHV and its oncogene vGPCR were causing KS through the generation of reactive oxygen species and, at the same time, explore ways to block that process to cure the disease.
“In our prior research, we studied how viral genes were able to recruit the machinery responsible for generating reactive oxygen species,” said Goldschmidt. “The importance of this was that we were able to show, using mouse models generated in our laboratories, that we could target this machinery using anti-oxidants and Rac1 inhibitors to treat KS tumors.”
“Yet, an important breakthrough in this study happened when we used proteomics to identify the key host protein recruited by KSHV to cause KS tumors, the receptor for growth factor PDGF, known as PDGFR — which we also found was prominently activated by the virus in all the KS lesions we tested,” said Mesri. “The importance of this discovery, which we are now exploiting and developing in the new award, is that it took us in two very promising directions.”
The first direction will be an effort to understand why some KS patients do not respond to the cancer drug Imatinib/Gleevec, and to find new ways to overcome such resistance. The researchers plan to use molecular genetic methods to study how KSHV activates PDGFR in combination with new animal models of KSHV tumorigenesis.
In addition, the researchers will be employing state-of-the-art techniques, such as next-generation sequencing and proteomics, which will provide an unbiased analysis of how KS tumors respond and resist PDGFR-targeted therapies. This will generate insights and create new tools that will allow the creation of personalized therapies for AIDS-KS.
The other promising direction involves learning why KSHV uses PDGFR to transform cells. Answering that question will enable the researchers to go back to the prehistory of KS tumors. In the last stages of their prior R01 award, Mesri and Goldschmidt began a collaboration with Joshua M. Hare, M.D., Louis Lemberg Professor of Medicine and Director of the Interdisciplinary Stem Cell Institute, which will continue under the new grant.
“Combining our expertise in stem cell biology with Dr. Mesri’s lab’s expertise in KS, we were able to show for the first time that KSHV may form tumors through its ability to infect a special type of stem cell,” said Hare.
“This is truly novel and exciting,” said Mesri. “Under the new grant, we plan to demonstrate how this infected stem cell could indeed become a cancer stem cell for KS, which is primary to understanding KS tumor development and how KS tumors resist certain therapies.
“This will have enormous implications for our understanding of cancer induced by viruses —12 percent of all cancers — and for finding new cures and prevention methods for a devastating cancer that further burdens HIV/AIDS patients.”