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7.23.2018

Researcher Identifies Viral Activation Pathway, Pointing Toward Therapies for AIDS-Kaposi Sarcoma

A Sylvester Comprehensive Cancer Center viral oncology researcher has discovered a key cellular pathway associated with activating Kaposi sarcoma, a rare cancer most often found in people with HIV/AIDS or otherwise compromised immune systems.

“We have identified the main oncogenic driver of the tumor and the viral mechanism of activation,” said Enrique A. Mesri, Ph.D., professor of microbiology and immunology at the Miller School of Medicine, director of the Miami Center for AIDS Research (CFAR) AIDS Malignancies Program, and lead author of a study published in the journal PLOS Pathogens.

“Our findings support the repurposing of Olaratumab/Lartruvo, an anti-cancer drug recently approved by the U.S. Food and Drug Administration, for its use in AIDS-associated Kaposi sarcoma,” Mesri said. “Our team’s initial concept for a clinical trial of the drug has been favorably viewed by Eli Lilly and members of the AIDS Malignancies Consortium, and is now being reviewed by the National Cancer Institute.”

Mesri led a University of Miami Miller School of Medicine research team that included Pascal Goldschmidt, M.D., professor of cardiology and former dean of the Miller School of Medicine; Julian Naipauer, Ph.D., a postdoctoral associate; and Lucas Cavallin, M.D., Ph.D., and Qi Ma, M.D., Ph.D., two former lab members. Their study, “KSHV-Induced Ligand Mediated Activation of PDGF Receptor-Alpha Drives Kaposi’s Sarcomagenesis,” was done in collaboration with the Departments of Dermatology and Pathology. Other Miller School co-authors were Sachin Gupta, Ph.D., Mani Kurian, Ph.D., Paola Locatelli, M.D., Ph.D., Paolo Romanelli, M.D., and Mehrdad Nadji, M.D.

Kaposi sarcoma, which causes lesions to grow in the skin, lymph nodes, internal organs, and mucous membranes, is caused by a type of herpes virus called Kaposi sarcoma herpes virus (KSHV). It is most common in individuals with late-stage HIV/AIDS or those taking immunosuppressant medications.

Mesri’s study focused on how the KSHV virus activates normal “host” tissue cells to induce Kaposi sarcoma. “We found that the PDGF receptor alpha (PDGFRA) on the host cells plays the key role in the development of KSHV-induced tumors in laboratory mice,” he said. “The invading virus carries genes that activate the production of PDGF– the proteins ligands that trigger the PDGF receptors – and signal the host cell to drive the process of malignant proliferation.”

Treating Kaposi sarcoma is very challenging, because most patients are already taking antiretroviral therapy (ART) for HIV/AIDS, Mesri said. “Managing this cancer becomes even more complicated when patients fall out of compliance with their ART regimen,” he added. “Therefore, we need to find new strategies for preventing KSHV from triggering this deadly cancer and therapies that can be combined with ART. Our study opens the possibility of using Olaratumab as an anti-PDGF receptor immunotherapy – a promising and straightforward approach because it could be given in combination with Doxorubicin, which is an AIDS-KS frontline therapy.”

Mesri added that the discovery that the viral mechanism of PDGFRA carcinogenicity involves the need for ligand activation of the PDGF receptor will pave the way for the use of Olaratumab/Lartruvo, which is a monoclonal antibody that blocks this ligand-receptor interaction.

“Since we also found that PDGFRA activation is a prominent feature of most KS tumors, we are confident that efficacious targeting of PDGFRA via immunotherapy or inhibitory drugs could benefit many AIDS-KS patients.”

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