Tyro3 is highly upregulated and expressed in primary effusion lymphoma

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The researchers reported in the journal Proceedings of the National Academy of Sciences they identified a novel therapeutic target for primary effusion lymphoma, a type of non-Hodgkin lymphoma caused by infection with the Kaposi’s sarcoma-associated herpesvirus, also known as human herpesvirus-8.

Researchers at the UNC Lineberger Comprehensive Cancer Center have discovered a hyperactive cell signal that contributes to tumor growth in an aggressive blood cancer.

They also developed an experimental therapeutic to block the signal and slow tumor growth.

“We found a protein called Tyro3 that’s highly upregulated and expressed in a subtype of non-Hodgkin lymphoma, called primary effusion lymphoma,” said UNC Lineberger’s Blossom Damania, Ph.D., vice dean for research in the UNC School of Medicine, the Cary C. Boshamer Distinguished Professor of Microbiology and Immunology, and co-director of the UNC Lineberger virology and global oncology programs.

“We also developed a compound that targeted Tyro3, and we found that it killed primary effusion lymphoma cells and tumors.”

Primary effusion lymphoma is a highly aggressive subtype of non-Hodgkin lymphoma, a type of blood cancer involving abnormally growing white blood cells.

“Patients with primary effusion lymphoma have a poor prognosis with a median survival time of approximately six months post-diagnosis,” said Jason Wong, the paper’s first author and a graduate student in the UNC School of Medicine Department of Microbiology and Immunology.

“Since current treatment options can be ineffective, finding new therapeutic targets is a high priority.

In their recent study, Damania and her colleagues searched for cell signals called kinases that were hyperactive in primary effusion lymphoma, as well as in other types of non-Hodgkin lymphoma.

They collaborated with UNC Lineberger’s Gary Johnson, Ph.D., Kenan Distinguished Professor in the UNC School of Medicine, to characterize the activity of the kinase signals in the cancer cells.

Kinases help to control cell signaling, telling cells to grow and divide.

Their studies showed that Tyro3 kinase was uniquely hyperactive in primary effusion lymphoma cells compared with normal cells, and they found it could activate a pathway that promotes the cancer’s survival.

When they treated the cells with a compound they developed, UNC3810A, they saw a dose-dependent activation of cell death and significant suppression of tumor growth.

The compound was developed in the lab of UNC Lineberger’s Xiaodong Wang, Ph.D., research associate professor in the UNC Eshelman School of Pharmacy and medicinal chemistry director of the UNC Center for Integrative Chemical Biology and Drug Discovery.

“UNC3810A was used as an in vivo tool compound to understand the biological roles of Tyro3 in primary effusion lymphoma in this study,” Wang said.

“The work towards optimizing UNC3810A to preclinical candidate will be continued in my lab.”

“We identified a new target in a subtype of non-Hodgkin lymphoma, and this target is also upregulated in other types of cancers besides lymphomas, and so potentially the drug we developed can be used for multiple cancers,” Damania said.


Primary effusion lymphoma (PEL) is a rare and aggressive disease, affecting a unique population of patients who are often elderly or immunocompromised.

PEL is associated with human herpesvirus type-8 infection and most commonly presents as malignant effusions of the body cavities.

Patients diagnosed with PEL often have a compromised immune system from secondary conditions such as HIV. Chemotherapy has traditionally been the cornerstone of treatment for patients with a good performance status and no significant comorbidities.

However, an optimal regimen does not exist.

Most patients with PEL experience a relapse after frontline therapy within 6–8 months and subsequently require further treatment.

In recent years, our understanding of the molecular drivers and environmental factors affecting the pathogenesis of PEL has expanded.

This review will discuss the pathogenesis of PEL and various management approaches available in the frontline and relapsed setting as well as targeted agents that have shown promise in this disease.

Originally referred to as body cavity lymphoma, primary effusion lymphoma (PEL) is a distinct B-cell non-Hodgkin lymphoma (NHL) with an aggressive phenotype.

It is caused by human herpesvirus type 8 (HHV8), also referred to as Kaposi sarcoma-associated herpesvirus (KSHV).1

This virus was initially described in association with AIDS-associated Kaposi sarcoma (KS) in 1994.2 

Subsequently, PEL was found to be associated with HHV8 in 1995 and was first reported as a unique neoplasm by the World Health Organization (WHO) classification in 2001.3

Epidemiology

PEL is rare and accounts for ~4% of HIV-associated NHL and <1% of non-HIV-related lymphomas.4 There is a male predominance of 6:1.5 

PEL typically presents in middle-aged patients infected with HIV or harboring other immunocompromised states, such as recipients of solid-organ transplants, patients with cirrhosis, and in the elderly, often in HHV8 endemic areas.610 Epstein Bar virus (EBV) co-infection is commonly found (60%–90% of cases) although its role in the pathogenesis of PEL is not clear.11 EBV-negative PELs are typically found in elderly HIV-negative patients from HHV8-endemic areas.12

Pathogenesis

The gamma-herpesvirus HHV8 is found in association with a variety of malignancies including PEL, KS, a variant of Multicentric Castleman Disease, HHV8-positive diffuse large B-cell lymphoma (DLBCL), and germinotropic lymphoproliferative disease.4,13

It is universally implicated with the oncogenesis of PEL, infecting the B-cell during its latent phase and replicating during the lytic phase.6,14 

In the latent phase of infection by HHV8, many viral transcripts are expressed promoting oncogenesis.

These include latency-associated nuclear antigen (LANA), viral FLICE inhibitory protein (v-FLIP) and viral cyclin (vCyclin) and are implicated in the progression of HHV8-associated malignancies.3 

LANA maintains the latent phase of the virus, and additionally represses the tumor suppressor protein p53 and retinoblastoma protein, leading to cell growth and survival.15,16 

It also may contribute to NOTCH dysregulation and tumor progression.17 vCyclin and v-FLIP contribute to tumor growth via constitutively activating cyclin-dependent kinase 6 and the transcription factor nuclear factor kappa B (NF-κB) pathway, respectively, leading to tumor proliferation and inhibition of apoptosis while maintaining viral latency.18 HHV8 additionally produces interleukin IL-6 (vIL-6) which is found in a high concentration in PEL-related effusions and induces VEGF increasing vascular permeability and augmenting the formation of PEL-related effusions.19 

Additionally, vIL-6 prevents apoptosis by suppressing proapoptotic cathepsin D. Other HHV8 genes expressed during the latent phase of the viral life cycle affect oncogenesis via cell binding, proliferation, apoptosis, angiogenesis, cytokine production, B-cell proliferation all leading to tumor growth.4,13 

The lytic and reproductive phase of HHV8 leads to lysis and death of the infected cell therefore it behooves the disease and virus to remain in the latent phase to promote tumor growth and cell mortality.


More information: Jason P. Wong el al., “Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma,” PNAS (2019). www.pnas.org/cgi/doi/10.1073/pnas.1903991116

Journal information: Proceedings of the National Academy of Sciences
Provided by UNC Lineberger Comprehensive Cancer Center

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