DLX1008 (brolucizumab), a single-chain anti-VEGF-A antibody fragment with low picomolar affinity, leads to tumor involution in an in vivo model of Kaposi Sarcoma

Eason, Anthony; Sin, Sang-Hoon; Shah, Mohsin; Yuan, Hong; Phillips, Douglas J.; Droste, Miriam; Shamshiev, Abdijapar; Dittmer, Dirk P.

doi:10.1371/journal.pone.0233116

Cited by 10 publications

(5 citation statements)

References 68 publications

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“…6a, b ). Vascular endothelial growth factor (VEGF) is important for endothelial cell growth and angiogenesis, and it is expressed in KS lesions [ 26 ]. Expression of vPK in HUVECs resulted in higher secreted VEGF levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

Kaposi’s sarcoma-associated herpesvirus viral protein kinase augments cell survival

Wu,

Zhang,

Wong

et al. 2023

Cell Death Dis

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Oncogenic viruses have developed various strategies to antagonize cell death and maintain lifelong persistence in their host, a relationship that may contribute to cancer development. Understanding how viruses inhibit cell death is essential for understanding viral oncogenesis. Kaposi’s sarcoma-associated herpesvirus (KSHV) is associated with three different cancers in the human population, including Kaposi’s sarcoma (KS), the most common cancer in HIV patients. Previous studies have indicated that the KSHV-encoded viral protein kinase (vPK) impacts many processes dysregulated in tumorigenesis. Here, we report that vPK protects cells from apoptosis mediated by Caspase-3. Human umbilical vein endothelial cells (HUVECs) expressing vPK (HUVEC-vPK) have a survival advantage over control HUVEC under conditions of extrinsic- and intrinsic-mediated apoptosis. Abolishing the catalytic activity of vPK attenuated this survival advantage. We found that KSHV vPK-expressing HUVECs exhibited increased activation of cellular AKT kinase, a cell survival kinase, compared to control cells without vPK. In addition, we report that vPK directly binds the pleckstrin homology (PH) domain of AKT1 but not AKT2 or AKT3. Treatment of HUVEC-vPK cells with a pan-AKT inhibitor Miransertib (ARQ 092) reduced the overall phosphorylation of AKT, resulting in the cleavage of Caspase-3 and the induction of apoptosis. Furthermore, vPK expression activated VEGF/VEGFR2 in HUVECs and promoted angiogenesis through the AKT pathway. vPK expression also inhibited the cytotoxicity of cisplatin in vitro and in vivo. Collectively, our findings demonstrate that vPK’s ability to augment cell survival and promote angiogenesis is critically dependent on AKT signaling, which is relevant for future therapies for treating KSHV-associated cancers.

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Section: Resultsmentioning

confidence: 99%

Kaposi’s sarcoma-associated herpesvirus viral protein kinase augments cell survival

Wu,

Zhang,

Wong

et al. 2023

Cell Death Dis

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“…Formalin‐fixed paraffin‐embedded blocks containing the skin biopsies were sectioned at the UNC Pathology core facility. Sections were stained for LANA following a previously described protocol 36 (Figure S1). A dilution factor of 1:100 of mouse anti‐human LANA antibodies was used (Leica Biosystems Cat# NCL‐L‐HHV8‐LNA).…”

Section: Methodsmentioning

confidence: 99%

A prospective cohort study identifies two types of HIV+ Kaposi Sarcoma lesions: proliferative and inflammatory

Moorad,

Kasonkanji,

Gumulira

et al. 2023

Intl Journal of Cancer

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Kaposi sarcoma (KS) is the most common cancer in people living with HIV (PLWH) in many countries where KS‐associated herpesvirus is endemic. Treatment has changed little in 20 years, but the disease presentation has. This prospective cohort study enrolled 122 human immunodeficiency virus (HIV) positive KS patients between 2017 and 2019 in Malawi. Participants were treated with bleomycin, vincristine and combination antiretroviral therapy, the local standard of care. One‐year overall survival was 61%, and progression‐free survival was 58%. The 48‐week complete response rate was 35%. RNAseq (n = 78) differentiated two types of KS lesions, those with marked endothelial characteristics and those enriched in inflammatory transcripts. This suggests that different KS lesions are in different disease states consistent with the known heterogeneous clinical response to treatment. In contrast to earlier cohorts, the plasma HIV viral load of KS patients in our study was highly variable. A total of 25% of participants had no detectable HIV; all had detectable KSHV viral load. Our study affirms that many KS cases today develop in PLWH with well‐controlled HIV infection and that different KS lesions have differing molecular compositions. Further studies are needed to develop predictive biomarkers for this disease.

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“…It is composed of only 255 amino acids (molecular mass of approximately 26 kDa), with high solubility and high permeability, which facilitate its delivery from the vitreous into the retina and choroid ( Tadayoni et al, 2021 ). Meanwhile, brolucizumab was reported to be more effective to bind VEGF (binding affinity in a low picomolar range) than other anti-VEGF agents, about 11 times more efficient than aflibercept ( Eason et al, 2020 ; Rahman and Singer, 2020 ). It is also a long duration anti-nAMD drug, which requires monthly intravitreal administration.…”

Section: Inhibitors Targeting Vegf/vegfr Interactionmentioning

confidence: 99%

Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis

Wang,

Liu,

Broussy

et al. 2024

Front. Pharmacol.

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Vascular endothelial growth factors (VEGF), Vascular endothelial growth factor receptors (VEGFR) and their downstream signaling pathways are promising targets in anti-angiogenic therapy. They constitute a crucial system to regulate physiological and pathological angiogenesis. In the last 20 years, many anti-angiogenic drugs have been developed based on VEGF/VEGFR system to treat diverse cancers and retinopathies, and new drugs with improved properties continue to emerge at a fast rate. They consist of different molecular structures and characteristics, which enable them to inhibit the interaction of VEGF/VEGFR, to inhibit the activity of VEGFR tyrosine kinase (TK), or to inhibit VEGFR downstream signaling. In this paper, we reviewed the development of marketed anti-angiogenic drugs involved in the VEGF/VEGFR axis, as well as some important drug candidates in clinical trials. We discuss their mode of action, their clinical benefits, and the current challenges that will need to be addressed by the next-generation of anti-angiogenic drugs. We focus on the molecular structures and characteristics of each drug, including those approved only in China.

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DLX1008 (brolucizumab), a single-chain anti-VEGF-A antibody fragment with low picomolar affinity, leads to tumor involution in an in vivo model of Kaposi Sarcoma

Cited by 10 publications

References 68 publications

Kaposi’s sarcoma-associated herpesvirus viral protein kinase augments cell survival

Kaposi’s sarcoma-associated herpesvirus viral protein kinase augments cell survival

A prospective cohort study identifies two types of HIV+ Kaposi Sarcoma lesions: proliferative and inflammatory

Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis

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