Combined VEGFR and MAPK pathway inhibition in angiosarcoma

Abstract

Angiosarcoma is an aggressive malignancy of endothelial cells that carries a high mortality rate. Cytotoxic chemotherapy can elicit clinical responses, but the duration of response is limited. Sequencing reveals multiple mutations in angiogenesis pathways in angiosarcomas, particularly in vascular endothelial growth factor (VEGFR) and mitogen-activated protein kinase (MAPK) signaling. We aimed to determine the biological relevance of these pathways in angiosarcoma. Tissue microarray consisting of clinical formalin-fixed paraffin embedded tissue archival samples were stained for phospho- extracellular signal-regulated kinase (p-ERK) with immunohistochemistry. Angiosarcoma cell lines were treated with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, pan-VEGFR inhibitor cediranib, or combined trametinib and cediranib and viability was assessed. Reverse phase protein array (RPPA) was performed to assess multiple oncogenic protein pathways. SVR angiosarcoma cells were grown in vivo and gene expression effects of treatment were assessed with whole exome RNA sequencing. MAPK signaling was found active in over half of clinical angiosarcoma samples. Inhibition of MAPK signaling with the MEK inhibitor trametinib decreased the viability of angiosarcoma cells. Combined inhibition of the VEGF and MAPK pathways with cediranib and trametinib had an additive effect in in vitro models, and a combinatorial effect in an in vivo model. Combined treatment led to smaller tumors than treatment with either agent alone. RNA-seq demonstrated distinct expression signatures between the trametinib treated tumors and those treated with both trametinib and cediranib. These results indicate a clinical study of combined VEGFR and MEK inhibition in angiosarcoma is warranted.

Hedyotis diffusa Willd. Suppresses Hepatocellular Carcinoma via Downregulating AKT/mTOR Pathways

“…The development of cancer is strictly regulated by a variety of intracellular signaling pathways, such as AKT [ 17 ], mitogen-activated protein kinase (MAPK) [ 18 ], and STAT3 [ 19 ] pathways. The AKT signaling pathway is related to various types of cancer and is often related to anticancer therapy.…”

Genetic context of oncogenic drivers dictates vascular sarcoma development in aP2‐Cre mice

“…We and others have previously identified activation of the RAS-MEK-ERK and mTOR pathways in mouse angiosarcoma tumors illustrated by hyperphosphorylation of ERK and S6, respectively (see supplementary material, Figure S1A) [18,46]. To determine the relevance of these pathways in the ADC106 cells, we treated cells with the MEK inhibitor trametinib to inhibit the RAS-MEK-ERK pathway and the mTOR pathway inhibitor rapamycin.…”

Angiosarcomas of the head and neck: Impact of large data analysis on clinical management

“…Other agents which target blood vessel development are chemical modulators of the vascular endothelial growth factor receptor pathway, which provide significant response in angiosarcomas. [37][38][39] Altogether, the rarity of head and neck angiosarcomas has limited empiric determination of its optimal treatment paradigm.…”

“…The goal of neoadjuvant approaches is to reduce the extent of ablative surgery and reconstruction, select patients who may benefit from postoperative taxane‐based chemotherapy, and improve overal outcome. Other agents which target blood vessel development are chemical modulators of the vascular endothelial growth factor receptor pathway, which provide significant response in angiosarcomas 37–39 . Altogether, the rarity of head and neck angiosarcomas has limited empiric determination of its optimal treatment paradigm.…”