Product information and disease description Place of product in therapy Disease description

Pathophysiology

6 evidence topics · 4 sources

Summary: cholangiocarcinogenesis, molecular subtypes, and angiogenic signalling

Biliary tract cancers arise from cholangiocytes and related biliary epithelium, and can also develop from peribiliary glands and hepatocytes depending on the underlying liver disease and location. Chronic inflammation and bile stasis drive cholangiocarcinogenesis through pro-inflammatory cytokines, growth factors, and bile acids in the tumour microenvironment. The tumours are highly desmoplastic, with a reactive stroma of cancer-associated fibroblasts that secrete paracrine factors promoting proliferation, chemotaxis, and angiogenesis, including VEGF-A and VEGF-C.

Genomic alterations track with anatomic subtype. FGFR2 fusions and IDH1 and IDH2 mutations occur almost exclusively in intrahepatic disease, while PRKACA and PRKACB fusions and ELF3 mutations characterize extrahepatic tumours. In a real-world comprehensive genomic profiling series of 91 biliary tract tumours, the most frequently altered genes were TP53 (51 of 91, 56.0%), KRAS (21 of 91, 23.1%), CDKN2A (18 of 91, 19.8%), SMAD4 (14 of 91, 15.4%), and ARID1A or PBRM1 (12 of 91, 13.2%).

Angiogenesis is a relevant pathway for the disease and for the mechanism of tovecimig. Transcriptomic stratification of cholangiocarcinoma identified VEGF signalling among the main oncogenic networks in participants with poor overall survival. In intrahepatic cholangiocarcinoma, NOTCH1, HES1, MMP13, DLL4, and VEGFA were significantly upregulated in tumours compared with adjacent non-tumorous tissue, and selective NOTCH1 inhibition downregulated VEGFA, HES1, and MMP13 and inhibited vessel formation in an in vitro angiogenesis model.

Pathophysiology: cell of origin and desmoplastic tumour immune microenvironment

“CCA displays features of cholangiocyte differentiation and probably arises predominantly from the epithelial cells lining the bile ducts, which are termed cholangiocytes; however, the cancers may also develop from peribiliary glands and hepatocytes, depending on the underlying liver disease and location” (opens the source at this quote in a new tab)
“These cancers are highly desmoplastic and are enmeshed in dense networks of inflammatory cells and matrix termed the tumour immune microenvironment” (opens the source at this quote in a new tab)

“CCA tumours, and particularly iCCAs and pCCAs, are characterized by a reactive desmoplastic stroma containing cancer-associated fibroblasts (CAFs) that crosstalk with CCA cells secreting paracrine factors such as heparin-binding EGF-like growth factor, stromal-cell derived factor 1 (SDF1), platelet-derived growth factor (PDGF)-B and extracellular matrix (ECM) proteins” (opens the source at this quote in a new tab)
“CAFs secrete a multitude of signalling molecules (such as IL-1β, PDGF-B, heparin-binding EGF-like growth factor and SDF1) that promote cancer progression by enhancing proliferation, survival, chemotaxis and angiogenesis” (opens the source at this quote in a new tab)
“Following stimulation by PDGF-D originated from the tumoural cholangiocytes in vitro, CAFs secrete VEGF-A and VEGF-C, which recruit and assemble lymphatic endothelial cells in vascular structures susceptible to tumour cell intravasation” (opens the source at this quote in a new tab)

Pathophysiology: cholangiocarcinogenesis driven by inflammatory and growth factor signalling

“Cholangiocarcinogenesis is orchestrated by a complex interplay of extracellular ligands (such as pro-inflammatory cytokines, growth factors and bile acids, among others), which are present in the tumour microenvironment (TME), and increased expression and/or aberrant activation of cell surface receptors and the deregulation of intracellular signalling pathways, finally leading to cell proliferation, survival and genetic and/or epigenetic alterations” (opens the source at this quote in a new tab)
“The most common genes that might be mutated or amplified resulting in the overactivation of some of these pathways are KRAS, BRAF, ARID1, PBRM1, BAP1, IDH1 and IDH2.” (opens the source at this quote in a new tab)
“The main oncogenic networks comprised WNT-CTNNB1, MYC, ERBB, TNF and VEGF signalling, emphasizing cell survival signalling pathways in patients with poor OS” (opens the source at this quote in a new tab)

Pathophysiology: genomic alterations differ by anatomic subtype

“Among CCAs, genetic aberrations differ depending on their anatomic locations; for example, FGFR2 fusions are almost exclusively found in iCCAs, whereas PRKCA–PRKCB fusions are observed in pCCAs and dCCAs” (opens the source at this quote in a new tab)

“Small bile duct iCCA can be characterized by isocitrate dehydrogenase (IDH1, IDH2) mutations or fibroblast growth factor receptor 2 (FGFR2) fusions” (opens the source at this quote in a new tab)

Pathophysiology: frequency of recurrent alterations in a real-world profiling series

“The most frequently altered genes were TP53 (51/91, 56.0%), KRAS (21/91, 23.1%), CDKN2A (18/91, 19.8%), SMAD4 (14/91, 15.4%), and ARID1A/PBRM1 (12/91, 13.2%).” (opens the source at this quote in a new tab)

Pathophysiology: DLL4, VEGFA, and Notch-dependent angiogenesis in intrahepatic cholangiocarcinoma

“Finally, RNA-sequencing expression data of iCCA patients and matched surrounding normal liver tissues downloaded from the GEO database demonstrated that NOTCH1, HES1, MMP13, DLL4, and VEGFA genes were significantly upregulated in tumors compared with adjacent nontumorous tissues.” (opens the source at this quote in a new tab)
“Furthermore, gene expression analysis of iCCA mouse tissues treated with LY3039478 revealed a downregulation of VEGFA, HES1, and MMP13 genes.” (opens the source at this quote in a new tab)
“In the same tissues, DLL4 and CD31 co-localized, and their expression was significantly inhibited in the treated mice, as it happened in the case of MMP13.” (opens the source at this quote in a new tab)
“In an in vitro angiogenesis model, LY3039478 inhibited vessel formation, which was restored by the addition of MMP13.” (opens the source at this quote in a new tab)
“Thus, the present data provide new knowledge on Notch signaling in iCCA, and support the inhibition of the Notch cascade as a promising strategy for the treatment of this disease.” (opens the source at this quote in a new tab)