AbstractIntroduction: EVT801 is a highly selective small molecule inhibitor of VEGFR-3 and acts by inhibiting tumor lymphangiogenesis and angiogenesis. Among the tyrosine kinase inhibitors, EVT801 has shown compelling activity in a wide range of cancer models and favorable preclinical toxicology profile. A phase I clinical study (NCT05114668) is underway to characterize safety, tolerability, pharmacokinetics of EVT801, and explore patient stratification which will be key for further development. Literature reports VEGFR-3 expression in several tumor cells - especially in kidney and liver cancers. However, we did not detect VEGFR-3 in tumor cells in translational in vivo models we explored (i.e., chemo-induced liver cancer and panel of PDX models). To clarify the situation, we validated a highly specific protocol for VEGFR-3 immunohistochemistry labelling, readily transferable to clinical centers.
Results: We evaluated many different tumor types, and eventually focused our analysis on kidney cancer and soft tissue sarcomas. Initially, VEGFR-3 expression was assessed in 29 primary kidney cancer samples and 23 metastatic kidney cancer samples with CD34 to stain vessels and D2-40 to track lymphatics. We detected VEGFR-3 expression in the endothelial cells within the kidney tumor but not in the tumor cells. Remarkably, we observed a very distinct delineation between the kidney tumor vasculature, which showed high VEGFR-3 expression, and the normal adjacent tissue, which was devoid of VEGFR-3 expression. All vessels around and in the tumor were stained by CD34, whereas D2-40 staining was limited to the peritumoral regions. In addition, we found that VEGFR-3 expression in metastases from kidney tumors matched the expression pattern of the primary tumor. This held true even in patients treated with sunitinib, positioning EVT801 as a potential treatment option after failure of such multi tyrosine kinase inhibitors. Among the samples from 103 patients with soft tissue sarcomas, VEGFR-3 was generally highly expressed; however, 3 distinct groups emerged: i) tumors with high VEGFR-3 expression in tumor cells, tumor vessels and peritumoral vessels; ii) tumors with high expression in all vessels (tumor and peritumoral) but not in the tumor cells (similar to kidney tumors); iii) tumors with intermediate expression in peritumoral vessels.
Conclusion: We were able to quantify VEGFR-3 expression in the kidney and soft tissue sarcoma cohorts plus several others, such as hepatocarcinoma and non-small cell lung cancer. This enables us selecting indications that might benefit from EVT801 as a monotherapy (e.g., clear cell renal cell carcinoma and soft tissue sarcomas) or in combination with standard of care. Accordingly, VEGFR-3 expression is retrospectively quantified during EVT801 clinical trial phase 1 trial and may be used to stratify patients in the future.
- Forums
- ASX - By Stock
- KZA
- AACR 2023 April 14-19
AACR 2023 April 14-19, page-2
-
- There are more pages in this discussion • 4 more messages in this thread...
You’re viewing a single post only. To view the entire thread just sign in or Join Now (FREE)
Featured News
Add KZA (ASX) to my watchlist
Currently unlisted public company.
The Watchlist
LU7
LITHIUM UNIVERSE LIMITED
Alex Hanly, CEO
Alex Hanly
CEO
SPONSORED BY The Market Online