Published Wednesday, December 25, 2019
EBioMedicine by THE LANCET
The oncogenic and druggable hPG80 (Progastrin) is overexpressed in multiple cancers and detected in the blood of patients.
Benoit You, Frédéric Mercier, Eric Assenat, Carole Langlois-Jacques, Olivier Glehen, Julien Soulé, Léa Payen, Vahan Kepenekian, Marie Dupuy, Fanny Belouin, Eric Morency, Véronique Saywell, Maud Flacelière, Philippe Elies, Pierre Liaud, Thibault Mazard, Delphine Maucort-Boulch, Winston Tan, Bérengère Vire, Laurent Villeneuve, Marc Ychou, Manish Kohli, Dominique Joubert, Alexandre Prieur
Research in context
Evidence before study
The National Cancer Institute recently highlighted the need for biomarkers to improve early detection of cancers, monitor treatment effects and detect disease relapses. Therefore, the identification of a new tumor blood-based marker with broad expression across tumor types might have a significant impact on diagnostic and follow-up of patients. hPG80 (progastrin) was shown to be over-expressed in human colorectal tumor cells. Interestingly, GAST is a direct target of the Wnt/ß-catenin/ Tcf4 oncogenic pathway. Since this pathway is activated in many other cancers and plays a major function in cancer stem cells survival, we hypothesized that hPG80 (i) might be expressed by other types of cancers, and would be present in the blood of patients with tumors different from colorectal cancers and (ii) might be a drug target for various type of cancers.
Added value of this study
Here we show that hPG80 is expressed by the tumor and present in the blood of 11 different types of cancer patients. Two retrospective kinetic studies where blood samples were collected regularly from cancer patients undergoing different treatments revealed strong associations between longitudinal hPG80 concentrations and anti-cancer treatment efficacy. We provide data showing the decrease of hPG80 after surgery in a cohort of patients with peritoneal involvements from gastrointestinal cancers, treated with peri-operative chemotherapy regimens and cytoreductive surgery. We also show the correlation between hPG80 levels and standard imaging in a cohort of patients with hepatocellular carcinoma, managed with local or systemic treatments, including patients with no detectable levels of alpha-fetoprotein. Finally, we show that targeting hPG80 with our humanized antibody decreases self-renewal capacity of cancer stem cells from various origins.
Implications of all available evidence
The technology we developed to detect hPG80 in the blood is robust, reliable and inexpensive, making this test easy to implement by oncologists. This technology could be used to improve early cancer diagnosis and treatment efficacy monitoring. Furthermore, in this study we show that our anti-hPG80 therapeutic antibody, that was initially found to target the Wnt pathway and decrease self-renewal capacity in cancer stem cells from colorectal cancer, is envisioned to have the same effect on tumors from other origins.