Last updated: Jully 2, 2021
Prognostic Value of Plasma hPG80 (Circulating Progastrin) in Metastatic Renal Cell Carcinoma
Jan, 2021
Simple Summary
Metastatic renal cell carcinoma (mRCC) accounts for one-third of all newly diagnosed renal cell cancers. A better understanding of the biology and molecular basis of disease progression has resulted in several drug targets being identified and led to approval of several new drugs for treating mRCC in the past decade. A growing need has emerged for identifying novel molecular tumor biology based and stage-specific prognostic and predictive biomarkers in mRCC reflective of biology beyond the currently available prognostic models which are solely based on clinical characteristics. We investigated hPG80 (circulating progastrin), which is associated with kidney cancer biology and found that hPG80 levels is both an independent prognostic marker in mRCC and also improves current clinical prognostic models. This will help stratify mRCC patients more accurately in future and improve the management of mRCC patients.
Abstract
Precise management of kidney cancer requires the identification of prognostic factors. hPG80 (circulating progastrin) is a tumor promoting peptide present in the blood of patients with various cancers, including renal cell carcinoma (RCC). In this study, we evaluated the prognostic value of plasma hPG80 in 143 prospectively collected patients with metastatic RCC (mRCC). The prognostic impact of hPG80 levels on overall survival (OS) in mRCC patients after controlling for hPG80 levels in non-cancer age matched controls was determined and compared to the International Metastatic Database Consortium (IMDC) risk model (good, intermediate, poor). ROC curves were used to evaluate the diagnostic accuracy of hPG80 using the area under the curve (AUC). Our results showed that plasma hPG80 was detected in 94% of mRCC patients. hPG80 levels displayed high predictive accuracy with an AUC of 0.93 and 0.84 when compared to 18–25 year old controls and 50–80 year old controls, respectively. mRCC patients with high hPG80 levels (>4.5 pM) had significantly lower OS compared to patients with low hPG80 levels (<4.5 pM) (12 versus 31.2 months, respectively; p = 0.0031).
Adding hPG80 levels (score of 1 for patients having hPG80 levels > 4.5 pM) to the six variables of the IMDC risk model showed a greater and significant difference in OS between the newly defined good-, intermediate- and poor-risk groups (p = 0.0003 compared to p = 0.0076). Finally, when patients with IMDC intermediate-risk group were further divided into two groups based on hPG80 levels within these subgroups, increased OS were observed in patients with low hPG80 levels (<4.5 pM). In conclusion, our data suggest that hPG80 could be used for prognosticating survival in mRCC alone or integrated to the IMDC score (by adding a variable to the IMDC score or by substratifying the IMDC risk groups), be a prognostic biomarker in mRCC patients.
Manish Kohli 1,*, Winston Tan 2, Bérengère Vire 3, Pierre Liaud 3, Mélina Blairvacq 3, Frederic Berthier 4,
Daniel Rouison 4, George Garnier 4, Léa Payen 5, Thierry Cousin 6, Dominique Joubert 6 and Alexandre Prieur 6,*
The oncogenic and druggable hPG80 (Progastrin) is overexpressed in multiple cancers and detected in the blood of patients
Dec, 2019
EBiomedicine by THE LANCET déc. 2019
Authors : Benoit You Frédéric Mercier Eric Assenat Carole Langlois-Jacques Olivier Glehen Julien Soulé et al.
In colorectal cancer, hPG80 (progastrin) is released from tumor cells, promotes cancer stem cells (CSC) self-renewal and is detected in the blood of patients. Because the gene GAST that encodes hPG80 is a target gene of oncogenic pathways that are activated in many tumor types, we hypothesized that hPG80 could be expressed by tumors from various origins other than colorectal cancers, be a drug target and be detectable in the blood of these patients. […]
Research in context
Evidence before study
The National Cancer Institute recently highlighted the need forbiomarkers 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 inmany 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 gastroin-testinal cancers, treated with peri-operative chemotherapy regimens and cytoreductive surgery. We also show the correlationbetween 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 isr obust, 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.
Direct Comparison of Diagnostic Performance of 9 Quantitative Fecal Immunochemical Tests for Colorectal Cancer Screening
Sep, 2017
Gastroenterology, 2017 September
Authors : Anton Gies1, Katarina Cuk2, Petra Schrotz-King1, Hermann Brenner
A variety of fecal immunochemical tests (FITs) for hemoglobin (Hb) are used in colorectal cancer screening. It is unclear to what extent differences in reported sensitivities and specificities reflect true heterogeneity in test performance or differences in study populations or varying pre-analytical conditions. We directly compared the sensitivity and specificity values with which 9 quantitative (laboratory-based and point-of-care) FITs detected advanced neoplasms (AN) in a single colorectal cancer screening study. […]
Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study.
Dec, 2016
JAMA Oncol. 2016 Dec 3.
Authors : Global Burden of Disease Cancer Collaboration, Fitzmaurice, Allen, Barber, Barregard, Bhutta, Brenner, Dicker .../... Zaidi, Zaki, Zenebe, Murray, Naghavi.
Cancer is the second leading cause of death worldwide. Current estimates on the burden of cancer are needed for cancer control planning. OBJECTIVE:
To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 32 cancers in 195 countries and territories from 1990 to 2015. […]
Progastrin a new pro-angiogenic factor in colorectal cancer
Jun, 2015
Oncogene. 2015 June Authors : Najib S1, Kowalski-Chauvel A1, Do C1, Roche S2, Cohen-Jonathan-Moyal E3, Seva C1.Angiogenesis is essential in tumor progression and metastatic process, and increased angiogenesis has been associated with poor prognosis and relapse of colorectal cancer (CRC). VEGF has become the main target of anti-angiogenic therapy. However, most patients relapse after an initial response or present a resistance to the treatment. Identification of new pro-angiogenic factors may help to improve anti-angiogenic therapy. In this study, we demonstrated that the pro-hormone progastrin (PG), over-expressed in[…]
Wnt Signaling in Cancer
May, 2012
Cold Spring Harb Perspect Biol. 2012 MayAuthors : Paul PolakisAberrant regulation of the Wnt signaling pathway is a prevalent theme in cancer biology. From the earliest observation that Wnt overexpression could lead to malignant transformation of mouse mammary tissue to the most recent genetic discoveries gleaned from tumor genome sequencing, the Wnt pathway continues to evolve as a central mechanism in cancer biology. This article summarizes the evidence supporting a role for Wnt signaling in human cancer. This includes a review of […]
Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis
Aug, 2000
J Clin Invest. 2000 August Authors : Theodore J. Koh,1 Clemens J. Bulitta,1 John V. Fleming,1 Graham J. Dockray,2 Andrea Varro,2 and Timothy C. Wang1Mutations in the adenomatous polyposis coli (APC) tumor suppressor gene occur in most colorectal cancers and lead to activation of β-catenin. Whereas several downstream targets of β-catenin have been identified (c-myc, cyclin D1, PPARδ), the precise functional significance of many of these targets has not been examined directly using genetic approaches. Previous studies have shown that […]
Targeting the Wnt pathway and cancer stem cells with anti-progastrin humanized antibodies:
a major breakthrough for K-RAS mutated colorectal cancer treatment
Jun, 2017
Clinical Cancer Research, 2017 JuneAuthors : Alexandre Prieur, Monica Cappellini, Guillaume Habif, Marie-Paule Lefranc, Thibault Mazard, Eric Morency, Jean-Marc Pascussi, .../... Chris Planque, Eric Assenat, Frédéric Bibeau, Jean-François Bourgaux, Pascal Pujol, Alain Sézeur, Marc Ychou and Dominique JoubertPatients with metastatic colorectal cancer (CRC) suffer from disease relapse mainly due to cancer stem cells (CSC). Interestingly, they have an increased level of blood progastrin, a tumor-promoting peptide essential for[…]
Autocrine Secretion of Progastrin Promotes the Survival and Self-Renewal of Colon Cancer Stem-like Cells.
Jun, 2016
Cancer Res. 2016 June Authors : Giraud, Failla, Pascussi, Lagerqvist, Ollier, Finetti, Bertucci, Ya, Gasmi, Bourgaux, Prudhomme, Mazard, Ait-Arsa, Houhou, Birnbaum, Pélegrin, Vincent, Ryall, Joubert, Pannequin, Hollande.Subpopulations of cancer stem-like cells (CSC) are thought to drive tumor progression and posttreatment recurrence in multiple solid tumors. However, the mechanisms that maintain stable proportions of self-renewing CSC within heterogeneous tumors under homeostatic conditions remain poorly understood. Progastrin is a secreted peptide that exhibits tumor-forming potential in colorectal cancer, where it regulates pathways known to modulate colon CSC behaviors. In this study, we investigated the role of progastrin in […]
Novel roles of gastrin
Jul, 2014
J Physiol. 2014 Jul 15Authors : Dimaline, VarroThe existence of the hormone gastrin in the distal stomach (antrum) has been known for almost 110 years, and the physiological function of this amidated peptide in regulating gastric acid secretion via the CCK2 receptor is now well established. In this brief review we consider important additional roles of gastrin, including regulation of genes encoding proteins such as […]
The wnt target jagged-1 mediates the activation of notch signaling by progastrin in human colorectal cancer cells.
Aug, 2009
Cancer Res. 2009 August Authors : Julie Pannequin, Caroline Bonnans, Nathalie Delaunay, Joanne Ryan, Jean-François Bourgaux, Dominique Joubert and Frédéric HollandeThe Wnt and Notch signaling pathways are both abnormally activated in colorectal cancer (CRC). We recently showed that progastrin depletion inhibited Wnt signaling and increased goblet cell differentiation of CRC cells. Here, we show that progastrin down-regulation restores the expression by CRC cells of the early secretory lineage marker Math-1/Hath-1 due to […]
Expression but incomplete maturation of progastrin in colorectal carcinomas
Apr, 1993
Gastroenterology. 1993 April Authors : Van Solinge WW1, Nielsen FC, Friis-Hansen L, Falkmer UG, Rehfeld JF.To evaluate the hypothesis that gastrin is a local growth factor in colonic carcinomas, the expression of gastrin messenger RNA (mRNA) and peptides were examined in five human colon carcinoma cell lines, 12 solid colon carcinomas, and normal colonic tissue... […]
Nature reviews, 2017 May Authors : William G. Kaelin JrAn alarming number of papers from laboratories nominating new cancer drug targets contain findings that cannot be reproduced by others or are simply not robust enough to justify drug discovery efforts. This problem probably has many causes, including an underappreciation of the danger of being misled by off-target effects when using pharmacological or genetic perturbants in complex biological assays. This danger is particularly acute when, as is often the case in cancer pharmacology, the biological phenotype being measured is a […]
The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: implications in targeted cancer therapies
Feb, 2016
Lab Invest. 2016 February Yang, Wang, Zhang, Wang, Nan, Li, Zhang, Mohammed, Haydon, Luu, Bi, He.he canonical WNT/β-catenin signaling pathway governs a myriad of biological processes underlying the development and maintenance of adult tissue homeostasis, including regulation of stem cell self-renewal, cell proliferation, differentiation, and apoptosis. WNTs are secreted lipid-modified glycoproteins that act as short-range ligands to activate receptor-mediated signaling pathways. The hallmark of the […]
Beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors
Nov, 2007
Clinical Cancer Research, 2017 JuneAuthors : Alexandre Prieur, Monica Cappellini, Guillaume Habif, Marie-Paule Lefranc, Thibault Mazard, Eric Morency, Jean-Marc Pascussi, .../... Chris Planque, Eric Assenat, Frédéric Bibeau, Jean-François Bourgaux, Pascal Pujol, Alain Sézeur, Marc Ychou and Dominique JoubertPatients with metastatic colorectal cancer (CRC) suffer from disease relapse mainly due to cancer stem cells (CSC). Interestingly, they have an increased level of blood progastrin, a tumor-promoting peptide essential for[…]
2020
Gastro Intestinal Cancers Symposium
628 Poster Session (Board #G9) : HPG80 (Progastrin), a novel blood-based biomarker for detection of neuroendocrine neoplasms.
Download the Poster
