hPG80 (Circulating Progastrin), a Novel Blood-Based Biomarker for Detection of Poorly Differentiated Neuroendocrine Carcinoma and Well Differentiated Neuroendocrine Tumors
Current blood-based biomarkers for neuroendocrine neoplasms (NENs) lack both sensitivity and specificity. Human circulating progastrin (hPG80) can be easily measured in plasma by ELISA. This study is the first to examine hPG80 in NENs. The study demonstrated increased levels of hPG80 in all sub-types of NENs, with a high sensitivity and specificity demonstrated. Plasma hPG80 in NENs may be a diagnostic blood biomarker for both low- and high-grade NENs; further study is warranted. A prospective multi-center trial is ongoing in NET to evaluate hPG80 as a means of monitoring disease (NCT04750954).
Current blood-based biomarkers for neuroendocrine neoplasms (NENs) lack both sensitivity and specificity. Human circulating progastrin (hPG80) is a novel biomarker that can be easily measured in plasma by ELISA. This study is the first to examine hPG80 in NENs. Plasma hPG80 was quantified from 95 stage IV NEN patients, using DxPG80technology (ECS Progastrin, Switzerland) and compared with hPG80 concentrations in two cohorts of healthy donor controls aged 50–80 (n = 252) and 18–25 (n = 137). Median hPG80 in NENs patients was 5.54 pM compared to 1.5 pM for the 50–80 controls and 0.29 pM the 18–25 cohort (p < 0.0001).
Subgroup analysis revealed median hPG80 levels significantly higher than for either control cohort in neuroendocrine carcinoma (NEC; n = 25) and neuroendocrine tumors (NET; n = 70) including the small-cell lung cancer (SCLC) sub-cohort (n = 13). Diagnostic accuracy, estimated by AUCs, was high for NENs, as well as both sub-groups (NEC/NET) when compared to the younger and older control groups. Plasma hPG80 in NENs may be a diagnostic blood biomarker for both low- and high-grade NENs; further study is warranted. A prospective multi-center trial is ongoing in NET to evaluate hPG80 as a means of monitoring disease (NCT04750954).
Aman Chauhan, Alexandre Prieur, Jill Kolesar, Susanne Arnold, Léa Payen, Younes Mahi, Berengere Vire, Madison Sands, B. Mark Evers, Dominique Joubert and Lowell Anthony.
Journals - Cancers 2022, 14, 863
Plasma hPG80 (Circulating Progastrin) as a Novel Prognostic Biomarker for Hepatocellular Carcinoma
Liver cancer is the sixth most common cancer world-wide and hepatocellular carcinoma (HCC), the most common form of primary liver cancer, accounts for 90% of the cases. The diagnosis of HCC is usually based on non-invasive criteria using detection of a liver nodule in abdominal ultrasonography or high serum alpha-fetoprotein (AFP) levels. However, as it is only elevated in 60% of patients with HCC, AFP has limited accuracy, especially in early stages, as both a diagnostic and prognostic test. We investigated hPG80 (circulating progastrin), which is associated with liver cancer biology, and found that hPG80 levels is both an independent prognostic marker in HCC and used in combination with AFP, it improves the stratification of the patients in good and poor prognosis, especially for those patients at early-stage. This will help stratify HCC patients more accurately in the future and improve the management of these patients.
Alpha-fetoprotein (AFP) is the most widely used biomarker for hepatocellular carcinoma (HCC) prognosis. However, AFP is not useful in establishing a prognosis for patients with a tumor in the early stages. hPG80 (circulating progastrin) is a tumor promoting peptide present in the blood of patients with various cancers, including HCC. In this study, we evaluated the prognostic value of plasma hPG80 in patients with HCC, alone or in combination with AFP. A total of 168 HCC patients were tested prospectively for hPG80 and analyzed retrospectively. The prognostic impact of hPG80 and AFP levels on patient survival was assessed using Kaplan-Meier curves and log-rank tests. hPG80 was detected in 84% of HCC patients. There was no correlation between hPG80 and AFP levels in the training and validation cohorts. Both cohorts showed higher sensitivity of hPG80 compared to AFP, especially at early stages. Patients with high hPG80(hPG80+) levels (optimal cutoff value 4.5 pM) had significantly lower median overall survival (OS) compared to patients with low hPG80 (hPG80−) levels (12.4 months versus not reached respectively, p < 0.0001).
Further stratification by combining hPG80 and AFP levels (cutoff 100 ng/mL) improved prognosis in particular for those patients with low AFP level (hPG80−/AFP+ and hPG80−/AFP−, 13.4 months versus not reached respectively, p < 0.0001 and hPG80+/AFP+ and hPG80+/AFP−, 5.7 versus 26 months respectively, p < 0.0001). This was corroborated when analyses were performed using the BCLC staging especially at early stages. Our findings show that hPG80 could serve as a new prognostic biomarker in HCC. Used in combination with AFP, it improves the stratification of the patients in good and poor prognosis, especially for those patients with negative AFP and early-stage HCC.
Marie Dupuy, Sarah Iltache, Benjamin Rivière, Alexandre Prieur, George Philippe Pageaux, José Ursic Bedoya, Stéphanie Faure, Heloïse Guillaumée and Eric Assenat.
Journals - Cancers 2022, 14(2), 402
A novel method to detect hPG80 (human circulating progastrin) in the blood
hPG80 (human circulating progastrin) is produced and released by cancer cells. We recently reported that hPG80 is detected in the blood of patients with cancers from different origins, suggesting its potential utility for cancer detection. To accurately measure hPG80 in the blood of patients, we developed the DxPG80 test, a sandwich Enzyme-Linked Immunosorbent Assay (ELISA). This test quantifies hPG80 in EDTA plasma samples. The analytical performances of the DxPG80 test were evaluated using standard procedures and guidelines specific to ELISA technology. We showed high specificity for hPG80 with no cross-reactivity with human glycine-extended gastrin (hG17-Gly), human carboxy-amidated gastrin (hG17-NH2) or the CTFP (C-Terminus Flanking Peptide) and no interference with various endogenous or exogenous compounds.
The test is linear between 0 and 50 pM hPG80 (native or recombinant). We demonstrated a trueness of measurement, an accuracy and a variability of hPG80 quantification with the DxPG80 test below the 20% relative errors as recommended in the guidelines. The limit of detection of hPG80and the limit of quantification were calculated as 1 pM and 3.3 pM respectively. In conclusion, these results show the strong analytical performance of the DxPG80 test to measure hPG80 in blood samples.
Cappellini Monica, Flaceliere Maud, Saywell Veronique, Soule Julien, Blanc Emilie, Belouin Fanny, Ortiz Erika, Canterel-Thouennon Lucile, Poupeau Sophie, Tigrett Sylvia, Vire Bérengère, Liaud Pierre, Blairvacq Mélina, Joubert Dominique, Prieur Alexandre
Journals - Analytical Methods - 2021, 13, 4468–4477
Prognostic Value of Plasma hPG80 (Circulating Progastrin) in Metastatic Renal Cell Carcinoma
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.
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
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
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. […]
Targeting the Wnt pathway and cancer stem cells with anti-progastrin humanized antibodies:
a major breakthrough for K-RAS mutated colorectal cancer treatment
Clinical Cancer Research, 2017 June
Authors : 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 Joubert
Patients 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[…]
Nature reviews, 2017 May
Authors : William G. Kaelin Jr
An 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 […]
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.
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. […]
Autocrine Secretion of Progastrin Promotes the Survival and Self-Renewal of Colon Cancer Stem-like Cells.
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 […]
The evolving roles of canonical WNT signaling in stem cells and tumorigenesis: implications in targeted cancer therapies
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 […]
Progastrin a new pro-angiogenic factor in colorectal cancer
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[…]
Novel roles of gastrin
J Physiol. 2014 Jul 15
Authors : Dimaline, Varro
The 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 […]
Curr Opin Gastroenterol. 2013 Nov
Authors : Shijian Chu;Mitchell Schubert;
The review summarizes the past year's literature, basic science and clinical, regarding the neural, paracrine, hormonal, and intracellular regulation of gastric acid secretion.[…]
Wnt Signaling in Cancer
Cold Spring Harb Perspect Biol. 2012 May
Authors : Paul Polakis
Aberrant 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 […]
The wnt target jagged-1 mediates the activation of notch signaling by progastrin in human colorectal cancer cells.
Cancer Res. 2009 August
Authors : Julie Pannequin, Caroline Bonnans, Nathalie Delaunay, Joanne Ryan, Jean-François Bourgaux, Dominique Joubert and Frédéric Hollande
The 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 […]
Beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors
Gastroenterology. 2007 Nov.
Authors : Pannequin J1, Delaunay N, Buchert M, Surrel F, Bourgaux JF, Ryan J, Boireau S, Coelho J, Pélegrin A, Singh P, Shulkes A, Yim M, Baldwin GS, Pignodel C, Lambeau G, Jay P, Joubert D, Hollande F.
Aberrant activation of the beta-catenin/Tcf-4 transcriptional complex represents an initiating event for colorectal carcinogenesis, shifting the balance from differentiation toward proliferation in colonic crypts. Here, we assessed whether endogenous progastrin, encoded by a target gene of this complex, was […]
Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis
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. Wang1
Mutations 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 […]
Expression but incomplete maturation of progastrin in colorectal carcinomas
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... […]
A synthesis of the knowledge of progastrin is available on the website of the Progastrin cancer control association.
Poster Session : Prognostic value of circulating progastrin (hPG80) in IDH-wild type glioblastoma treated with radio-chemotherapy.
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Poster Session : Plasma hPG80 (circulating progastrin) as a novel prognostic biomarker for hepatocellular carcinoma at early to intermediate stages (BCLC 0 to B)
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Poster Session : HPG80 (Progastrin), a novel blood-based biomarker for detection of neuroendocrine neoplasms.
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#GI ASCO 2020
628 Poster Session (Board #G9) : HPG80 (Progastrin), a novel blood-based biomarker for detection of neuroendocrine neoplasms.
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3037 / 29 - Progastrin, a novel ubiquitous cancer blood biomarker for early detection and monitoring.
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2289 / 18 - Prognostic impact of progastrin levels in blood compared to MSKCC based clinical prognosis in metastatic renal cell cancer patients
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2294 / 23 - Plasma progastrin level as a predictive and prognostic biomarker in advanced prostate cancer
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2222 / 11 - Progastrin a new biomarker for hepatocellular cancer patient follow-up
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119P - Progastrin, a new blood biomarker for the diagnostic and therapeutic monitoring, in gastro-intestinal cancers: A BIG-RENAPE project.