• Contract signed with: 
    CHU Montpellier, France

  • Principal investigator:
    Eric Assenat

hPG80 is a biomarker for monitoring of treatment response and recurrence in Hepatocellular Carcinoma patients

Last updated: August 3, 2020

Scientific context:

hPG80, a new blood based biomarker

When progastrin is maturated into gastrin, it is released from the cells. 

When gastrin is produced by the G cells of the stomach antrum, it plays its role to control acidic secretions during digestion.

Objective

When progastrin is not maturated into gastrin, it is released from the cells as such and named hPG80.

This only happens in tumor cells, whatever the tumor cell: progastrin becomes a circulating protein, hPG80, which can be detected in the blood of cancer patients. 

Objectives:

  1. Evaluate the value of hPG80 blood levels in monitoring of treatment response and recurrence in hepatocellular carcinoma patients.

  2. Examine whether hPG80 outperforms AFP to diagnose and monitor the disease.

  3. Analyze whether hPG80 levels were influenced by inflammation, assessed by CRP concentration. 

Patients:

The hepatocellular carcinoma (HCC) cohort (PRO-HCC) came from the CHU (Centre Hospitalier Universitaire) Montpellier biobank (BB-0033-00031; the “Liverpool” collection; DC 2014-2328; AC 2014-2335; Montpellier, France).

 

PRO-HCC is a cohort of 84 patients with HCC, managed with local or systemic treatments (nevaxar, tepotinib, regorafenib, nivolumab, anti-FGR or carbozantinib), including molecular targeted agents (“Liverpool” collection).

Results:

5.1

hPG80 is detected at all stages

Figure 2. 

 

hPG80 kinetics in patients receiving cancer treatments in PRO-HCC cohort at progression vs remission. 

 

(A) All patients (n=84): Changes in median hPG80 levels from baseline (11.54 pM (IQR: 3.25 pM-28.28 pM)), to progression (15.71 pM (IQR:6.33-37.26 pM)), or remission (1.99 pM (IQR: 0.00-8.30 pM)).

 

(B) Patients with normal alfa-fetoprotein (AFP) value (n=32): Changes in median hPG80 levels from baseline (14.16 pM (IQR: 7.56 pM-42.34 pM)), to progression (18.33 pM (IQR: 11.71 pM-53.70 pM)), or remission (1.47 pM (IQR: 0.21 pM-4.44 pM)).

Figure 1.

hPG80 levels at different disease stages (focal, n=23; locally advanced, n=42; metastatic, n=19) and at disease remission after treatment (n=32).

 

In order to simplify the reading of the graph, only statistically significant differences were shown on the graph.

 

All the other comparisons were tested and none of them were significant.

The study cohort comprises 84 patients with HCC at different disease stages: focal (n=23); locally advanced (n=42), metastatic (n=19) and at disease remission after treatment (n=32).

As shown in Figure 1 and 2A, hPG80 was detected in the blood of HCC patients whatever the stages.

 

Patients in remission after disease management had lower hPG80 levels compared to those with active cancers.

5.2

Comparison between hPG80 and AFP

Figure 3. 

 

hPG80 and AFP levels in all HCC patients. 

5.3

Diagnostic performance of hPG80 in HCC patients

Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic discriminative accuracy of hPG80 levels in HCC patients compared to healthy blood donors control group.

 

As shown on Figure 3, hPG80 levels displayed high predictive significance, with an area under the curve (AUC) value of 0.85 (95% CI: 0.79-0.91; p< 0.0001) when compared to healthy blood donors.

Figure 4. 

 

Diagnostic discriminative accuracy of hPG80 in patients with HCC compared to 137 healthy blood donors (age 18-25 years old) using Receiver Operating Characteristics (ROC) curve analysis.

5.4

hPG80 and AFP kinetics in HCC patients receiving cancer treatment

Individual concentration versus time curves of hPG80 evolved consistently with disease activity and AFP kinetics in most patients. This is illustrated by seven typical patients profiles (Figure 5, 6 and 7). 

Figure 5. 

hPG80 kinetics in patients receiving cancer treatments in PRO-HCC cohort. 

 

Longitudinal kinetics of alfa-fetoprotein (AFP) and hPG80 in 4 typical HCC patients during treatments.  

Figure 6. 

 

hPG80 kinetics in patients receiving cancer treatments in PRO-HCC cohort. 

Illustrative hPG80 longitudinal changes around and during disease management (baseline; remission; progression), with associated imaging obtained at the same times (multifocal liver involvement at baseline; remission after treatment with nivolumab; new liver lesions on ultrasound at progression) in a typical patient.

Figure 7. 

hPG80 kinetics in patients receiving cancer treatments in PRO-HCC cohort with imaging. 

 

Longitudinal kinetics of alfa-fetoprotein (AFP) and hPG80 during treatments in 2 typical HCC patients, with consistent imaging findings.

 

The AFP of the patient in panel A was not informative due to low concentration below the upper limit-of-normal 20 ng/ml cut-off.

5.5

hPG80 and AFP kinetics in HCC patients receiving cancer treatment

1

Scientific context

When progastrin is maturated into gastrin, it is released from the cells. 

When gastrin is produced by the G cells of the stomach antrum, it plays its role to control acidic secretions during digestion.

Objective

When progastrin is not maturated into gastrin, it is released from the cells as such and named hPG80.

This only happens in tumor cells, whatever the tumor cell: progastrin becomes a circulating protein, hPG80, which can be detected in the blood of cancer patients. 

  1. Evaluate the value of hPG80 blood levels in monitoring of treatment response and recurrence in hepatocellular carcinoma patients.

  2. Examine whether hPG80 outperforms AFP to diagnose and monitor the disease.

  3. Analyze whether hPG80 levels were influenced by inflammation, assessed by CRP concentration. 

The hepatocellular carcinoma (HCC) cohort (PRO-HCC) came from the CHU (Centre Hospitalier Universitaire) Montpellier biobank (BB-0033-00031; the “Liverpool” collection; DC 2014-2328; AC 2014-2335; Montpellier, France).

 

PRO-HCC is a cohort of 84 patients with HCC, managed with local or systemic treatments (nevaxar, tepotinib, regorafenib, nivolumab, anti-FGR or carbozantinib), including molecular targeted agents (“Liverpool” collection).

5.1

hPG80 is detected at all stages

Figure 2. 

 

hPG80 kinetics in patients receiving cancer treatments in PRO-HCC cohort at progression vs remission. 

 

(A) All patients (n=84): Changes in median hPG80 levels from baseline (11.54 pM (IQR: 3.25 pM-28.28 pM)), to progression (15.71 pM (IQR:6.33-37.26 pM)), or remission (1.99 pM (IQR: 0.00-8.30 pM)).

 

(B) Patients with normal alfa-fetoprotein (AFP) value (n=32): Changes in median hPG80 levels from baseline (14.16 pM (IQR: 7.56 pM-42.34 pM)), to progression (18.33 pM (IQR: 11.71 pM-53.70 pM)), or remission (1.47 pM (IQR: 0.21 pM-4.44 pM)).

Figure 1.

hPG80 levels at different disease stages (focal, n=23; locally advanced, n=42; metastatic, n=19) and at disease remission after treatment (n=32).

 

In order to simplify the reading of the graph, only statistically significant differences were shown on the graph.

 

All the other comparisons were tested and none of them were significant.

The study cohort comprises 84 patients with HCC at different disease stages: focal (n=23); locally advanced (n=42), metastatic (n=19) and at disease remission after treatment (n=32).

As shown in Figure 1 and 2A, hPG80 was detected in the blood of HCC patients whatever the stages.

 

Patients in remission after disease management had lower hPG80 levels compared to those with active cancers.

5.2

Comparison between hPG80 and AFP

Figure 3. 

 

hPG80 and AFP levels in all HCC patients. 

5.3

Diagnostic performance of hPG80 in HCC patients

Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic discriminative accuracy of hPG80 levels in HCC patients compared to healthy blood donors control group.

 

As shown on Figure 3, hPG80 levels displayed high predictive significance, with an area under the curve (AUC) value of 0.85 (95% CI: 0.79-0.91; p< 0.0001) when compared to healthy blood donors.

Figure 4. 

 

Diagnostic discriminative accuracy of hPG80 in patients with HCC compared to 137 healthy blood donors (age 18-25 years old) using Receiver Operating Characteristics (ROC) curve analysis.

5.4

hPG80 and AFP kinetics in HCC patients receiving cancer treatment

Individual concentration versus time curves of hPG80 evolved consistently with disease activity and AFP kinetics in most patients. This is illustrated by seven typical patients profiles (Figure 5, 6 and 7). 

Figure 5. 

hPG80 kinetics in patients receiving cancer treatments in PRO-HCC cohort. 

 

Longitudinal kinetics of alfa-fetoprotein (AFP) and hPG80 in 4 typical HCC patients during treatments.  

Figure 6. 

 

hPG80 kinetics in patients receiving cancer treatments in PRO-HCC cohort. 

Illustrative hPG80 longitudinal changes around and during disease management (baseline; remission; progression), with associated imaging obtained at the same times (multifocal liver involvement at baseline; remission after treatment with nivolumab; new liver lesions on ultrasound at progression) in a typical patient.

Figure 7. 

hPG80 kinetics in patients receiving cancer treatments in PRO-HCC cohort with imaging. 

 

Longitudinal kinetics of alfa-fetoprotein (AFP) and hPG80 during treatments in 2 typical HCC patients, with consistent imaging findings.

 

The AFP of the patient in panel A was not informative due to low concentration below the upper limit-of-normal 20 ng/ml cut-off.

5.5

hPG80 and AFP kinetics in HCC patients receiving cancer treatment

Figure 8. 

 

Impact of CRP on hPG80 levels in patients with cancer. Baseline hPG80 concentrations versus C reactive protein levels (CRP) in the PRO-HCC cohort.

As shown on Figure 8, we found no link between hPG80 and inflammation status, assessed by CRP concentration, suggesting that, if any, impact of inflammation is probably limited. 

hPG80 is detected in the blood of HCC patients whatever the stage and remission is associated to lower levels of hPG80.

Upon treatment, hG80 follows disease evolution and witnesses treatment efficacy and recurrence.

Therefore, these data support the potential use of hPG80 as a biomarker for HCC patient follow-up. 

In addition, we showed that hPG80 is a better biomarker than AFP to detect HCC.

1. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR.2019. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 16:589-604.

2. Global Burden of Disease Liver Cancer C, Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, Al-Raddadi R, Alvis-Guzman N, Amoako Y, Artaman A, Ayele TA, Barac A, Bensenor I, Berhane A, Bhutta Z, Castillo-Rivas J, Chitheer A, Choi JY, Cowie B, Dandona L, Dandona R, Dey S, Dicker D, Phuc H, Ekwueme DU, Zaki MS, Fischer F, Furst T, Hancock J, Hay SI, Hotez P, Jee SH, Kasaeian A, Khader Y, Khang YH, Kumar A, Kutz M, Larson H, Lopez A, Lunevicius R, Malekzadeh R, McAlinden C, Meier T, Mendoza W, Mokdad A, Moradi-Lakeh M, Nagel G, Nguyen Q, Nguyen G, et al.2017. The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level: Results From the Global Burden of Disease Study 2015.  3:1683-1691.

3. Renedo F DlRJ, Calleja JL.2008. Carcinoma hepatocelular. Medicine 10:770–6.

4. Bruix J, Llovet JM.2002. Prognostic prediction and treatment strategy in hepatocellular carcinoma. Hepatology 35:519-24.

5. Trevisani F, D'Intino PE, Morselli-Labate AM, Mazzella G, Accogli E, Caraceni P, Domenicali M, De Notariis S, Roda E, Bernardi M.2001. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol 34:570-5.

6. Zhang XF, Qi X, Meng B, Liu C, Yu L, Wang B, Lv Y.2010. Prognosis evaluation in alpha-fetoprotein negative hepatocellular carcinoma after hepatectomy: comparison of five staging systems. Eur J Surg Oncol 36:718-24.

7. Agopian VG, Harlander-Locke MP, Markovic D, Zarrinpar A, Kaldas FM, Cheng EY, Yersiz H, Farmer DG, Hiatt JR, Busuttil RW.2017. Evaluation of Patients With Hepatocellular Carcinomas That Do Not Produce alpha-Fetoprotein. JAMA Surg 152:55-64.

8. Toyoda H, Kumada T, Kiriyama S, Sone Y, Tanikawa M, Hisanaga Y, Hayashi K, Honda T, Kitabatake S, Kuzuya T, Nonogaki K, Kasugai T, Shimizu J.2004. Changes in the characteristics and survival rate of hepatocellular carcinoma from 1976 to 2000: analysis of 1365 patients in a single institution in Japan. Cancer 100:2415-21.

9. Song PP, Xia JF, Inagaki Y, Hasegawa K, Sakamoto Y, Kokudo N, Tang W.2016. Controversies regarding and perspectives on clinical utility of biomarkers in hepatocellular carcinoma. World J Gastroenterol 22:262-74.

10. You B, Mercier F, Assenat E, et al : The oncogenic and druggable hPG80 (Progastrin) is overexpressed in multiple cancers and detected in the blood of patients. EBioMedicine 51:102574, 2020

IT'S TIME TO CONTROL CANCER

It has been shown that hPG80 (Circulating Progastrin) is produced by all cancer cells across all stages, but in quantities 100 to 1000 times higher by cancer stem cells which are considered to be primarily responsible for recurrence and metastasis. 

hPG80 is released from the tumor and becomes detectable in the blood, making hPG80 the only blood biomarker that not only detect the presence but also the activity of the tumor.

16 different cancers have been tested, the 16 were positive. Of these 16 cancers, 11 have been published to date.

Detection and assay of hPG80 can provide Physicians with new information that can help them:

  • Evaluate treatment efficacy,

  • Monitor risk of relapse,

  • Assess Minimal Residual Disease (MRD) risk,

  • Diagnose cancers which have no biomarker and for at-risk populations, in order to detect early enough the tumor, easily located in these populations.

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Progastrine Invest SCSp and its subsidiaries:

  • focus on innovation in cancer diagnosis, localization, follow-up and treatment,

  • hold the rights to the first hPG80 (Circulating Progastrin) assay which is now available,

  • hold the rights to the cancer therapy project with an anti-hPG80 antibody.

 

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