Analysis of the Role of Hepatocyte SLAMF3 Receptor and Drug Resistance Proteins (MDR) in Resistance to Treatment With Sorafenib in CHC Patients (SLAMF3)

April 10, 2017 updated by: Centre Hospitalier Universitaire, Amiens

Primary liver cancer or hepatocellular carcinoma (HCC) is the 7th most common cancer in humans; 9th in women (figures from the Association for Research against Cancer ARC). This cancer is a major public health problem on a global scale. Patients, whose diagnosis is often late, are at advanced stages of the pathology, even those who benefit from locoregional treatments have a poor prognosis and suffer from a lack of curative therapeutic strategies. CHC is highly refractory to cytotoxic chemotherapy and so far the response rates to conventional systemic chemotherapy has provided a clinical benefit where survival was prolonged by more than 25% in patients with advanced CHC. Further efforts are needed to effectively manage HCC. Knowledge of the mechanisms regulating proliferation and inhibiting the sensitivity of transformed cells to apoptosis is the key to the development of more effective therapeutic strategies.

Several new therapies, called targeted therapies, are tested in clinical trials. Currently, the most effective molecular agent for targeting the Raf pathway is sorafenib capable of also inhibiting tyrosine kinases of VEGFR and PDGFR. Sorafenib, a multikinase inhibitor, decreases the proliferation of tumor cells in vitro that inhibit the activity of targets present in tumor cells (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and tumor vascularization VEGFR-2, VEGFR-3, and PDGFR-beta). Despite the real benefit of this treatment, its efficacy (three months of overall survival) and its indication remain limited to Child-Pugh A, WHO 0-2 patients in whom curative treatment is contraindicated. In addition, several patients have resistance to Sorafenib and thus find themselves in therapeutic failure, thus limiting the therapeutic choice for these patients.

Resistance to treatment with Sorafenib limits the therapeutic choice. The mechanisms responsible for this resistance remain to be elucidated. Drug resistance proteins, MDR Multi-Drug Resistance, is a family of molecules whose expression increases in the cancer cell and ensures the repression of chemotherapy molecules outside the target cancer cell. This family includes the proteins ABCG2, MDR and MRP1. Our in vitro studies show that treatment of CHC Huh-7 cells with Sorafenib (10 mM) induces the specific expression of the transcripts of the MRP-1 protein without any effect on the expression of the ABCG2 and MDR protein. In addition, sorafenib has an effect on the expression of hepatocyte SLAMF3 receptor transcripts, a receptor recently identified in hepatocyte tissue. Indeed, it has been shown that the expression of SLAMF3 is lowered in the cancerous tissue compared to the healthy tissue and that the reintroduction of a strong expression in the cancer cell inhibits its proliferation by inhibiting the MAPK Erk pathway, Cancer cells to apoptosis and inhibits the uptake of tumor masses in the Nude mouse (I. Marcq, et al., 2013).

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Study Type

Observational

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
    • Picardie
      • Amiens, Picardie, France, 80054
        • CHU Amiens Picardie

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Group 1: Tumor and peri-tumor tissue samples from patients with non-treated sorafenib CHC (surgical resection or other) Group 2: Tumor and peri-tumor tissue samples from tumor and peritumor tissues of patients not responding to sorafenib treatment Group 3: samples from patients responding to treatment with sorafenib

Description

Inclusion Criteria:

  • Patients over 18 years of age,
  • Diagnosis of hepatocellular carcinoma (histological or non-invasive criteria of Barcelona),

Group 1: Tumor and peri-tumor tissue samples from patients with untreated CHCs sorafenib

- Patients who received treatment other than sorafenib (chemo-embolization, radiofrequency, resection, ...),

Group 2: Tumor and peri-tumor tissue samples from patients with non-sorafenib CHC

  • Patients treated with sorafenib,
  • Patients not responding to treatment with sorafenib

Group 3: Tumor and peri-tumor tissue samples from patients with CHCs responding to sorafenib

  • Patients treated with sorafenib,
  • Patients responding to treatment with sorafenib

Exclusion Criteria:

  • Age <18 years,
  • Patients who do not have liver biopsy specimens (PBH) available at the tumor bank,
  • Patients who have refused to use their samples for biomedical research,
  • Pregnancy and breast feeding

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Retrospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Patients with untreated CHC not sorafenib
Other: Study on samples of tumor and peri-tumor tissues from patients with hepatocellular carcinoma

Retrospective study of samples of tumor and peri-tumor tissues from patients with hepatocellular carcinoma (HCC): three groups of samples will be selected:

Group 1: Tumor and peri-tumor tissue samples from patients with non-treated sorafenib CHC (surgical resection or other) Group 2: Tumor and peri-tumor tissue samples from tumor and peritumor tissues of patients not responding to sorafenib treatment Group 3: samples from patients responding to treatment with sorafenib
Patients with non-sorafenib CHC
Other: Study on samples of tumor and peri-tumor tissues from patients with hepatocellular carcinoma

Retrospective study of samples of tumor and peri-tumor tissues from patients with hepatocellular carcinoma (HCC): three groups of samples will be selected:

Group 1: Tumor and peri-tumor tissue samples from patients with non-treated sorafenib CHC (surgical resection or other) Group 2: Tumor and peri-tumor tissue samples from tumor and peritumor tissues of patients not responding to sorafenib treatment Group 3: samples from patients responding to treatment with sorafenib
Patients with CHCs responding to sorafenib
Other: Study on samples of tumor and peri-tumor tissues from patients with hepatocellular carcinoma

Retrospective study of samples of tumor and peri-tumor tissues from patients with hepatocellular carcinoma (HCC): three groups of samples will be selected:

Group 1: Tumor and peri-tumor tissue samples from patients with non-treated sorafenib CHC (surgical resection or other) Group 2: Tumor and peri-tumor tissue samples from tumor and peritumor tissues of patients not responding to sorafenib treatment Group 3: samples from patients responding to treatment with sorafenib

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Rate of expression of SLAM3 and MDR transcripts, correlation with the responder status or not with Sorafenib
Time Frame: 1 day
1 day

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centre Hospitalier Universitaire, Amiens

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 20, 2015

Primary Completion (Actual)

November 20, 2016

Study Completion (Actual)

November 20, 2016

Study Registration Dates

First Submitted

April 10, 2017

First Submitted That Met QC Criteria

April 10, 2017

First Posted (Actual)

April 13, 2017

Study Record Updates

Last Update Posted (Actual)

April 13, 2017

Last Update Submitted That Met QC Criteria

April 10, 2017

Last Verified

April 1, 2017

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • PI2015_843_0021

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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