Ignite Creation Date:
2024-05-06 @ 2:09 PM
Last Modification Date:
2024-10-26 @ 1:25 PM
Study NCT ID:
NCT04224064
Status:
RECRUITING
Last Update Posted:
2022-03-14
First Post:
2020-01-08
Brief Title:
Identification of a New Blood Biomarker for the Diagnosis and Prognosis of Liposarcomas
Sponsor:
Institut du Cancer de Montpellier - Val dAurelle
Organization:
Institut du Cancer de Montpellier - Val dAurelle
Study Overview
Official Title:
Identification of a New Blood Biomarker for the Diagnosis and Prognosis of Liposarcomas
Status:
RECRUITING
Status Verified Date:
2022-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ESPACE
Brief Summary:
The main objective of this project is to identify a new non-invasive biological test for the diagnosis of LPS by measuring circulating serine levels The current gold standard is the detection of Mdm2 amplification by the FISH
Detailed Description:
Sarcomas are rare diseases accounting for less than 1 of all malignant diseases in adultsĀ¹ Their incidence is about 6 new cases per 100000 in inhabitants per year ie 4000 to 5000 new cases estimated per year in France
Liposarcoma LPS is the most common soft tissue sarcoma subtype accounting for approximately 15 of all sarcomas
The OMS classification distinguishes 5 categories of LPS myxoid pleomorphe round-cell liposarcomas dedifferentiated DD-LPS and well-differentiated WD-LPS Research team is interested by the last two in this study
The diagnosis is suspected on the imaging examinations MRI for limb tumors and CT for retro-peritoneal LPS which should lead to a discussion at a multidisciplinary tumor board in an expert center to validate the biopsy for definitive diagnosis and define the best biopsy route to avoid the risk of spread In France the management of patients with sarcoma is organized around the network of 24 NETSARC centers
WD-LPS and DD-LPS may be difficult to distinguish from benign adipose tumors and undifferentiated sarcomas respectively Molecular analyze based on the detection of Mdm2 gene amplification by Fluorescence in situ Hybridization FISH is currently the gold standard It is performed on a tumor biopsy The biopsy is a radiologic biopsy as it is recommended in the guidelines to reduce the risk of disease spread The material allowing the diagnosis is thus limited complicating the realization of morphology immunohistochemistry and molecular biology on the same sample The other limitation is that this tumor fragment does not always reflect intra-tumor heterogeneity
The treatment is surgical with monobloc resection by a surgeon specialized in sarcomas Despite surgical excision the risk of local and distant recurrence is approximately 26 for well-differentiated liposarcomasāµ and up to 59 for dedifferentiated retroperitoneal liposarcomas Prognostic factors for recurrence are the quality of excision tumor size grade and retroperitoneal limb localization The problematic concerning these 2 types of liposarcomas is not the same In WD-LPS the question is to know the risk of recurrence in case of unplanned R1 resection representing approximately 50 of initial surgeries Indeed a systematic surgical revision of all these cases is expensive and morbid whereas in 50 of cases no tumor residue will be found on the surgical recovery For the DD-LPS the problem is different because the surgical revision must be systematic in case of non-R0 surgery but it is the risk of local recurrence despite adequate surgery and the metastatic risk that must be evaluated in order to propose an adjuvant treatment chemotherapy and or radiotherapy to patients with a high risk of recurrence also making it essential to identify a biological factor of prognosis to select patients with a high risk of relapse
Clinicians propose to identify a new blood test that would indicate the presence of the disease It would then serve for the diagnosis but also prognosis allowing us to evaluate the residual disease after surgery of excision Due to the complexity of sarcomas identifying an effective and reliable biomarker for WD-LPS and DD-LPS with non-invasive methods is a challenge but clinicians hope that their project will provide a more efficient and patient-friendly method for the detection of the disease Our project relies on the complementary expertise provided by clinicians researchers and biostatisticians in close collaboration
Clinicians have recently characterized a novel function of the p53 independent Mdm2 protein in serine metabolism which could play a fundamental role in the development of LPS Through pan-genome approaches clinicians have characterized a novel transcriptional activity of Mdm2 and demonstrated its role in the metabolism of cancer cells These data indicate that the presence of Mdm2 at chromatin makes it possible to control the transcription of genes involved in the metabolism and transport of certain amino acids such as serine
The endogenous serine pool is maintained by a balance between auxotrophy and de novo synthesis that are strongly deregulated during cell transformation to support the anabolic needs of cancer cells Mdm2 is recruited via transcription factors of the ATF family on target genes involved in de novo synthesis and serine transport
Clinicians propose to identify a biological test for the prognosis and diagnosis of LPS that does not require invasive biopsy Patients included in the study will be patients with WD-LPS or DD-LPS with the goal of including 100 patients over 2 years
Based on recent data showing that LPS growth is mediated by Mdm2-mediated regulation of serine metabolism clinicians propose to measure serine blood levels as a surrogate marker for LPS development To maintain the intracellular level of serine Mdm2 controls both de novo serine synthesis a metabolic pathway that uses the glycolytic intermediate 3-Phospho-Glycerate to generate serine in cells and the entry of the serine in the cell by auxotrophy Given the size of LPS which can often reach several tens of centimeters clinicians hypothesized that LPS may result in significant demand for serine that could be produced by the microenvironment and transmitted to the tumor by circulating pools of serine and glycine which can be inter-converted to serine by cells The profiling of plasma amino acids is of great clinical interest since they are easy to measure by liquid chromatography HPLC Clinicians have already validated an HPLC method to measure different amino acids including serine and glycine in the serum Our preliminary data are in line with our hypothesis since the serum serine level is higher in the xenografted mice with patient tumor compared to serum levels measured in the control mice In addition in response to treatment with an Mdm2 inhibitor which induces a drastic reduction in tumor growth a decrease in circulating serine can be observed
Clinicians will use an HPLC coupled with mass spectrometry already developed to measure amino acids from Agilent technology The quantitative analysis of amino acids combines speed and sensitivity with the reliability of the derivation reaction and the analytical technique These goals are achieved by automated and online derivatization using o-phthalaldehyde OPA for primary amino acids and 9-fluorenylmethyl chloroformate FMOC for secondary amino acids Automated derivation is then integrated into robust HPLC analysis The complete procedure is fast accurate sensitive and reproducible using Agilent 1190 HPLC
The main objective of this project is to identify a new non-invasive biological test for the diagnosis of LPS by measuring circulating serine levels The current gold standard is the detection of Mdm2 amplification by the FISH
Liposarcoma LPS is the most common soft tissue sarcoma subtype accounting for approximately 15 of all sarcomas
The OMS classification distinguishes 5 categories of LPS myxoid pleomorphe round-cell liposarcomas dedifferentiated DD-LPS and well-differentiated WD-LPS Research team is interested by the last two in this study
The diagnosis is suspected on the imaging examinations MRI for limb tumors and CT for retro-peritoneal LPS which should lead to a discussion at a multidisciplinary tumor board in an expert center to validate the biopsy for definitive diagnosis and define the best biopsy route to avoid the risk of spread In France the management of patients with sarcoma is organized around the network of 24 NETSARC centers
WD-LPS and DD-LPS may be difficult to distinguish from benign adipose tumors and undifferentiated sarcomas respectively Molecular analyze based on the detection of Mdm2 gene amplification by Fluorescence in situ Hybridization FISH is currently the gold standard It is performed on a tumor biopsy The biopsy is a radiologic biopsy as it is recommended in the guidelines to reduce the risk of disease spread The material allowing the diagnosis is thus limited complicating the realization of morphology immunohistochemistry and molecular biology on the same sample The other limitation is that this tumor fragment does not always reflect intra-tumor heterogeneity
The treatment is surgical with monobloc resection by a surgeon specialized in sarcomas Despite surgical excision the risk of local and distant recurrence is approximately 26 for well-differentiated liposarcomasāµ and up to 59 for dedifferentiated retroperitoneal liposarcomas Prognostic factors for recurrence are the quality of excision tumor size grade and retroperitoneal limb localization The problematic concerning these 2 types of liposarcomas is not the same In WD-LPS the question is to know the risk of recurrence in case of unplanned R1 resection representing approximately 50 of initial surgeries Indeed a systematic surgical revision of all these cases is expensive and morbid whereas in 50 of cases no tumor residue will be found on the surgical recovery For the DD-LPS the problem is different because the surgical revision must be systematic in case of non-R0 surgery but it is the risk of local recurrence despite adequate surgery and the metastatic risk that must be evaluated in order to propose an adjuvant treatment chemotherapy and or radiotherapy to patients with a high risk of recurrence also making it essential to identify a biological factor of prognosis to select patients with a high risk of relapse
Clinicians propose to identify a new blood test that would indicate the presence of the disease It would then serve for the diagnosis but also prognosis allowing us to evaluate the residual disease after surgery of excision Due to the complexity of sarcomas identifying an effective and reliable biomarker for WD-LPS and DD-LPS with non-invasive methods is a challenge but clinicians hope that their project will provide a more efficient and patient-friendly method for the detection of the disease Our project relies on the complementary expertise provided by clinicians researchers and biostatisticians in close collaboration
Clinicians have recently characterized a novel function of the p53 independent Mdm2 protein in serine metabolism which could play a fundamental role in the development of LPS Through pan-genome approaches clinicians have characterized a novel transcriptional activity of Mdm2 and demonstrated its role in the metabolism of cancer cells These data indicate that the presence of Mdm2 at chromatin makes it possible to control the transcription of genes involved in the metabolism and transport of certain amino acids such as serine
The endogenous serine pool is maintained by a balance between auxotrophy and de novo synthesis that are strongly deregulated during cell transformation to support the anabolic needs of cancer cells Mdm2 is recruited via transcription factors of the ATF family on target genes involved in de novo synthesis and serine transport
Clinicians propose to identify a biological test for the prognosis and diagnosis of LPS that does not require invasive biopsy Patients included in the study will be patients with WD-LPS or DD-LPS with the goal of including 100 patients over 2 years
Based on recent data showing that LPS growth is mediated by Mdm2-mediated regulation of serine metabolism clinicians propose to measure serine blood levels as a surrogate marker for LPS development To maintain the intracellular level of serine Mdm2 controls both de novo serine synthesis a metabolic pathway that uses the glycolytic intermediate 3-Phospho-Glycerate to generate serine in cells and the entry of the serine in the cell by auxotrophy Given the size of LPS which can often reach several tens of centimeters clinicians hypothesized that LPS may result in significant demand for serine that could be produced by the microenvironment and transmitted to the tumor by circulating pools of serine and glycine which can be inter-converted to serine by cells The profiling of plasma amino acids is of great clinical interest since they are easy to measure by liquid chromatography HPLC Clinicians have already validated an HPLC method to measure different amino acids including serine and glycine in the serum Our preliminary data are in line with our hypothesis since the serum serine level is higher in the xenografted mice with patient tumor compared to serum levels measured in the control mice In addition in response to treatment with an Mdm2 inhibitor which induces a drastic reduction in tumor growth a decrease in circulating serine can be observed
Clinicians will use an HPLC coupled with mass spectrometry already developed to measure amino acids from Agilent technology The quantitative analysis of amino acids combines speed and sensitivity with the reliability of the derivation reaction and the analytical technique These goals are achieved by automated and online derivatization using o-phthalaldehyde OPA for primary amino acids and 9-fluorenylmethyl chloroformate FMOC for secondary amino acids Automated derivation is then integrated into robust HPLC analysis The complete procedure is fast accurate sensitive and reproducible using Agilent 1190 HPLC
The main objective of this project is to identify a new non-invasive biological test for the diagnosis of LPS by measuring circulating serine levels The current gold standard is the detection of Mdm2 amplification by the FISH
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None