Development of Therapeutic Approaches Modulating Molecular Targets Implicated on Cancer Stem Cell-related Aggressiveness

March 29, 2024 updated by: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Strategies for the Development of Multimodal Therapies in Tumors of the Central Nervous System: Identification of New Molecular and Metabolic Targets Implicated in Survival and Chemoresistance Involving Endothelial and Cancer Stem Cells

Tumors of the central nervous system affect 21 people per 100,000 every year, a figure that refers to countries with advanced economies, with an increase in incidence over time. Experimental evidence suggests that cancer stem cells (CSCs) may play a key role in the malignancy of these tumors. In fact, due to the hypoxic tumor microenvironment, these cells are able to create compensatory pathways that confer stem-like, angiogenic and pro-tumoral functions. Furthermore, it has been demonstrated that brain tumor stem cells are radio- and chemo-resistant and therefore not treatable with the therapeutic protocols currently in use. To date, in fact, there are no definitive treatments for the eradication of brain tumors. In this scenario, sphingolips, a class of lipid deputized to several physiological functions, are also involved in tumor onset, progression, drug resistance, and aggressiveness. In hypoxic tumor microenvironment, CSCs present a modified rheostat in the metabolism of sphingolipid, in favor of Sphingosine-1-phosphate (S1P).

S1P is an intermediate of sphingolipid metabolism, formed from sphingosine through the action of sphingosine kinases (SK). Increasing evidence suggests that S1P acts as a tumor-promoting signal, predominantly in the extracellular environment, regulating important cellular properties correlated with tumor potential.

The project aims to identify new molecular and metabolic targets involved in the survival and chemo-resistance of tumor stem cells in relation to the tumor microenvironment.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Recruiting

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Tumors of the central nervous system affect 21 people per 100,000 every year, a figure that refers to countries with advanced economies, with an increase in incidence over time. Among tumors of the central nervous system, Glioblastoma (GBM) is the most frequent and aggressive malignant tumor with an average life expectancy of approximately 12 months and a survival of less than 5% in the following 5 years to the diagnosis. The growth and progression of GBM are dependent on a specialized subpopulation of tumor cells called "cancer stem cells" (CSCs). CSCs are chemo- and radio-resistant, are responsible for relapses and therefore should constitute an important target of therapeutic strategies, but the mechanisms underlying their biology are still poorly understood. Hypoxia, through the hypoxia-inducible factor (HIF) and sphingolipid pathway, plays a key role in the control of tumor growth and angiogenesis and represents, perhaps, the most effective adaptation mechanism of the tumor itself. Indeed, The hypoxic microenvironment of solid tumors gives them greater aggressiveness, an increase in the expression of proteins linked to angiogenesis, anaerobic energy metabolism and adaptation to oxidative stress which facilitates the onset and proliferation of CSCs.

This study supports the evidence that the hypoxic microenvironment regulates the state of CSCs, and therefore influencing the response to the current pharmacological treatments.

Although S1P can act as an intracellular second messenger, most of its effects are exerted as an extracellular mediator, through binding to specific G protein-coupled receptors, originally known as EDGs and now called S1P receptors (S1PRs). Our group has previously demonstrated that acquired modifications in the metabolism of sphingolipids, in particular in the regulation of S1P, are able to confer stem-like and chemo-resistance properties to CSCs in patients with GBM.

The project aims to identify new molecular and metabolic targets involved in the survival and chemo-resistance of tumor stem cells in relation to the tumor microenvironment.

Through the study of sphingolipid metabolism, new markers and inhibitors will be identified to be delivered to inhibit CSC proliferation and tumor progression.

With this approach the investigators will be able to evaluate how the tumor microenvironment and the molecular and metabolic characteristics of the tumor influence cellular communication and whether this process can be influenced by new pharmacological treatments. This study could highlight new pathways and tumor-specific alterations to stratify new therapeutic strategies and to identify new potential biomarkers in diagnosis and monitoring, thus improving the prognosis of patients suffering from brain tumors.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Estimated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
400

Contacts and Locations

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

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Contact Backup

Study Locations

  • Italy
      • Milan, Italy, 20122
        • Recruiting
        • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Giovanni Marfia, MD, PhD
        • Sub-Investigator:
          • Laura Guarnaccia, PhD
        • Sub-Investigator:
          • Laura Begani, MSc
        • Sub-Investigator:
          • Marco Locatelli, Md, PhD
        • Sub-Investigator:
          • Giulio Bertani, MD
        • Sub-Investigator:
          • Claudia Fanizzi, MD
        • Sub-Investigator:
          • Giorgio Fiore, MD
        • Sub-Investigator:
          • Luigi Schisano, MD
        • Sub-Investigator:
          • Manuela Caroli, MD
        • Sub-Investigator:
          • Antonella Ampollini, MD
        • Principal Investigator:
          • Stefania Navone, PhD
        • Sub-Investigator:
          • Antonio D Ammando, MD
        • Sub-Investigator:
          • Elena Scagliotti, MSc
        • Sub-Investigator:
          • Giorgia Abete Fornara, MSc

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Considering the high heterogeneity of gliomas in relation to age, sex, surgical radicality, WHO performance status, MGMT methylation, molecular and biochemical characteristics, to demonstrate a benefit of the treatments that will be administered to stem and endothelial cells it will be necessary to consider a high sample size to allow for adequate subgroup analysis and to generate reliable data. To this end, the investigators will begin the study by analyzing 400 subjects affected by glioma.

Description

Inclusion Criteria:

  • Patients with glioma diagnosed histologically confirmed (WHO) undergoing surgical resection;
  • hypomethylation or hypermethylation of MGMT assessed post-surgery for patients affected by GBM;
  • adult patients (≥18 years), both sexes;
  • Patients undergoing Stupp protocol including patients aged > 70 years performing the hypofractionated protocol and three weeks of chemotherapy;
  • Karnofsky Performance Status (KPS)> 60 assessed post-surgery;
  • freely given written informed consent prior to any activity related to the study. erine

Exclusion Criteria:

  • patients who do not sign the informed consent

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

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Glioma
Patients affected by brain tumors undergoing surgical resection; hypomethylation or hypermethylation of MGMT assessed post-surgery for patients affected by GBM; adult patients (≥18 years), both sexes; Patients undergoing Stupp protocol including patients aged > 70 years performing the hypofractionated protocol and three weeks of chemotherapy; Karnofsky Performance Status (KPS)> 60 assessed post-surgery; freely given written informed consent prior to any activity related to the study.
Other: cell isolation from tumor biopsies and biomarker investigation
cellular and molecular analysis on cancer stem cells and endothelial cells from tumor biopsies and investigation of tissue and systemic biomarkers

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Investigation of molecular and metabolic signature of cancer stem cells to assess specific markers related to gliomagenesis and cancerogenesis.
Time Frame: Through study completion, an average of 3 years
Evaluation of prognostic and predictive role of molecular and metabolic markers of the tumor. Determination of gene and protein expression of a panel of markers related to stemness, angiogenesis/hypoxia, and sphingolipid signaling.
Through study completion, an average of 3 years

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Biomarker investigation
Time Frame: Through study completion, an average of 3 years
Identification of new tissue and circulating biomarkers with predictive and prognostic significance
Through study completion, an average of 3 years
Cellular response to pharmacological treatments
Time Frame: Through study completion, an average of 3 years
Investigation of cellular response following new treatments determined by molecular and metabolic specific signature; determination of a panel of markers differently expressed following pharmacological treatments; evaluation of the prognostic and predictive role of tumor marker expression
Through study completion, an average of 3 years

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Director: Marco Locatelli, MD, PhD, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
  • Study Chair: Giovanni Marfia, MD, PhD, Fondazione IRCCS Ca' Granda Osp. Maggiore Policlinico, Istituto di Medicina Aerospaziale di Milano-Aeronautica Militare
  • Principal Investigator: Stefania E Navone, PhD, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

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)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 19, 2017

Primary Completion (Estimated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 21, 2025

Study Completion (Estimated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 21, 2025

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 21, 2024

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 29, 2024

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 5, 2024

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
April 5, 2024

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 29, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • Gliotherapy

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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