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

NCT06348693 | Recruiting

• 1 other identifier: Gliotherapy
• Study Type: observational
• Target: 400
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Glioblastoma; Glioma; Glioma Glioblastoma Multiforme

Keywords

cancer stem cells; tumor endothelial cells; sphingolipids; sphingosine-1-phosphate; platelets; biomarkers

Outcome Measures

Primary Outcomes (1)

• Investigation of molecular and metabolic signature of cancer stem cells to assess specific markers related to gliomagenesis and cancerogenesis.

  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 Outcomes (2)

• Biomarker investigation

  Through study completion, an average of 3 years

• Cellular response to pharmacological treatments

  Through study completion, an average of 3 years

Study Arms (1)

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

Interventions

cell isolation from tumor biopsies and biomarker investigation OTHER

cellular and molecular analysis on cancer stem cells and endothelial cells from tumor biopsies and investigation of tissue and systemic biomarkers

Glioma

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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

You may not qualify if:

• patients who do not sign the informed consent

Sponsors & Collaborators

• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: lead

Study Sites (1)

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

RECRUITING

Related Publications (9)

• Marfia G, Navone SE, Fanizzi C, Tabano S, Pesenti C, Abdel Hadi L, Franzini A, Caroli M, Miozzo M, Riboni L, Rampini P, Campanella R. Prognostic value of preoperative von Willebrand factor plasma levels in patients with Glioblastoma. Cancer Med. 2016 Aug;5(8):1783-90. doi: 10.1002/cam4.747. Epub 2016 May 28.

  PMID: 27236861 BACKGROUND

• Navone SE, Guarnaccia L, Rizzaro MD, Begani L, Barilla E, Alotta G, Garzia E, Caroli M, Ampollini A, Violetti A, Gervasi N, Campanella R, Riboni L, Locatelli M, Marfia G. Role of Luteolin as Potential New Therapeutic Option for Patients with Glioblastoma through Regulation of Sphingolipid Rheostat. Int J Mol Sci. 2023 Dec 21;25(1):130. doi: 10.3390/ijms25010130.

  PMID: 38203299 RESULT

• Guarnaccia M, Guarnaccia L, La Cognata V, Navone SE, Campanella R, Ampollini A, Locatelli M, Miozzo M, Marfia G, Cavallaro S. A Targeted Next-Generation Sequencing Panel to Genotype Gliomas. Life (Basel). 2022 Jun 24;12(7):956. doi: 10.3390/life12070956.

  PMID: 35888045 RESULT

• Campanella R, Guarnaccia L, Caroli M, Zarino B, Carrabba G, La Verde N, Gaudino C, Rampini A, Luzzi S, Riboni L, Locatelli M, Navone SE, Marfia G. Personalized and translational approach for malignant brain tumors in the era of precision medicine: the strategic contribution of an experienced neurosurgery laboratory in a modern neurosurgery and neuro-oncology department. J Neurol Sci. 2020 Oct 15;417:117083. doi: 10.1016/j.jns.2020.117083. Epub 2020 Aug 6.

  PMID: 32784071 RESULT

• Riboni L, Abdel Hadi L, Navone SE, Guarnaccia L, Campanella R, Marfia G. Sphingosine-1-Phosphate in the Tumor Microenvironment: A Signaling Hub Regulating Cancer Hallmarks. Cells. 2020 Feb 1;9(2):337. doi: 10.3390/cells9020337.

  PMID: 32024090 RESULT

• Campanella R, Guarnaccia L, Cordiglieri C, Trombetta E, Caroli M, Carrabba G, La Verde N, Rampini P, Gaudino C, Costa A, Luzzi S, Mantovani G, Locatelli M, Riboni L, Navone SE, Marfia G. Tumor-Educated Platelets and Angiogenesis in Glioblastoma: Another Brick in the Wall for Novel Prognostic and Targetable Biomarkers, Changing the Vision from a Localized Tumor to a Systemic Pathology. Cells. 2020 Jan 25;9(2):294. doi: 10.3390/cells9020294.

  PMID: 31991805 RESULT

• Abdel Hadi L, Anelli V, Guarnaccia L, Navone S, Beretta M, Moccia F, Tringali C, Urechie V, Campanella R, Marfia G, Riboni L. A bidirectional crosstalk between glioblastoma and brain endothelial cells potentiates the angiogenic and proliferative signaling of sphingosine-1-phosphate in the glioblastoma microenvironment. Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Oct;1863(10):1179-1192. doi: 10.1016/j.bbalip.2018.07.009. Epub 2018 Jul 26.

  PMID: 30056170 RESULT

• Marfia G, Campanella R, Navone SE, Di Vito C, Riccitelli E, Hadi LA, Bornati A, de Rezende G, Giussani P, Tringali C, Viani P, Rampini P, Alessandri G, Parati E, Riboni L. Autocrine/paracrine sphingosine-1-phosphate fuels proliferative and stemness qualities of glioblastoma stem cells. Glia. 2014 Dec;62(12):1968-81. doi: 10.1002/glia.22718. Epub 2014 Jul 5.

  PMID: 25042636 RESULT

• Navone SE, Marfia G, Invernici G, Cristini S, Nava S, Balbi S, Sangiorgi S, Ciusani E, Bosutti A, Alessandri G, Slevin M, Parati EA. Isolation and expansion of human and mouse brain microvascular endothelial cells. Nat Protoc. 2013 Sep;8(9):1680-93. doi: 10.1038/nprot.2013.107. Epub 2013 Aug 8.

  PMID: 23928501 RESULT

Related Links

• website Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Biospecimen

Retention: SAMPLES WITH DNA

cells from tumor biospsies and blood circulation

MeSH Terms

Conditions

Glioblastoma; Glioma

Condition Hierarchy (Ancestors)

Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Study Officials

• Marco Locatelli, MD, PhD

  Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

  STUDY DIRECTOR

• Giovanni Marfia, MD, PhD

  Fondazione IRCCS Ca' Granda Osp. Maggiore Policlinico, Istituto di Medicina Aerospaziale di Milano-Aeronautica Militare

  STUDY CHAIR

• Stefania E Navone, PhD

  Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Stefania E Navone, PhD

CONTACT

0255034268; stefania.navone@policlinico.mi.it

Giovanni Marfia, MD, PhD

CONTACT

0255034268; giovanni.marfia@policlinico.mi.it

Study Design

• Study Type: observational
• Observational Model: OTHER
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 21, 2024
• First Posted: April 5, 2024
• Study Start: April 19, 2017
• Primary Completion: November 21, 2025
• Study Completion: November 21, 2025
• Last Updated: April 5, 2024

Record last verified: 2024-03

Locations

IT (1)