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

NCT ID: NCT06348693

Last Updated: 2024-04-05

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 400 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2017-04-19
• Study Completion Date: 2025-11-21

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.

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.

Conditions

Glioblastoma; Glioma; Glioma Glioblastoma Multiforme

Study Design

• Observational Model Type: OTHER
• Study Time Perspective: PROSPECTIVE

Study Groups

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.

cell isolation from tumor biopsies and biomarker investigation

Intervention Type: OTHER

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

Interventions

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

Intervention Type: OTHER

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marco Locatelli, MD, PhD

Role: STUDY_DIRECTOR

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Giovanni Marfia, MD, PhD

Role: STUDY_CHAIR

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

Stefania E Navone, PhD

Role: PRINCIPAL_INVESTIGATOR

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Locations

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, , Italy

Site Status: RECRUITING

Countries

Italy

Central Contacts

Stefania E Navone, PhD

Role: CONTACT

stefania.navone@policlinico.mi.it

0255034268 ext. +39

Giovanni Marfia, MD, PhD

Role: CONTACT

giovanni.marfia@policlinico.mi.it

0255034268 ext. +39

Facility Contacts

Stefania E Navone, PhD

Role: primary

stefania.navone@policlinico.mi.it

0255034268 ext. +39

Giovanni Marfia, MD, PhD

Role: backup

giovanni.marfia@policlinico.mi.it

0255034268 ext. +39

References

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.

Reference Type: BACKGROUND

PMID: 27236861 (View on PubMed)

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.

Reference Type: RESULT

PMID: 38203299 (View on PubMed)

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.

Reference Type: RESULT

PMID: 35888045 (View on PubMed)

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.

Reference Type: RESULT

PMID: 32784071 (View on PubMed)

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.

Reference Type: RESULT

PMID: 32024090 (View on PubMed)

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.

Reference Type: RESULT

PMID: 31991805 (View on PubMed)

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.

Reference Type: RESULT

PMID: 30056170 (View on PubMed)

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.

Reference Type: RESULT

PMID: 25042636 (View on PubMed)

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.

Reference Type: RESULT

PMID: 23928501 (View on PubMed)

Related Links

https://www.policlinico.mi.it/reparti/40/neurochirurgia

website Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Other Identifiers

Gliotherapy

Identifier Type: -

Identifier Source: org_study_id