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

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.

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.

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