PI: Susan Costantini – Istituto Nazionale Tumori Fondazione Giovanni Pascale
IRE Principal Collaborators Involved: Claudia Abbruzzese, Veronica Villani, Andrea Sacconi, Luigi Fattore

Project duration: 24 months

Project code: PNRR-MCNT2-2023-12377462

Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis, rapid growth, and high invasiveness. Despite advancements in standard therapies, GBM remains a challenging disease with high recurrence rates and limited treatment options. This project aims to repurpose clinically approved drugs to target pyruvate kinase M2 (PKM2), a key glycolytic enzyme involved in GBM bioenergetics and the Warburg effect, which supports cancer cell survival and proliferation.

The study is based on recent findings that chlorpromazine (CPZ), an antipsychotic, hinders GBM growth by inducing PKM2 tetramerization, thus reducing its oncogenic functions. The project seeks to identify additional molecules capable of interfering with PKM2's oncogenic activity through virtual screening and experimental validation.

The approach involves:

In Silico Screening: Virtual screening of drug libraries to identify candidates that stabilize PKM2 tetramers.

Preclinical Evaluation: Testing the selected compounds' efficacy in GBM cell lines and animal models.

Molecular Analysis: Investigating the molecular mode of action and signaling pathways affected by the selected compounds.

Biomarker Identification: Evaluating PKM2 expression and surrogate markers for clinical prognosis and treatment response prediction.

The main objective is to explore the therapeutic potential of repurposing clinically approved drugs targeting PKM2 to improve GBM treatment. The project aims to provide a cost-effective and faster pathway to innovative therapies by utilizing drugs with known safety profiles, thus reducing development time and costs.

Identification of Drug Candidates: Discovery of new drugs capable of inhibiting PKM2's oncogenic functions.

Preclinical Validation: Demonstration of antitumor efficacy in GBM models.

Biomarker Development: Identification of PKM2-related biomarkers for patient stratification and personalized treatment approaches.

Clinical Translation: Establishing a solid foundation for future clinical trials to repurpose identified drugs for GBM therapy.

Impact on Healthcare: Offering more effective treatment options for GBM, potentially improving patient survival and reducing healthcare costs associated with this aggressive cancer.