Anti-glioblastomas - New Chemical Entities for glioblastoma treatment

BACKGROUND Glioblastoma multiforme (GBM, aka grade IV astrocytoma aka primary glioblastoma) is one of the cancers with the highest unmeet medical needs. GlobalData 2024 market forecast for GBM is $3.3 billions with a CAGR of 17.4%. GBM represents the large majority of glioblastomas and is the most aggressive: survival is between 1 and 2 years. There is no available curative treatment. The treatment of reference, Temozolomide (Temodar®/Temodal®, TMZ) is highly toxic with a relatively low efficacy (Overall Survival with radiotherapy and TMZ: 14.6 versus 12.1 months for radiotherapy alone). Cancer stem-like cells (Glioblastoma Stem Cells, GSCs) are thought to be responsible for the poor efficacy of treatments. Initiation of GBM, recurrence and resistance to treatment are driven by GSCs. Our strategy is to target GSCs with new small molecules to double the effectiveness of chemotherapy. HOW IT WORKS These new cancer stem cell inhibitors show alone 3 effects in vitro: - Stop GSCs proliferation - Block reprogramming of cancer cells into GSCs: prevent glioblastoma cells from becoming resistant to treatment - Drive differentiation of GSCs into sensitive cells Our current best compound candidate (DXXX -50 µM) sensitizes primary stem-cell like glioblastoma cells (GB5 and TG6) to TMZ treatment (400 µM) and improves its efficacy from 30 to 80% death (figure). KEY BENEFITS vs. STATE OF THE ART - Stop glioblastoma stem cells growth in vitro - 2,5 times more cancer cell death with TMZ + NCE co-treatment - No toxicity observed at 50 µM on primary normal cells: neuronal, hepatic, kidney… - New strategy to address glioblastoma resistance problem by specifically targeting cancer stem cells properties DEVELOPMENT STATUS On-going development funded by SATT: - In vivo experiments - Rational Drug Design to improve efficacy - Target and off-target studies - Safety and tolerability studies APPLICATIONS - Glioblastomas - Other solid tumors with resistance due to stem cells