Treatment of glioblastoma multiforme (GBM) is a formidable challenge. The intense investigation of numerous strategies to improve drug delivery in the context of GBM reflects the difficulty posed by the blood brain barrier (BBB), which provides both physical and biochemical barriers that limit penetration of most drugs into regions of invasive GBM.
The aim of the present research project is that to fully evaluate the potential of new ATI and ARDAP derivatives in glioblastoma treatment.
Preliminary results suggested that the replacement of the 3-methoxy group of the 3,4,5-trimethoxy portion with the bromine atom boost both inhibition of tubulin polymerization and anticancer activity. Aims of the present research project are: 1. design of the new compounds and molecular modelling studies; 2. chemical synthesis of the most promising compounds; 3. biological evaluation of the newly prepared compounds as inhibitors of tubulin polymerization and [3H]colchicine binding; 4. further biological characterization of the selected compounds in glioblastoma cells; 6. in vitro and in vivo pharmacokinetic characterization of the selected compounds.
The final goal of the present research project is the identification of one or more lead compounds with potent anti-glioblastoma activity and improved pharmacokinetic profile for the treatment of glioblastoma patients.
Glioblastoma (GBM) is a rare tumor and one of the most challenging malignancies to treat in all of oncology. Although advances have been made in the treatment of GBM, encouraging outcomes typically are not observed; patients diagnosed with these tumors generally have a dismal prognosis and poor quality of life as the disease progresses. Despite considerable effort, little progress has been made toward prolonged survival in GBM. Treatment of GBM is a formidable challenge. The intense investigation of numerous strategies to improve drug delivery in the context of GBM reflects the difficulty posed by the BBB, which provides both physical and biochemical barriers that limit penetration of most drugs into regions of invasive GBM. Overcoming these challenges will be key in refining therapies for GBM, where the reason for failure may be inadequate delivery of an effective drug. Progress in treating this disease will require not only delivering the right drugs to the right targets, but also delivering an adequate amount of drug throughout the entire tumor to effectively modulate the pharmacological targets in all tumor cells.
Taken together, these data suggest that delivery of therapeutic agents across the BBB to all tumor regions is essential to make significant progress in GBM treatment. Therefore it is critical to understand the mechanisms that limit drug distribution to invasive tumor sites and develop strategies to overcome these limitations (1-4).
The aim of the present research project is that to fully evaluate the potential of new ATI and ARDAP derivatives with enhanced lipophilicity in treatment of GBM. The replacement of the methoxy group in the 3,4,5-trimethoxy portion with the bromine atom could be a promising approach for the development of potential antiglioblastoma compounds, able to cross the BBB. Preliminary results suggested that the introduction of a bromine atom at this position boost both inhibition of tubulin polymerization and anticancer activity by additional favourable interactions into the colchicine binding site of tubulin.
1) R. K. Oberoi Neuro-Oncology 18(1), 27¿36, 2016 2) S. I. Rapoport Am J Physiol. 223(2):323-331, 1972; 3) R.A. Kroll Neurosurgery. 42(5):1083-1099, 1998; 4) E. A:. Neuwelt Neurosurgery. 19(4):573-582, 1986.