TARGETING THERAPY OF MALIGNANT BRAIN TUMOR BY A LOCAL INTERSTITIAL DELIVERY SYSTEM LOADING WITH A NOVEL SMALL MOLECULE IND FOR PHASE I/IIA APPROVED BY FDA (IND 128388)
Horng-Jyh Harn, Tzyy-Wen Chiou, Mao-Hsuan Huang, Hong-Meng Chuang, Ssu-Yin Yen, Shinn-Zong Lin and Pei-Wen Chou
Bioinovation center, Buddhist Tzu Chi Medical Foundation, Room 615, 6F, Xie-Li building, No. 707, Sec. 3, Chung Yang Rd., Hualien 970, Taiwan, Republic of China
Abstract
The anti-glioblastoma pharmacology effect of BP (butylidenephthalide) is identified in yellowish brown root of the plant Angelica sinensis, a well-known Chinese medicine. This antitumor activity was suggested resulting from suppression of telomerase level, up-regulation of nuclear receptor Nur77, reducing tumor migration and invasion mediated by Axl-1 tyrosine receptor as well as Sox-2 gene.
In order to overcome the limitation of blood-brain barrier, a local interstitial delivery system which BP incorporated into a biodegradable polyanhydride material CPPSA, namely, the BP/polymer wafer was applied. The results of both subcutaneous and intracranial implantation of BP wafer revealed that BP wafer significantly reduced tumor size in a dose-dependent manner in a human GBM xenograft nude mouse model and a spontaneous brain tumor mouse model, respectively.
Comparing with BCNU wafer (Gliadel® wafers); BP/polymer wafer has been reported to be less toxic and more specific and penetrable to the brain tissue. Furthermore, TMZ resistance is another critical issue of GBM treatment. BP showed the significant effects on reversing TMZ resistance by suppressing MGMT mRNA and its protein expression. This novelty contributes the efficient effects on survival (2.44 time prolonged more than Gliadel® wafers).
At present, we have completed the project in a chemical manufacturing and control, preclinical efficacy and preclinical safety assessment and other tests. The IND of cerebraca wafer has been approved by FDA for phase I/IIa. This clinical trial will be conducted at Tzu-Chi University Hospital in, Haulien, Taiwan.