gms | German Medical Science

Targeted cancer therapies use drugs that block the growth and spread of cancer by interfering with specific target molecules that play a key role in the cancer development and tumor progression. The selection of an appropriate target proves to be the first and crucial step for determining success or failure of a drug candidate. An optimal molecular cancer target plays a key role in cancer disease progression by promoting the vital functions of the tumor, thus making it difficult to be by-passed by the tumor. An ideal candidate fulfilling this prerequisite is the transforming growth factor beta (TGF-b, which plays a key role in malignant progression of various tumors by inducing proliferation, metastasis and invasiveness, epithelial to mesenchymal transition (EMT), and escape from immunosurveillance. High-grade gliomas are characterized by marked overexpression of TGF-b2. Considering the pivotal role of TGF-b2 in malignant gliomas a multimodal approach has been developed based on the specific inhibition of TGF-b2 synthesis by the antisense compound AP12009. Preclinical proof of concept was provided employing patient-derived glioma and immune cells. AP 12009 reduced TGF-b2 secretion in glioma cells, inhibited glioma cell migration more effectively than anti-TGF-b2-antibody, and markedly increased the anti-tumor activity of patient-derived lymphokine-activated killer cells against autologous tumor cells. In a preceding phase I/II dose-escalation study AP 12009 proved to be well tolerated and revealed an excellent safety profile. Furthermore, efficacy data including two complete remissions were observed. In the current phase IIb study adult patients with malignant glioma were treated with AP 12009, which was delivered locoregionally by convection enhanced delivery (CED). Primary objective of this study was to determine the efficacy and safety of different doses of AP 12009 with repeated treatment courses. The treatment was compared to standard of care chemotherapy, i.e. TMZ or PCV. Recruitment was completed in April 2005 with 145 recurrent or refractory malignant glioma (anaplastic astrocytoma, WHO III or glioblastoma, WHO IV) patients. Both, safety and efficacy data will be presented at the conference.