Analysis of chemotherapeutic-induced tumor dormancy in Glioblastoma Multiforme and alternative therapy approaches
Glioblastoma Multiforme is a malignant, primary brain tumor. Its incurability relies on the ability of the tumor to evade therapy and develop recurrences. Due to the impeded transport of molecules across the blood-brain barrier (BBB), subletal doses of agents within the tumor result in chemotherapeutically triggered therapy escape like tumor cell dormancy. This study aimed at both a more detailed understanding of molecular pathways as well as environmental influences on the entry into and exit from dormancy and, based on this knowledge, the improvement of therapy by introducing alternative compounds and strategies. Upon treatment with temozolomide (TMZ), the standard therapeutic, glioma cells entered an unproliferative state, which was not only described by dormant but also stem-cell features, indicated by an upregulation of dormancy and stem-cell markers and the ability of dormant cells to form spheroids. Moreover, dormancy entry was characterized by an increased expression of CCL2 and SAA2, while in dormancy exit, THSD4, FSTL3 and VEGFC were upregulated. Interestingly, co-stimulation with chemokines, mimicking an inflammatory environment, delayed the entry into and exit from dormancy. The use of alternative drugs and stimulation schemes appeared to be promising in overcoming therapy escape including dormancy. Especially, sequential application of TMZ+AT101, the R-(-)-enantiomer of the cottonseed-derived polyphenol gossypol, followed by AT101 alone increased glioma cell death. However, GBM cells were protected by astrocytes and microglia in an incomplete tumor-resection co-culture model, while glioma cells enhanced astrocytic cell death. Considering sequential application of TMZ and AT101, AT101 was encapsulated into cubosomes to improve passaging across the BBB. Further, a PDMS implant based on ZnO tetrapods was developed showing a high drug loading capacity and a sustained, long-term release of AT101 in artificial liquor for an improved therapy for patients.