Combination therapy as a potential strategy in Glioblastoma treatment

Glioblastoma is a highly aggressive, difficult to treat malignancy that almost invariably has invaded surrounding tissue upon presentation. The current standard of care consists of maximal safe surgical resection of the tumor, followed by radio- and chemotherapy with the alkylating agent temozolomide. Despite this aggressive treatment regime patient survival is only approximately 15 months.

In a compassionate use setting we have treated patients whose tumors no longer responded to standard therapy with the so-called RIST protocol, a complex combination therapy consisting of two pharmacological inhibitors rapamycin and sunitinib targeting the PI3K/Akt/mTOR pathway and tyrosine kinases as well as the two chemotherapeutics temozolomide and irinotecan, which induce cell death via two distinct molecular mechanisms.

Interestingly, we could show that the selection of inhibitor is not necessarily intuitive: Comparing inhibition of PI3K with inhibition of mTOR, i.e. targeting the signaling cascade apically versus only blocking a side arm, the former is more potent in vitro and also strongly reduces the pro-migratory side effects of radiotherapy. However, in vivo blocking of PI3K ablates the potent therapeutic effect the RIST protocol exerts when mTOR is targeted. This is most likely due to the fact that inhibition of PI3K is too effective and alters the tumor's microenvironment. Similarly, replacing the multi-targeted receptor tyrosine kinase inhibitor sunitinib with dasatinib, which is a particularly strong inhibitor of Src does not potently enhance the efficacy of the RIST protocol.

While the RIST protocol is a potent therapeutic weapon against several types of therapy-resistant tumor entities, further optimization has proven difficult. In the context of failure of personalized medicine over physicians' choice these data further emphasize the complexity of signaling network interactions and the multiple roles such pathways can have in individual cancer cells, as well as in different cell populations found in a single tumor.