Influence of Anti-Angiogenic Therapy on Drug Delivery to Brain Tumors
Anti-angiogenic therapy (AAT) targeting the vascular endothelial growth factor (VEGF) axis is an important component of treatment for recurrent glioblastoma multiforme (GBM).
Many novel therapeutic strategies are being developed in combination with anti-angiogenic therapy in the next generation of clinical trials for glioblastoma multiforme.
Unfortunately, these combinations have been developed without an understanding of how AAT influences the integrity of the blood-brain barrier in and around the tumor core and the subsequent delivery of novel chemotherapeutic agents across the blood-brain barrier.
During gliomagenesis, expression of VEGF and other pro-angiogenic factors promotes development of an immature tumor vasculature with partial blood-brain barrier disruption. AAT-mediated inhibition of VEGF signaling can restore tight junction integrity and potentially promote expression of blood-brain barrier drug efflux transporters — that is, normalize the blood-brain barrier vasculature.
Many drugs being tested in glioblastoma multiforme clinical trials in combination with anti-angiogenic therapy have limited blood-brain barrier penetration. Studies in this application will test the central hypothesis that AAT-mediated restoration of blood-brain barrier integrity may paradoxically reduce delivery of concomitantly administered drugs to the tumor, leading to reduced efficacy.
This hypothesis will be tested both in the Mayo Clinic panel of primary glioblastoma multiforme xenografts and in University of Minnesota-derived genetically engineered GBM models (GEMMs).
The planned aims are:
- Aim 1: Determine the influence of the anti-VEGF antibody Bev, the VEGFR inhibitor cediranib and a novel PI3K/mTOR inhibitor GNE-317 on brain microvasculature function (perfusion, tight junctions and efflux transport) in primary glioblastoma multiforme xenografts and GEMMs.
- Aim 2: Examine how anti-angiogenic effects of Bev and GNE-317 alter drug delivery (site-specific pharmacokinetics) for relevant agents that have different blood-brain barrier permeability characteristics (for example: temozolomide, erlotinib, GDC-0980 and GNE-317). We hypothesize that anti-angiogenic therapy will have a variable detrimental impact on delivery and resultant efficacy depending on the combination therapy.
- Aim 3: Test two distinct strategies to improve the efficacy of combination therapies:
- Disruption of blood-brain barrier efflux transporter activity to enhance the efficacy of AAT-transporter substrate combinations
- Manipulation of chemical structure to reduce efflux liability and increase passive permeability to enhance efficacy of AAT plus PI3K/mTOR inhibitor combinations
Many novel agents for glioblastoma multiforme being developed in combination with anti-angiogenic therapy are excluded by the blood-brain barrier. Thus, understanding the impact of AAT on blood-brain barrier integrity and drug delivery is critical for successful development of AAT combination therapies for recurrent glioblastoma multiforme.
The planned studies will define critical parameters that influence the efficacy of AAT combination regimens and use that information to improve patient outcomes in future trials that combine anti-angiogenic agents with other novel therapeutics.