Glioblastoma (GBM) is among the most aggressive cancers. The prognosis for GBM patients is dismal, with average survival of 12-15 months. High interstitial fluid pressure (IFP) represents a major obstacle in solid cancers and a barrier for drg uptake. Solid tumors are associated with increased IFP due to vascular leakiness and drainage resistance via stromal cell mediated release of factors and contraction of the interstitial matrix. Fluid accumulation and high cell density compresses tumor and surrounding normal tissue and promotes osmotic swelling of tumor cells. Although studies have clarified the role of tumor vasculature, it is still unclear how mechanical stresses and osmotic changes regulate tumor cell biology. Our laboratory has developed a novel method that enables precise measurements of IFP in xenografted GBMs during tumor progression. Intriguingly, our preliminary data suggest that elevated IFP drives tumor growth. Extended studies in vitro confirmed that elevated hydrostatic pressure increases GBM cell proliferation. In this proposal, we will use novel in vitro and in vivo methodology to study the effects of hydrostatic and osmotic pressures on GBM biology. We will study the relationship between elevated IFP on 1) tumor growth and 2) uptake of chemotherapeutics in human GBM xenografts. Using 3D-cultures and tumor slices, we will then test if increased hydrostatic or osmotic pressure components regulate 1) GBM cell proliferation and 2) the cytotoxic effects of chemotherapy. Early efforts to identify a treatment that prevents cholera toxin-induced hypersecretion from the intestine resulted in the identification of antisecretory factor (AF). AF-induction is safe in patients, reduces elevated intracranial pressure in rodents, and lowers IFP in subcutaneous solid tumors. In two aims, we will test if AF lowers IFP in GBM xenografts, leading to reduced tumor growth and increased uptake of chemotherapies in tumors. Mechanistic studies in 3D-cultures and tumor slices will test if AF can regulate GBM cell proliferation and the cytotoxic effects of chemotherapies under conditions of elevated hydrostatic or osmotic pressures. Our work will establish a role for mechanical stresses and osmotic changes as potential therapeutic targets in solid cancers. As a novel IFP-reducing therapy, we firmly believe that AF induction represents an attractive strategy to improve overall survival in GBM patients.
High interstitial fluid pressure (IFP) in solid cancers presents a barrier for drug uptake, but it is still unclear if IFP also regulates cell division and cell deah of tumor cells. We have developed methodology to investigate the effects of IFP on cell division and cell death in human glioblastoma tumors, the most common and aggressive brain tumor, when grown in 3D-cultures or transplanted into mice. In this proposal, we will investigate if antisecretory factor (AF), a regulator of fluid secretion, 1) reverses elevated IFP in human glioblastoma models, leading to reduced proliferation and increased cell death, and 2) potently promotes uptake of chemotherapies in tumors, ultimately with the goal to improve survival of glioblastoma patients.
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|Li, Nan; Maly, Dustin J; Chanthery, Yvan H et al. (2015) Radiotherapy followed by aurora kinase inhibition targets tumor-propagating cells in human glioblastoma. Mol Cancer Ther 14:419-28|