Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation

Batchelor, Tracy T.; Gerstner, Elizabeth R.; Emblem, Kyrre E.; Duda, Dan G.; Kalpathy–Cramer, Jayashree; Snuderl, Matija; Ancukiewicz, Marek; Polaskova, Pavlina; Pinho, Marco da Cunha; Jennings, Dominique; Plotkin, Scott R.; Andrew, S.; Eichler, April F.; Dietrich, Jörg; Hochberg, Fred H.; Lu-Emerson, Christine; Iafrate, A. John; Ivy, S. Percy; Rosen, Bruce R.; Loeffler, Jay S.; Wen, Patrick Y.; Sorensen, A. G.; Jain, Rakesh K.

doi:10.1073/pnas.1318022110

Cited by 301 publications

(314 citation statements)

References 43 publications

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“…Previously we have shown that the inhibition of VEGF during tumor growth leads to vascular normalization, the extent of which was associated with survival in preclinical models (10,11,27) and GBM patients (47)(48)(49)(50). Recent clinical data suggest that improved tumor perfusion and oxygenation in both newly diagnosed and rGBM patients during anti-VEGF therapy correlates with significantly longer survival than seen in patients whose tumor blood perfusion does not increase or decreases (47)(48)(49)(50).…”

Section: Discussionmentioning

confidence: 98%

“…Recent clinical data suggest that improved tumor perfusion and oxygenation in both newly diagnosed and rGBM patients during anti-VEGF therapy correlates with significantly longer survival than seen in patients whose tumor blood perfusion does not increase or decreases (47)(48)(49)(50). In both U87 and Gl261 tumors dual therapy resulted in a vasculature that more closely resembled that of the surrounding brain.…”

Section: Discussionmentioning

confidence: 99%

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Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

Peterson

Kirkpatrick

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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254

216

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Glioblastomas (GBMs) rapidly become refractory to anti-VEGF therapies. We previously demonstrated that ectopic overexpression of angiopoietin-2 (Ang-2) compromises the benefits of anti-VEGF receptor (VEGFR) treatment in murine GBM models and that circulating Ang-2 levels in GBM patients rebound after an initial decrease following cediranib (a pan-VEGFR tyrosine kinase inhibitor) administration. Here we tested whether dual inhibition of VEGFR/Ang-2 could improve survival in two orthotopic models of GBM, Gl261 and U87. Dual therapy using cediranib and MEDI3617 (an anti–Ang-2–neutralizing antibody) improved survival over each therapy alone by delaying Gl261 growth and increasing U87 necrosis, effectively reducing viable tumor burden. Consistent with their vascular-modulating function, the dual therapies enhanced morphological normalization of vessels. Dual therapy also led to changes in tumor-associated macrophages (TAMs). Inhibition of TAM recruitment using an anti–colony-stimulating factor-1 antibody compromised the survival benefit of dual therapy. Thus, dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs. This approach may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients by integrating the complementary effects of anti-Ang2 treatment on vessels and immune cells.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

Peterson

Kirkpatrick

Huang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

254

216

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“…33 We speculate that these effects relate to the ability of such protocols to utilize the vascular normalization window for chemotherapeutic delivery and overcome evasive mechanisms of tumor cells. 8,33 A limitation of this study in addition to the not fully homogenous study cohort is the possibility of methodological uncertainties in parameter estimation. Assessment of tissue metabolism using DSC raw data requires the use of literature values for parameters that cannot be directly measured.…”

Section: Discussionmentioning

confidence: 98%

“…3 Indeed, the effects of antiangiogenic agents on tumor oxygenation status remain controversial, with evidence supporting either vascular regression, which is associated with increased intratumoral hypoxia, 5,6 or a so-called ''normalization'' of the tumor vasculature, resulting in improved tumor oxygenation and cytotoxic chemotherapy sensitivity. [7][8][9] The tumor microcirculation is characterized by abnormal capillary bed topology, elevated edema pressure, and microthromboses, all of which give rise to shunting of oxygenated blood through the tissue. 10 The resulting reduction in oxygen extraction efficacy is not accounted for by the classical flow-diffusion equation, 11 which we normally use to assess tissue oxygenation based on CBF and CBV.…”

Section: Introductionmentioning

confidence: 99%

Assessment of tumor oxygenation and its impact on treatment response in bevacizumab-treated recurrent glioblastoma

Bonekamp

Mouridsen

Radbruch

et al. 2016

J Cereb Blood Flow Metab

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Antiantiogenic therapy with bevacizumab in recurrent glioblastoma is currently understood to both reduce microvascular density and to prune abnormal tumor microvessels. Microvascular pruning and the resulting vascular normalization are hypothesized to reduce tumor hypoxia and increase supply of systemic therapy to the tumor; however, the underlying pathophysiological changes and their timing after treatment initiation remain controversial. Here, we use a novel dynamic susceptibility contrast MRI-based method, which allows simultaneous assessment of tumor net oxygenation changes reflected by the tumor metabolic rate of oxygen and vascular normalization represented by the capillary transit time heterogeneity. We find that capillary transit time heterogeneity, and hence the oxygen extraction fraction combine with the tumoral blood flow (cerebral blood flow) in such a way that the overall tumor oxygenation appears to be worsened despite vascular normalization. Accordingly, hazards for both progression and death are found elevated in patients with a greater reduction of tumor metabolic rate of oxygen in response to bevacizumab and patients with higher intratumoral tumor metabolic rate of oxygen at baseline. This implies that tumors with a higher degree of angiogenesis prior to bevacizumab-treatment retain a higher level of angiogenesis during therapy despite a greater antiangiogenic effect of bevacizumab, hinting at evasive mechanisms limiting bevacizumab efficacy in that a reversal of their biological behavior and relative prognosis does not occur.

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“…In a clinical situation, the optimal dose can be determined by the changes that chemotherapy induces in tumor vessel permeability and perfusion. Both vessel permeability and perfusion can be measured clinically with magnetic resonance imaging (MRI) (42,43); thus, the optimal dose and schedule to reduce vessel permeability and improve perfusion can be inferred using MRI. Given the continuously evolving nature of each cancer, as well as differences among tumor types, among tumors of the same type, and between a primary tumor and its metastases, the selection of an optimal dosage schedule must be patient-specific.…”

Section: Discussionmentioning

confidence: 99%

Role of vascular normalization in benefit from metronomic chemotherapy

Mpekris

Baish

Stylianopoulos

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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140

113

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Metronomic dosing of chemotherapy-defined as frequent administration at lower doses-has been shown to be more efficacious than maximum tolerated dose treatment in preclinical studies, and is currently being tested in the clinic. Although multiple mechanisms of benefit from metronomic chemotherapy have been proposed, how these mechanisms are related to one another and which one is dominant for a given tumor-drug combination is not known. To this end, we have developed a mathematical model that incorporates various proposed mechanisms, and report here that improved function of tumor vessels is a key determinant of benefit from metronomic chemotherapy. In our analysis, we used multiple dosage schedules and incorporated interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature. We found that metronomic chemotherapy induces functional normalization of tumor blood vessels, resulting in improved tumor perfusion. Improved perfusion alleviates hypoxia, which reprograms the immunosuppressive tumor microenvironment toward immunostimulation and improves drug delivery and therapeutic outcomes. Indeed, in our model, improved vessel function enhanced the delivery of oxygen and drugs, increased the number of effector immune cells, and decreased the number of regulatory T cells, which in turn killed a larger number of cancer cells, including cancer stem-like cells. Vessel function was further improved owing to decompression of intratumoral vessels as a result of increased killing of cancer cells, setting up a positive feedback loop. Our model enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of metronomic therapy.thrompospondin-1 | tumor perfusion | oxygenation | immune response | drug delivery

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Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation

Cited by 301 publications

References 43 publications

Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

Assessment of tumor oxygenation and its impact on treatment response in bevacizumab-treated recurrent glioblastoma

Role of vascular normalization in benefit from metronomic chemotherapy

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