effect of Antiangiogenic Therapy on tumor associated macrophages in recurrent glioblastoma

2010 Background: Antiangiogenic Therapy is associated with increased radiographic responses in glioblastoma (GBM), but tumors invariably recur. Tumor associated macrophages (TAMs) have been proposed as a mechanism of resistance to anti-angiogenic Therapy in preclinical models. To examine the role of TAMs in recurrent GBM, we analyzed autopsy specimens from patients with or without history of Antiangiogenic Therapy. Methods: We compared autopsy brain specimens from 17 recurrent GBM patients who received anti-angiogenic treatment and chemoradiation (AAT+) to 7 patients who received chemoTherapy and/or radioTherapy without anti-angiogenic Therapy, or no treatment (AAT-). TAMs were morphologically and phenotypically identified with flow cytometry and immunohistochemistry (IHC) with CD68, CD11b, CD14, and CD163 markers. All specimens were obtained from the Department of Pathology at Massachusetts General Hospital and clinical information gained through review of the patients’ records. Results: Using flow cytom…

biomarkers of response and resistance to Antiangiogenic Therapy

No validated biomarkers currently exist for appropriately selecting cancer patients for Antiangiogenic Therapy. A number of potential systemic, circulating, tissue and imaging biomarkers have emerged as suitable candidate biomarkers, but all require prospective validation. The authors discuss the current challenges in establishing biomarkers, the advantages and disadvantages of systemic, circulating, tissue and imaging biomarkers, and the future opportunities for validating biomarkers of Antiangiogenic Therapy.

effect of vascular normalization by Antiangiogenic Therapy on interstitial hypertension peritumor edema and lymphatic metastasis insights from a mathematical model

Preclinical and clinical evidence shows that Antiangiogenic agents can decrease tumor vessel permeability and interstitial fluid pressure (IFP) in a process of vessel “normalization.” The resulting normalized vasculature has more efficient perfusion, but little is known about how tumor IFP and interstitial fluid velocity (IFV) are affected by changes in transport properties of the vessels and interstitium that are associated with Antiangiogenic Therapy. By using a mathematical model to simulate IFP and IFV profiles in tumors, we show here that Antiangiogenic Therapy can decrease IFP by decreasing the tumor size, vascular hydraulic permeability, and/or the surface area per unit tissue volume of tumor vessels. Within a certain window of Antiangiogenic effects, interstitial convection within the tumor can increase dramatically, whereas fluid convection out of the tumor margin decreases . This would result in increased drug convection within the tumor and decreased convection of drugs, growth factors, or metastatic cancer cells from the tumor margin into the peritumor fluid or tissue. Decreased convection of growth factors, such as vascular endothelial growth factor-C (VEGF-C), would limit peritumor hyperplasia, and decreased VEGF-A would limit angiogenesis in sentinel lymph nodes. Both of these effects would reduce the probability of lymphatic metastasis. Finally, decreased fluid convection into the peritumor tissue would decrease peritumor edema associated with brain tumors and ascites accumulation in the peritoneal or pleural cavity, a major complication with a number of malignancies. [Cancer Res 2007;67(6):2729–35]

effect of vascular normalization by Antiangiogenic Therapy on interstitial hypertension peritumor edema and lymphatic metastasis insights from a mathematical model

Preclinical and clinical evidence shows that Antiangiogenic agents can decrease tumor vessel permeability and interstitial fluid pressure (IFP) in a process of vessel “normalization.” The resulting normalized vasculature has more efficient perfusion, but little is known about how tumor IFP and interstitial fluid velocity (IFV) are affected by changes in transport properties of the vessels and interstitium that are associated with Antiangiogenic Therapy. By using a mathematical model to simulate IFP and IFV profiles in tumors, we show here that Antiangiogenic Therapy can decrease IFP by decreasing the tumor size, vascular hydraulic permeability, and/or the surface area per unit tissue volume of tumor vessels. Within a certain window of Antiangiogenic effects, interstitial convection within the tumor can increase dramatically, whereas fluid convection out of the tumor margin decreases . This would result in increased drug convection within the tumor and decreased convection of drugs, growth factors, or metastatic cancer cells from the tumor margin into the peritumor fluid or tissue. Decreased convection of growth factors, such as vascular endothelial growth factor-C (VEGF-C), would limit peritumor hyperplasia, and decreased VEGF-A would limit angiogenesis in sentinel lymph nodes. Both of these effects would reduce the probability of lymphatic metastasis. Finally, decreased fluid convection into the peritumor tissue would decrease peritumor edema associated with brain tumors and ascites accumulation in the peritoneal or pleural cavity, a major complication with a number of malignancies. [Cancer Res 2007;67(6):2729–35]

Effect of vascular normalization by Antiangiogenic Therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: Insights from a mathematical model

Preclinical and clinical evidence shows that Antiangiogenic agents can decrease tumor vessel permeability and interstitial fluid pressure (IFP) in a process of vessel “normalization.” The resulting normalized vasculature has more efficient perfusion, but little is known about how tumor IFP and interstitial fluid velocity (IFV) are affected by changes in transport properties of the vessels and interstitium that are associated with Antiangiogenic Therapy. By using a mathematical model to simulate IFP and IFV profiles in tumors, we show here that Antiangiogenic Therapy can decrease IFP by decreasing the tumor size, vascular hydraulic permeability, and/or the surface area per unit tissue volume of tumor vessels. Within a certain window of Antiangiogenic effects, interstitial convection within the tumor can increase dramatically, whereas fluid convection out of the tumor margin decreases. This would result in increased drug convection within the tumor and decreased convection of drugs, growth factors, or metastatic cancer cells from the tumor margin into the peritumor fluid or tissue. Decreased convection of growth factors, such as vascular endothelial growth factor-C (VEGF-C), would limit peritumor hyperplasia, and decreased VEGF-A would limit angiogenesis in sentinel lymph nodes. Both of these effects would reduce the probability of lymphatic metastasis. Finally, decreased fluid convection into the peritumor tissue would decrease peritumor edema associated with brain tumors and ascites accumulation in the peritoneal or pleural cavity, a major complication with a number of malignancies.

a mathematical model of the contribution of endothelial progenitor cells to angiogenesis in tumors implications for Antiangiogenic Therapy

The traditional view of angiogenesis emphasizes proliferation and migration of vessel wall-associated endothelial cells. However, circulating endothelial progenitor cells have recently been shown to contribute to tumor angiogenesis. Here we quantify the relative contributions of endothelial and endothelial progenitor cells to angiogenesis using a mathematical model. The model predicts that during the early stages of tumor growth, endothelial progenitors have a significant impact on tumor growth and angiogenesis, mediated primarily by their localization in the tumor, not by their proliferation. The model also shows that, as the tumor grows, endothelial progenitors adhere preferentially near the tumor periphery, coincident with the location of highest vascular density, supporting their potential utility as vectors for targeted delivery of therapeutics. Model simulations of various Antiangiogenic strategies show that those therapies that effectively target both endothelial and endothelial progenitor cells, either by restoring the balance between angiogenic stimulators and inhibitors or by targeting both types of cells directly, are most effective at delaying tumor growth. The combination of continuous low-dose chemoTherapy and Antiangiogenic Therapy is predicted to have the most significant effect on therapeutic outcome. The model offers new insight into tumor angiogenesis with implications for the rational design of Antiangiogenic Therapy. (Blood. 2003;102:2555-2561)

increase in tumor associated macrophages after Antiangiogenic Therapy is associated with poor survival among patients with recurrent glioblastoma

Antiangiogenic Therapy is associated with increased radiographic responses in glioblastomas, but tumors invariably recur. Because tumor-associated macrophages have been shown to mediate escape from Antiangiogenic Therapy in preclinical models, we examined the role of macrophages in patients with recurrent glioblastoma. We compared autopsy brain specimens from 20 patients with recurrent glioblastoma who received Antiangiogenic treatment and chemoradiation with 8 patients who received chemoTherapy and/or radioTherapy without Antiangiogenic Therapy or no treatment. Tumor-associated macrophages were morphologically and phenotypically analyzed using flow cytometry and immunohistochemistry for CD68, CD14, CD163, and CD11b expression. Flow cytometry showed an increase in macrophages in the Antiangiogenic-treated patients. Immunohistochemical analysis demonstrated an increase in CD68+ macrophages in the tumor bulk (P < .01) and infiltrative areas (P = .02) in Antiangiogenic-treated patients. We also observed an increase in CD11b+ cells in the tumor bulk (P < .01) and an increase in CD163+ macrophages in infiltrative tumor (P = .02). Of note, an increased number of CD11b+ cells in bulk and infiltrative tumors (P = .05 and P = .05, respectively) correlated with poor overall survival among patients who first received Antiangiogenic Therapy at recurrence. In summary, recurrent glioblastomas showed an increased infiltration in myeloid populations in the tumor bulk and in the infiltrative regions after Antiangiogenic Therapy. Higher numbers of CD11b+ cells correlated with poor survival among these patients. These data suggest that tumor-associated macrophages may participate in escape from Antiangiogenic Therapy and may represent a potential biomarker of resistance and a potential therapeutic target in recurrent glioblastoma.

abstract lb 339 increase in tumor associated macrophages tams after Antiangiogenic Therapy is associated with poor survival in recurrent glioblastoma gbm patients

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC

Antiangiogenic Therapy is associated with increased radiographic responses in glioblastomas (GBMs), but tumors invariably recur. Because tumor-associated macrophages (TAMs) have been shown to mediate escape from Antiangiogenic Therapy in preclinical models, we examined the role of TAMs in recurrent glioblastoma (rGBM) patients. We compared autopsy brain specimens from 20 rGBM patients who received Antiangiogenic treatment and chemoradiation (AAT+) to 8 patients who received chemoTherapy and/or radioTherapy without Antiangiogenic Therapy, or no treatment (AAT-). TAMs were morphologically and phenotypically analyzed using flow cytometry and immunohistochemistry (IHC) for CD68, CD14, CD163, and CD11b expression. Flow cytometry showed an increase in TAMs in the AAT+ patients. IHC analysis demonstrated an increase in CD68+ TAMs in the tumor bulk (p<0.01) and infiltrative areas (p=0.02) in AAT+ patients. We also observed an increase in CD11b+ cells in the tumor bulk (p<0.01) and an increase in CD163+ TAMs in infiltrative tumor (p=0.02). Of note, an increased number of CD11b+ cells in bulk and infiltrative tumor (p=0.05 and p=0.05, respectively) correlated with poor overall survival in patients who first received Antiangiogenic Therapy at recurrence. In summary, rGBMs showed an increased infiltration in myeloid populations in the tumor bulk and in the infiltrative regions after Antiangiogenic Therapy. Higher numbers of CD11b+ cells correlated with poor survival in rGBM patients. These data suggest that TAMs may participate in escape from Antiangiogenic Therapy and may represent a potential biomarker of resistance and a potential therapeutic target in rGBM.

Citation Format: Christine Lu-Emerson, Matija Snuderl, Nathaniel D. Kirkpatrick, Jermaine Goveia, Jennie Taylor, Christian Davidson, Yuhui Huang, Lars Riedemann, S. Percy Ivy, G. Dan Duda, Marek Ancukiewicz3, Scott R. Plotkin, Andrew Chi, Elizabeth R. Gerstner, April F. Eichler, Jorg Dietrich, Anat O. Stemmer-Rachamimov, Tracy T. Batchelor, Rakesh K. Jain. Increase in tumor-associated macrophages (TAMs) after Antiangiogenic Therapy is associated with poor survival in recurrent glioblastoma (GBM) patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-339. doi:10.1158/1538-7445.AM2013-LB-339

effect of Antiangiogenic Therapy on tumor associated macrophages in recurrent glioblastoma

2010 Background: Antiangiogenic Therapy is associated with increased radiographic responses in glioblastoma (GBM), but tumors invariably recur. Tumor associated macrophages (TAMs) have been proposed as a mechanism of resistance to anti-angiogenic Therapy in preclinical models. To examine the role of TAMs in recurrent GBM, we analyzed autopsy specimens from patients with or without history of Antiangiogenic Therapy. Methods: We compared autopsy brain specimens from 17 recurrent GBM patients who received anti-angiogenic treatment and chemoradiation (AAT+) to 7 patients who received chemoTherapy and/or radioTherapy without anti-angiogenic Therapy, or no treatment (AAT-). TAMs were morphologically and phenotypically identified with flow cytometry and immunohistochemistry (IHC) with CD68, CD11b, CD14, and CD163 markers. All specimens were obtained from the Department of Pathology at Massachusetts General Hospital and clinical information gained through review of the patients’ records. Results: Using flow cytom…