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Matthew Morrison - One of the best experts on this subject based on the ideXlab platform.

  • monitoring tumor response to Antiangiogenic sunitinib therapy with 18f fluciclatide an 18f labeled αvβ3 integrin and αvβ5 integrin imaging agent
    The Journal of Nuclear Medicine, 2011
    Co-Authors: Mark Battle, Lucy Allen, Jon Barnett, Julian Goggi, Matthew Morrison
    Abstract:

    Arginine-glycine-aspartate (RGD)-binding aVb3-integrin and aVb5-integrin play key roles in tumor angiogenesis. We examined an 18 F-labeled small peptide (fluciclatide [United States Adopted Name (ASAN)–approved, International Nonproprietary Name (INN)–proposed name], previously referred to as AH111585) containing an RGD sequence. Fluciclatide binds with a high (nM) affinity to aVb3-integrin and aVb5-integrin, which are highly expressed on tumors and the tumor neovasculature. In this study, 18 F-fluciclatide was used to examine the response of human glioblastoma xenografts to treatment with the Antiangiogenic agent sunitinib. Methods: U87-MG tumor uptake of 18 F-fluciclatide was determined by small-animal PET after longitudinal administration of the Antiangiogenic agent sunitinib (a 2-wk dosing regimen). Tumor sizes were measured throughout the study, and tumor volumes were calculated. Tumor microvessel density (MVD) after therapy was also analyzed. Results: Dynamic small-animal PET of 18F-fluciclatide uptake after administration of the clinically relevant Antiangiogenic agent sunitinib revealed a reduction in the tumor uptake of 18F-fluciclatide compared with that in vehicle-treated controls over the 2-wk dosing regimen. Skeletal muscle, used as a reference tissue, showed equivalent 18 F-fluciclatide uptake in both therapy and control groups. A reduction in tumor MVD was also observed after treatment with the Antiangiogenic agent. No significant changes in tumor volume were observed in the 2 groups. Conclusion: The data demonstrated that 18 F-fluciclatide detected changes in tumor uptake after acute Antiangiogenic therapy markedly earlier than any significant volumetric changes were observable. These results suggest that this imaging agent may provide clinically important information for guiding patient care and monitoring the response to Antiangiogenic therapy.

  • monitoring tumor response to Antiangiogenic sunitinib therapy with 18f fluciclatide an 18f labeled αvβ3 integrin and αvβ5 integrin imaging agent
    The Journal of Nuclear Medicine, 2011
    Co-Authors: Mark Battle, Lucy Allen, Jon Barnett, Julian Goggi, Matthew Morrison
    Abstract:

    Arginine-glycine-aspartate (RGD)-binding aVb3-integrin and aVb5-integrin play key roles in tumor angiogenesis. We examined an 18 F-labeled small peptide (fluciclatide [United States Adopted Name (ASAN)–approved, International Nonproprietary Name (INN)–proposed name], previously referred to as AH111585) containing an RGD sequence. Fluciclatide binds with a high (nM) affinity to aVb3-integrin and aVb5-integrin, which are highly expressed on tumors and the tumor neovasculature. In this study, 18 F-fluciclatide was used to examine the response of human glioblastoma xenografts to treatment with the Antiangiogenic agent sunitinib. Methods: U87-MG tumor uptake of 18 F-fluciclatide was determined by small-animal PET after longitudinal administration of the Antiangiogenic agent sunitinib (a 2-wk dosing regimen). Tumor sizes were measured throughout the study, and tumor volumes were calculated. Tumor microvessel density (MVD) after therapy was also analyzed. Results: Dynamic small-animal PET of 18F-fluciclatide uptake after administration of the clinically relevant Antiangiogenic agent sunitinib revealed a reduction in the tumor uptake of 18F-fluciclatide compared with that in vehicle-treated controls over the 2-wk dosing regimen. Skeletal muscle, used as a reference tissue, showed equivalent 18 F-fluciclatide uptake in both therapy and control groups. A reduction in tumor MVD was also observed after treatment with the Antiangiogenic agent. No significant changes in tumor volume were observed in the 2 groups. Conclusion: The data demonstrated that 18 F-fluciclatide detected changes in tumor uptake after acute Antiangiogenic therapy markedly earlier than any significant volumetric changes were observable. These results suggest that this imaging agent may provide clinically important information for guiding patient care and monitoring the response to Antiangiogenic therapy.

Max S Wicha - One of the best experts on this subject based on the ideXlab platform.

  • crlx101 an investigational camptothecin containing nanoparticle drug conjugate targets cancer stem cells and impedes resistance to Antiangiogenic therapy in mouse models of breast cancer
    Breast Cancer Research and Treatment, 2015
    Co-Authors: Sarah J Conley, Trenton L Baker, Joseph Burnett, Rebecca Theisen, Douglas Lazarus, Christian G Peters, Shawn G Clouthier, Scott Eliasof, Max S Wicha
    Abstract:

    Antiangiogenic therapies inhibit the development of new tumor blood vessels, thereby blocking tumor growth. Despite the advances in developing Antiangiogenic agents, clinical data indicate that these drugs have limited efficacy in breast cancer patients. Tumors inevitably develop resistance to Antiangiogenics, which is attributed in part to the induction of intra-tumoral hypoxia and stabilization of hypoxia-inducible factor 1α (HIF-1α), a transcription factor that promotes tumor angiogenesis, invasion, metastasis, and cancer stem cell (CSC) self-renewal. Here, we tested whether inhibiting HIF-1α can reverse the stimulatory effects of Antiangiogenic-induced hypoxia on breast CSCs. Breast cancer cells grown under hypoxic conditions were treated with the dual topoisomerase-1 (TOPO-1) and HIF-1α inhibitor camptothecin and assessed for their CSC content. In a preclinical model of breast cancer, treatment with bevacizumab was compared to the combination treatment of bevacizumab with CRLX101, an investigational nanoparticle-drug conjugate with a camptothecin payload or CRLX101 monotherapy. While exposure to hypoxia increased the number of breast CSCs, treatment with CPT blocked this effect. In preclinical mouse models, concurrent administration of CRLX101 impeded the induction of both HIF-1α and CSCs in breast tumors induced by bevacizumab treatment. Greater tumor regression and delayed tumor recurrence were observed with the combination of these agents compared to bevacizumab alone. Tumor reimplantation experiments demonstrated that the combination therapy effectively targets the CSC populations. The results from these studies support the combined administration of dual TOPO-1- and HIF-1α-targeted agents like CRLX101 with Antiangiogenic agents to increase the efficacy of these treatments.

  • abstract pr09 synergistic activity of crlx101 a nanopharmaceutical in phase ii clinical trials with Antiangiogenic therapies mediated through hif 1alpha inhibition a translational research program
    Molecular Cancer Therapeutics, 2013
    Co-Authors: Scott Eliasof, Robert S Kerbel, Douglas Lazarus, Max S Wicha, Sarah Conley, Stephen M Keefe, C N Krasner, Christian Peters, Elizabeth Pham, Edward Graeme Garmey
    Abstract:

    Background: Antiangiogenic drugs reduce blood flow to tumors and thereby inhibit tumor growth by starving tumors of oxygen and nutrients. However, Antiangiogenic drugs have achieved limited success as monotherapies, in part because of their induction of hypoxia and the concomitant up-regulation of hypoxia-inducible factor 1α (HIF-1α), now well implicated in the promotion of tumor angiogenesis, invasion, metastasis, and cancer stem cell formation. We describe here a translational research program to investigate whether the efficacy of Antiangiogenic drugs can be improved through combination with CRLX101, a camptothecin (CPT) containing nanopharmaceutical that inhibits both topoisomerase-1 and HIF-1α. Material and methods: We will present preclinical and clinical projects conducted across several major research institutions intended to demonstrate the anti-HIF-1α activity of CRLX101, the capacity of this drug to block the epithelial-mesenchymal transition (EMT) and the formation of cancer stem cells, and the synergistic activity of CRLX101 given in combination with Antiangiogenic drugs. We will further describe two ongoing clinical trials evaluating these hypotheses, one at the University of Pennsylvania in advanced renal cell carcinoma (RCC) and one at the Massachusetts General Hospital in relapsed ovarian cancer following progression through prior platinum-containing chemotherapy. Results: A single dose of CRLX101 durably inhibits HIF-1α protein levels across multiple tumor types. Evaluation of CRLX101 in combination with bevacizumab, aflibercept or pazopanib in the A2780 ovarian xenograft tumor model demonstrates synergistic inhibition of tumor growth inhibition as well as increases in the rate of long-term survivorship. While all three Antiangiogenic drugs alone increased HIF-1α protein levels, levels were inhibited in response to combination with CRLX101. In clinical evaluations, a CRLX101-bevacizumab combination appears safe and well tolerated with no dose limiting toxicities observed to date. Notable tumor decreases and long periods of progression free survival have been noted among patients treated with CRLX101-based mono and combination therapy. Conclusions: Results generated through this translational research program suggest that CRLX101 can overcome HIF-1α-mediated acquired resistance to Antiangiogenic drugs, supporting the use of CRLX101 in combination with Antiangiogenic drugs as an exciting new paradigm for the treatment of cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR09. Citation Format: Scott Eliasof, Sarah Conley, Stephen M. Keefe, Robert Kerbel, Carolyn N. Krasner, Douglas Lazarus, Christian Peters, Elizabeth Pham, Max S. Wicha, Edward G. Garmey. Synergistic activity of CRLX101, a nanopharmaceutical in Phase II clinical trials, with Antiangiogenic therapies mediated through HIF-1alpha inhibition: A translational research program. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PR09.

  • Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia
    Proceedings of the National Academy of Sciences of the United States of America, 2012
    Co-Authors: Sarah J Conley, Shawn G Clouthier, Elizabeth Gheordunescu, Pramod Kakarala, Bryan Newman, Hasan Korkaya, Amber Heath, Max S Wicha
    Abstract:

    Antiangiogenic therapy has been thought to hold significant potential for the treatment of cancer. However, the efficacy of such treatments, especially in breast cancer patients, has been called into question, as recent clinical trials reveal only limited effectiveness of Antiangiogenic agents in prolonging patient survival. New research using preclinical models further suggests that Antiangiogenic agents actually increase invasive and metastatic properties of breast cancer cells. We demonstrate that by generating intratumoral hypoxia in human breast cancer xenografts, the Antiangiogenic agents sunitinib and bevacizumab increase the population of cancer stem cells. In vitro studies revealed that hypoxia-driven stem/progenitor cell enrichment is primarily mediated by hypoxia-inducible factor 1α. We further show that the Akt/β-catenin cancer stem cell regulatory pathway is activated in breast cancer cells under hypoxic conditions in vitro and in sunitinib-treated mouse xenografts. These studies demonstrate that hypoxia-driven cancer stem cell stimulation limits the effectiveness of Antiangiogenic agents, and suggest that to improve patient outcome, these agents might have to be combined with cancer stem cell-targeting drugs.

Robert S Kerbel - One of the best experts on this subject based on the ideXlab platform.

  • abstract pr09 synergistic activity of crlx101 a nanopharmaceutical in phase ii clinical trials with Antiangiogenic therapies mediated through hif 1alpha inhibition a translational research program
    Molecular Cancer Therapeutics, 2013
    Co-Authors: Scott Eliasof, Robert S Kerbel, Douglas Lazarus, Max S Wicha, Sarah Conley, Stephen M Keefe, C N Krasner, Christian Peters, Elizabeth Pham, Edward Graeme Garmey
    Abstract:

    Background: Antiangiogenic drugs reduce blood flow to tumors and thereby inhibit tumor growth by starving tumors of oxygen and nutrients. However, Antiangiogenic drugs have achieved limited success as monotherapies, in part because of their induction of hypoxia and the concomitant up-regulation of hypoxia-inducible factor 1α (HIF-1α), now well implicated in the promotion of tumor angiogenesis, invasion, metastasis, and cancer stem cell formation. We describe here a translational research program to investigate whether the efficacy of Antiangiogenic drugs can be improved through combination with CRLX101, a camptothecin (CPT) containing nanopharmaceutical that inhibits both topoisomerase-1 and HIF-1α. Material and methods: We will present preclinical and clinical projects conducted across several major research institutions intended to demonstrate the anti-HIF-1α activity of CRLX101, the capacity of this drug to block the epithelial-mesenchymal transition (EMT) and the formation of cancer stem cells, and the synergistic activity of CRLX101 given in combination with Antiangiogenic drugs. We will further describe two ongoing clinical trials evaluating these hypotheses, one at the University of Pennsylvania in advanced renal cell carcinoma (RCC) and one at the Massachusetts General Hospital in relapsed ovarian cancer following progression through prior platinum-containing chemotherapy. Results: A single dose of CRLX101 durably inhibits HIF-1α protein levels across multiple tumor types. Evaluation of CRLX101 in combination with bevacizumab, aflibercept or pazopanib in the A2780 ovarian xenograft tumor model demonstrates synergistic inhibition of tumor growth inhibition as well as increases in the rate of long-term survivorship. While all three Antiangiogenic drugs alone increased HIF-1α protein levels, levels were inhibited in response to combination with CRLX101. In clinical evaluations, a CRLX101-bevacizumab combination appears safe and well tolerated with no dose limiting toxicities observed to date. Notable tumor decreases and long periods of progression free survival have been noted among patients treated with CRLX101-based mono and combination therapy. Conclusions: Results generated through this translational research program suggest that CRLX101 can overcome HIF-1α-mediated acquired resistance to Antiangiogenic drugs, supporting the use of CRLX101 in combination with Antiangiogenic drugs as an exciting new paradigm for the treatment of cancer. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PR09. Citation Format: Scott Eliasof, Sarah Conley, Stephen M. Keefe, Robert Kerbel, Carolyn N. Krasner, Douglas Lazarus, Christian Peters, Elizabeth Pham, Max S. Wicha, Edward G. Garmey. Synergistic activity of CRLX101, a nanopharmaceutical in Phase II clinical trials, with Antiangiogenic therapies mediated through HIF-1alpha inhibition: A translational research program. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PR09.

  • Antiangiogenic therapy impact on invasion disease progression and metastasis
    Nature Reviews Clinical Oncology, 2011
    Co-Authors: John M L Ebos, Robert S Kerbel
    Abstract:

    Antiangiogenic drugs targeting the VEGF pathway have slowed metastatic disease progression in some patients, leading to progression-free survival (PFS) and overall survival benefits compared with controls. However, the results are more modest than predicted by most preclinical testing and benefits in PFS are frequently not accompanied by overall survival improvements. Questions have emerged about the basis of drug resistance and the limitations of predictive preclinical models, and also about whether the nature of disease progression following Antiangiogenic therapy is different to classic cytotoxic therapies-in particular whether therapy may lead to more invasive or metastatic behavior. In addition, because of recent clinical trial failures of Antiangiogenic therapy in patients with early-stage disease, and the fact that there are hundreds of trials underway in perioperative neoadjuvant and adjuvant settings, there is now greater awareness about the lack of appropriate preclinical testing that preceded these studies. Improved preclinical assessment of all stages of metastatic disease should be a priority for future Antiangiogenic drug discovery and development.

  • Antiangiogenic therapy impact on invasion disease progression and metastasis
    Nature Reviews Clinical Oncology, 2011
    Co-Authors: John M L Ebos, Robert S Kerbel
    Abstract:

    Antiangiogenic drugs targeting the VEGF pathway have slowed metastatic disease progression in some patients, leading to progression-free survival (PFS) and overall survival benefits compared with controls. However, the results are more modest than predicted by most preclinical testing and benefits in PFS are frequently not accompanied by overall survival improvements. Questions have emerged about the basis of drug resistance and the limitations of predictive preclinical models, and also about whether the nature of disease progression following Antiangiogenic therapy is different to classic cytotoxic therapies-in particular whether therapy may lead to more invasive or metastatic behavior. In addition, because of recent clinical trial failures of Antiangiogenic therapy in patients with early-stage disease, and the fact that there are hundreds of trials underway in perioperative neoadjuvant and adjuvant settings, there is now greater awareness about the lack of appropriate preclinical testing that preceded these studies. Improved preclinical assessment of all stages of metastatic disease should be a priority for future Antiangiogenic drug discovery and development.

  • anticancer therapies combining Antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem like cell fraction in glioma xenograft tumors
    Cancer Research, 2007
    Co-Authors: Chris Folkins, Daniel J Hicklin, Shan Man, Yuval Shaked, Robert S Kerbel
    Abstract:

    Vascular endothelial cells have been identified as a critical component of the neural stem cell niche, raising the possibility that brain tumor stem-like cells (TSLC) may also rely on signaling interactions with nearby tumor vasculature to maintain their stem-like state. The disruption of such a TSLC vascular niche by an Antiangiogenic therapy could result in loss of stemness characteristics associated with intrinsic drug resistance and, thus, preferentially sensitize TSLC to the effects of chemotherapy. Considering these possibilities, we investigated the impact of Antiangiogenic anticancer therapy on the TSLC fraction of glioma tumors. Athymic nude mice bearing s.c. tumor xenografts of the C6 rat glioma cell line were treated with either a targeted Antiangiogenic agent, Antiangiogenic schedules of low-dose metronomic chemotherapy, combination therapies of Antiangiogenic agents and chemotherapy, or, for the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose chemotherapy using cyclophosphamide. Targeted Antiangiogenic therapy or cytotoxic chemotherapy did not reduce the fraction of tumor sphere-forming units (SFU) in the tumor, whereas all treatment groups that combined both Antiangiogenic and cytotoxic drug effects caused a significant reduction in SFU. This work highlights the possibility that selective eradication of TSLC may be achieved by targeting the tumor microenvironment (and potentially a supportive TSLC niche) rather than the TSLC directly. Furthermore, this work suggests a possible novel effect of Antiangiogenic therapy, namely, as a chemosensitizer of TSLC, and thus represents a possible new mechanism to explain the ability of Antiangiogenic therapy to enhance the efficacy of chemotherapy.

  • therapeutic implications of intrinsic or induced angiogenic growth factor redundancy in tumors revealed
    Cancer Cell, 2005
    Co-Authors: Robert S Kerbel
    Abstract:

    Summary There is a large family of known proangiogenic growth factors, many of which can be expressed by a single tumor, especially in advanced stages of disease. Such redundancy, which can be amplified by hypoxia, has long been suspected as a potential cause of acquired resistance when tumors are treated with highly specific targeted Antiangiogenic drugs. Definitive preclinical evidence for Antiangiogenic drug evasion by alternate pathways of angiogenesis in tumor cells, likely induced by Antiangiogenic drug-mediated increases in tumor hypoxia, is reported in this issue of Cancer Cell (Casanovas et al., 2005); it has major implications for the development of strategies to prolong the effectiveness of Antiangiogenic drugs as monotherapies, and for their use as chemosensitizing agents in combination treatment strategies.

Mark Battle - One of the best experts on this subject based on the ideXlab platform.

  • monitoring tumor response to Antiangiogenic sunitinib therapy with 18f fluciclatide an 18f labeled αvβ3 integrin and αvβ5 integrin imaging agent
    The Journal of Nuclear Medicine, 2011
    Co-Authors: Mark Battle, Lucy Allen, Jon Barnett, Julian Goggi, Matthew Morrison
    Abstract:

    Arginine-glycine-aspartate (RGD)-binding aVb3-integrin and aVb5-integrin play key roles in tumor angiogenesis. We examined an 18 F-labeled small peptide (fluciclatide [United States Adopted Name (ASAN)–approved, International Nonproprietary Name (INN)–proposed name], previously referred to as AH111585) containing an RGD sequence. Fluciclatide binds with a high (nM) affinity to aVb3-integrin and aVb5-integrin, which are highly expressed on tumors and the tumor neovasculature. In this study, 18 F-fluciclatide was used to examine the response of human glioblastoma xenografts to treatment with the Antiangiogenic agent sunitinib. Methods: U87-MG tumor uptake of 18 F-fluciclatide was determined by small-animal PET after longitudinal administration of the Antiangiogenic agent sunitinib (a 2-wk dosing regimen). Tumor sizes were measured throughout the study, and tumor volumes were calculated. Tumor microvessel density (MVD) after therapy was also analyzed. Results: Dynamic small-animal PET of 18F-fluciclatide uptake after administration of the clinically relevant Antiangiogenic agent sunitinib revealed a reduction in the tumor uptake of 18F-fluciclatide compared with that in vehicle-treated controls over the 2-wk dosing regimen. Skeletal muscle, used as a reference tissue, showed equivalent 18 F-fluciclatide uptake in both therapy and control groups. A reduction in tumor MVD was also observed after treatment with the Antiangiogenic agent. No significant changes in tumor volume were observed in the 2 groups. Conclusion: The data demonstrated that 18 F-fluciclatide detected changes in tumor uptake after acute Antiangiogenic therapy markedly earlier than any significant volumetric changes were observable. These results suggest that this imaging agent may provide clinically important information for guiding patient care and monitoring the response to Antiangiogenic therapy.

  • monitoring tumor response to Antiangiogenic sunitinib therapy with 18f fluciclatide an 18f labeled αvβ3 integrin and αvβ5 integrin imaging agent
    The Journal of Nuclear Medicine, 2011
    Co-Authors: Mark Battle, Lucy Allen, Jon Barnett, Julian Goggi, Matthew Morrison
    Abstract:

    Arginine-glycine-aspartate (RGD)-binding aVb3-integrin and aVb5-integrin play key roles in tumor angiogenesis. We examined an 18 F-labeled small peptide (fluciclatide [United States Adopted Name (ASAN)–approved, International Nonproprietary Name (INN)–proposed name], previously referred to as AH111585) containing an RGD sequence. Fluciclatide binds with a high (nM) affinity to aVb3-integrin and aVb5-integrin, which are highly expressed on tumors and the tumor neovasculature. In this study, 18 F-fluciclatide was used to examine the response of human glioblastoma xenografts to treatment with the Antiangiogenic agent sunitinib. Methods: U87-MG tumor uptake of 18 F-fluciclatide was determined by small-animal PET after longitudinal administration of the Antiangiogenic agent sunitinib (a 2-wk dosing regimen). Tumor sizes were measured throughout the study, and tumor volumes were calculated. Tumor microvessel density (MVD) after therapy was also analyzed. Results: Dynamic small-animal PET of 18F-fluciclatide uptake after administration of the clinically relevant Antiangiogenic agent sunitinib revealed a reduction in the tumor uptake of 18F-fluciclatide compared with that in vehicle-treated controls over the 2-wk dosing regimen. Skeletal muscle, used as a reference tissue, showed equivalent 18 F-fluciclatide uptake in both therapy and control groups. A reduction in tumor MVD was also observed after treatment with the Antiangiogenic agent. No significant changes in tumor volume were observed in the 2 groups. Conclusion: The data demonstrated that 18 F-fluciclatide detected changes in tumor uptake after acute Antiangiogenic therapy markedly earlier than any significant volumetric changes were observable. These results suggest that this imaging agent may provide clinically important information for guiding patient care and monitoring the response to Antiangiogenic therapy.

Patrick Y Wen - One of the best experts on this subject based on the ideXlab platform.

  • angiogenesis inhibitors in tackling recurrent glioblastoma
    Expert Review of Anticancer Therapy, 2017
    Co-Authors: Thomas Hundsberger, David A Reardon, Patrick Y Wen
    Abstract:

    ABSTRACTIntroduction: Despite aggressive multimodality treatment of glioblastoma, outcome remains poor and patients mostly die of local recurrences. Besides reoperation and occasionally reirradiation, systemic treatment of recurrent glioblastoma consists of alkylating chemotherapy (lomustine, temozolomide), bevacizumab and combinations thereof. Unfortunately, Antiangiogenic agents failed to improve survival either as a monotherapy or in combination treatments. This review provides current insights into tumor-derived escape mechanisms and other areas of treatment failure of Antiangiogenic agents in glioblastoma.Areas covered: We summarize the current literature on Antiangiogenic agents in the treatment of glioblastoma, with a focus on recurrent disease. A literature search was performed using the terms ‘glioblastoma’, ‘bevacizumab’, ‘Antiangiogenic’, ‘angiogenesis’, ‘resistance’, ‘radiotherapy’, ‘chemotherapy’ and derivations thereof.Expert commentary: New insights in glioma neoangiogenesis, increasing und...

  • Antiangiogenic therapies for high grade glioma
    Nature Reviews Neurology, 2009
    Co-Authors: Andrew D Norden, Jan Drappatz, Patrick Y Wen
    Abstract:

    High-grade gliomas (HGGs) are vascular tumors that represent attractive targets for Antiangiogenic therapies. In this Review, we present the rationale and clinical trial evidence for targeting angiogenesis in HGGs, focusing predominantly on agents that target vascular endothelial growth factor (VEGF) and its receptors. Bevacizumab, a humanized monoclonal antibody against VEGF, was recently approved by the FDA for treatment of recurrent glioblastoma. Bevacizumab prolongs progression-free survival and controls peritumoral edema, but its effects on overall survival remain to be determined. Other inhibitors of VEGF, VEGF receptors and other proangiogenic signaling pathways are being evaluated. Antiangiogenic therapies are well tolerated, although potentially serious adverse events can occasionally occur, and resistance to Antiangiogenic therapy inevitably develops. Mechanisms of resistance include upregulation of alternative proangiogenic pathways, and increased perivascular tumor growth. Tumor progression on Antiangiogenic agents is a challenging problem for which no effective salvage therapy has been identified. Combining these agents with radiation therapy, cytotoxic chemotherapy, other targeted molecular agents, or anti-invasion therapies could be helpful. The international Response Assessment in Neuro-Oncology Working Group has developed consensus treatment response criteria for HGG that account for the complex effects of Antiangiogenic drugs.

  • colon perforation during Antiangiogenic therapy for malignant glioma
    Neuro-oncology, 2009
    Co-Authors: Andrew D Norden, Jan Drappatz, A S Ciampa, Lisa Doherty, Debra Lafrankie, Santosh Kesari, Patrick Y Wen
    Abstract:

    Antiangiogenic drugs have emerged as effective treatment options for patients with recurrent malignant gliomas (MGs). Though this class of drugs is generally well tolerated, rare life-threatening complications, including thromboembolism, hemorrhage, and gastrointestinal (GI) perforation, are reported. We describe six cases of GI perforation among 244 glioma patients (2.5%) during treatment with Antiangiogenic agents in combination with chemotherapy and corticosteroids. Two patients succumbed to this complication, and the others recovered. Because GI perforation is a life-threatening yet treatable complication, neurooncologists must have a low threshold to consider it in patients on Antiangiogenic drug therapy who present with abdominal pain and other GI complaints.