Evading anti-angiogenic therapy: resistance to anti-angiogenic therapy in solid tumours

2014 ◽  
Author(s):  
N Dey ◽  
P De ◽  
B Leyland-Jones
Keyword(s):  
Therapy Resistance ◽  
Solid Tumours ◽  
Angiogenic Therapy

scholarly journals Autophagy as a mechanism for anti-angiogenic therapy resistance

2020 ◽  
Vol 66 ◽  
pp. 75-88 ◽  
Author(s):  
Ankush Chandra ◽  
Jonathan Rick ◽  
Garima Yagnik ◽  
Manish K. Aghi
Keyword(s):  
Therapy Resistance ◽  
Angiogenic Therapy

scholarly journals ANGI-03. PHARMACOLOGICAL TARGETING OF APELIN/APLNR SIGNALING BLUNTS THERAPY RESISTANCE TO VEGFA/VEGFR2 ANTI-ANGIOGENIC TREATMENT IN GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi30-vi30
Author(s):  
Roland Kälin ◽  
Giorgia Mastrella ◽  
Mengzhuo Hou ◽  
Min Li ◽  
Veit Stoecklein ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Invasion ◽  
Therapy Resistance ◽  
Glioblastoma Cell ◽  
Loss Of Function ◽  
Human Glioblastoma ◽  
Angiogenic Switch ◽  
Angiogenic Therapy

Abstract Anti-angiogenic therapy of glioblastoma with bevacizumab, a vascular endothelial growth factor-A (VEGFA) blocking antibody, may accelerate tumor cell invasion and induce alternative angiogenic pathways. We investigated the roles of the pro-angiogenic receptor APLNR and its cognate ligand apelin in VEGFA/VEGFR2 anti-angiogenic therapy against distinct subtypes of glioblastoma. In proneural glioblastoma, apelin levels were downregulated by VEGFA or VEGFR2 blockade by use of bevacizumab or ramucirumab, respectively. A central role for apelin/APLNR in controlling glioblastoma vascularization was corroborated in a serial implantation model of the angiogenic switch that occurs in human glioblastoma. Apelin and APLNR are broadly expressed in human glioblastoma, and knockdown or knockout of APLN in orthotopic models of proneural or classical glioblastoma subtypes massively reduced glioblastoma vascularization as compared with controls. What is more, direct infusion of the bioactive peptide apelin-13 was able to rescue this vascular loss-of-function phenotype, demonstrating the specific control of tumor vascularization by apelin/APLNR signaling. While high levels of apelin correlated with reduced tumor cell invasiveness, the reduction in apelin expression led to accelerated glioblastoma cell invasion. Analysis of stereotactic glioblastoma biopsies from patients as well as from in vitro and in vivo experiments revealed increased dissemination of APLNR-positive tumor cells when apelin levels were reduced. Most interestingly, application of apelin-F13A, a mutant APLNR ligand, blocked both tumor angiogenesis and glioblastoma cell invasion. Furthermore, co-targeting VEGFR2 and APLNR synergistically improved survival of mice bearing proneural glioblastoma. In summary, we show that apelin/APLNR signaling controls glioblastoma angiogenesis and invasion directly, and that both pathological features are blunted by apelin-F13A. We suggest that apelin-F13A can improve the efficiency and reduce the side effects of established anti-angiogenic treatments for distinct glioblastoma subtypes.

scholarly journals DRES-01. ZEB1-MEDIATED INVASIVE MESENCHYMAL TRANSITION AT THE SINGLE CELL LEVEL PROMOTES ANTI-ANGIOGENIC THERAPY RESISTANCE IN GLIOBLASTOMA

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi75-vi75
Author(s):  
Ankush Chandra ◽  
Arman Jahangiri ◽  
William Chen ◽  
Garima Yagnik ◽  
Joseph Garcia ◽  
...  
Keyword(s):  
Single Cell ◽  
Therapy Resistance ◽  
Single Cell Level ◽  
Cell Level ◽  
Mesenchymal Transition ◽  
Angiogenic Therapy

scholarly journals A novel xenograft model reveals invasive mesenchymal transition and ineffective angiogenic response during anti-angiogenic therapy resistance

2018 ◽  
Author(s):  
Arman Jahangiri ◽  
William Chen ◽  
Ankush Chandra ◽  
Alan Nguyen ◽  
Garima Yagnik ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Xenograft Model ◽  
Therapy Resistance ◽  
Gene Signature ◽  
Duration Of Treatment ◽  
Mesenchymal Transition ◽  
Angiogenic Therapy ◽  
Bevacizumab Treatment ◽  
Evolution Of Resistance ◽  
Angiogenic Genes

ABSTRACTBevacizumab treatment of glioblastoma is limited by transient responses and acquired resistance. Because of the lengthy duration of treatment that can precede resistance in patients, in order to study changes underlying the evolution of bevacizumab resistance, we created a novel multigenerational xenograft model of acquired bevacizumab resistance. Glioblastoma xenografts were treated with bevacizumab or IgG, and the fastest growing tumor re-implanted into new mice, generating paired isogeneic responsive or resistant multigenerational xenografts. Microarray analysis revealed significant overexpression across generations of the mesenchymal subtype gene signature, paralleling results from patient bevacizumab-resistant glioblastomas (BRGs) that exhibited increasing mesenchymal gene expression correlating with increased bevacizumab treatment duration. Key mesenchymal markers, including YKL-40, CD44, SERPINE1, and TIMP1 were upregulated across generations, with altered morphology, increased invasiveness, and increased neurosphere formation confirmed in later xenograft generations. Interestingly, YKL-40 levels were elevated in serum of patients with bevacizumab-resistant vs. bevacizumab-naïve glioblastomas. Finally, despite upregulation of VEGF-independent pro-angiogenic genes across xenograft generations, immunostaining revealed increased hypoxia and decreased vessel density with increasing generation of treatment, mirroring our findings in patient BRGs and suggesting tumor growth despite effective devascularization caused by VEGF blockade. Besides identifying novel targets for preventing the evolution of resistance and offering a xenograft model for testing resistance inhibitors, our work suggests YKL-40 as a blood biomarker of bevacizumab resistance worthy of further evaluation.

scholarly journals Extracellular Vesicle Membrane-Associated Proteins: Emerging Roles in Tumor Angiogenesis and Anti-Angiogenesis Therapy Resistance

2020 ◽  
Vol 21 (15) ◽  
pp. 5418 ◽  
Author(s):  
Song Yi Ko ◽  
Honami Naora
Keyword(s):  
Tumor Angiogenesis ◽  
Therapy Resistance ◽  
Extracellular Vesicle ◽  
Biological Functions ◽  
Vesicle Membrane ◽  
Angiogenic Therapy ◽  
Anti Cancer ◽  
Associated Proteins ◽  
Tumor Growth And Metastasis ◽  
Prime Target

The tumor vasculature is essential for tumor growth and metastasis, and is a prime target of several anti-cancer agents. Increasing evidence indicates that tumor angiogenesis is stimulated by extracellular vesicles (EVs) that are secreted or shed by cancer cells. These EVs encapsulate a variety of biomolecules with angiogenic properties, and have been largely thought to stimulate vessel formation by transferring this luminal cargo into endothelial cells. However, recent studies have revealed that EVs can also signal to recipient cells via proteins on the vesicular surface. This review discusses and integrates emerging insights into the diverse mechanisms by which proteins associate with the EV membrane, the biological functions of EV membrane-associated proteins in tumor angiogenesis, and the clinical significance of these proteins in anti-angiogenic therapy.

scholarly journals Phase II trial of levocetirizine with capecitabine and bevacizumab to overcome the resistance of antiangiogenic therapies in refractory metastatic colorectal cancer.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 763-763
Author(s):  
Manik Amin ◽  
Monica Dandona Desai ◽  
Steven Sorscher ◽  
Kian-Huat Lim ◽  
Andrea Wang-Gillam ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Clinical Success ◽  
Prospective Trial ◽  
Therapy Resistance ◽  
Open Label ◽  
Significance Level ◽  
Angiogenic Therapy ◽  
Cytokine Analysis ◽  
The Impact

763 Background: Despite clinical success of VEGF blockade in mCRC, resistance to anti-angiogenic drugs invariably develops. IL-8 and other cytokines have been implicated in resistance development to anti-angiogenic therapy. Levocetirizine is a third generation antihistamine with anti-inflammatory and IL-8 suppression properties. We conducted a phase II trial combining levocetirizine with capecitabine and bevacizumab to potentially overcome anti-angiogenic therapy resistance in patients with refractory mCRC. Methods: This was a single-center open-label prospective trial in refractory mCRC patients. Treatment consisted of oral capecitabine 850mg/m2 – 7 days on and 7 days off, IV bevacizumab 5 mg/kg every 14 days and oral levocetirizine 5 mg daily in 14 day cycles. The primary end point was PFS and secondary endpoints included ORR and tolerability. An exploratory endpoint included correlation of PFS with cytokine (IL-8 & IL-6) levels. A sample size of 36 evaluable patients could identify a median PFS of 3.4 months at a 0.05 significance level. To document cytokine changes related to levocetirizine treatment, patients were randomized to Arm A where levocetirizine was started 7 days after starting chemotherapy or to Arm B where levocetirizine was started 7 days prior to chemotherapy. For PFS determination both arms were combined for analysis. Cytokine levels were measured at baseline and with each cycle of chemotherapy (up to three cycles). Results: 43 patients were enrolled in the trial to have 36 evaluable patients. Arm A enrolled 20 patients and Arm B enrolled 23 patients. Of the patients evaluable for best response, 19 had SD and 12 had PD. Median PFS of all patients on the study was 3.4 months (ranging 0.9 to 10.6 months). Conclusions: Median PFS in the trial was comparable to and possibly better than other regimens used in the refractory setting (e.g., median PFS of 1.9 months for regorafenib). Cytokine analysis is in progress and these results and correlations with patient outcomes will be presented to assess the impact of cytokine blockade on mCRC treatment. Clinical trial information: NCT01722162.

scholarly journals Normalizing Tumor Vasculature to Reduce Hypoxia, Enhance Perfusion, and Optimize Therapy Uptake

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4444
Author(s):  
Kathy Matuszewska ◽  
Madison Pereira ◽  
Duncan Petrik ◽  
Jack Lawler ◽  
Jim Petrik
Keyword(s):  
Tumor Angiogenesis ◽  
Clinical Success ◽  
Tumor Hypoxia ◽  
Lymphatic Vessels ◽  
Therapy Resistance ◽  
Therapeutic Area ◽  
Comprehensive Understanding ◽  
Angiogenic Therapy ◽  
Tumor Growth And Metastasis ◽  
And Function

A basic requirement of tumorigenesis is the development of a vascular network to support the metabolic requirements of tumor growth and metastasis. Tumor vascular formation is regulated by a balance between promoters and inhibitors of angiogenesis. Typically, the pro-angiogenic environment created by the tumor is extremely aggressive, resulting in the rapid vessel formation with abnormal, dysfunctional morphology. The altered morphology and function of tumor blood and lymphatic vessels has numerous implications including poor perfusion, tissue hypoxia, and reduced therapy uptake. Targeting tumor angiogenesis as a therapeutic approach has been pursued in a host of different cancers. Although some preclinical success was seen, there has been a general lack of clinical success with traditional anti-angiogenic therapeutics as single agents. Typically, following anti-angiogenic therapy, there is remodeling of the tumor microenvironment and widespread tumor hypoxia, which is associated with development of therapy resistance. A more comprehensive understanding of the biology of tumor angiogenesis and insights into new clinical approaches, including combinations with immunotherapy, are needed to advance vascular targeting as a therapeutic area.

scholarly journals Role of Endoglin (CD105) in the Progression of Hepatocellular Carcinoma and Anti-Angiogenic Therapy

2018 ◽  
Vol 19 (12) ◽  
pp. 3887 ◽  
Author(s):  
Aldona Kasprzak ◽  
Agnieszka Adamek
Keyword(s):  
Hepatocellular Carcinoma ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Primary Liver Cancer ◽  
Venous Blood ◽  
Transforming Growth Factor Β ◽  
Current Data ◽  
Solid Tumours ◽  
Angiogenic Therapy

The liver is perfused by both arterial and venous blood, with a resulting abnormal microenvironment selecting for more-aggressive malignancies. Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, the sixth most common cancer globally, and the third leading cause of cancer-related mortality worldwide. HCC is characterized by its hypervascularization. Improving the efficiency of anti-angiogenic treatment and mitigation of anti-angiogenic drug resistance are the top priorities in the development of non-surgical HCC therapies. Endoglin (CD105), a transmembrane glycoprotein, is one of the transforming growth factor β (TGF-β) co-receptors. Involvement of that protein in angiogenesis of solid tumours is well documented. Endoglin is a marker of activated endothelial cells (ECs), and is preferentially expressed in the angiogenic endothelium of solid tumours, including HCC. HCC is associated with changes in CD105-positive ECs within and around the tumour. The large spectrum of endoglin effects in the liver is cell-type- and HCC- stage-specific. High expression of endoglin in non-tumour tissue suggests that this microenvironment might play an especially important role in the progression of HCC. Evaluation of tissue expression, as well as serum concentrations of this glycoprotein in HCC, tends to confirm its role as an important biomarker in HCC diagnosis and prognosis. The role of endoglin in liver fibrosis and HCC progression also makes it an attractive therapeutic target. Despite these facts, the exact molecular mechanisms of endoglin functioning in hepatocarcinogenesis are still poorly understood. This review summarizes the current data concerning the role and signalling pathways of endoglin in hepatocellular carcinoma development and progression, and provides an overview of the strategies available for a specific targeting of CD105 in anti-angiogenic therapy in HCC.

ELECTRON MICROSCOPIC ASSESSMENT OF SMEARED OR IMPRINTED SPECIMENS OF SOLID TUMOURS

Pathology ◽  
2001 ◽  
Vol 33 (2) ◽  
pp. 226-229 ◽  
Author(s):  
Jane E. Dahlstrom ◽  
Lesley E. Maxwell
Keyword(s):  
Solid Tumours ◽  
Electron Microscopic
Sign in / Sign up

Export Citation Format

Share Document