Methods and compositions for improving antiangiogenic therapy with Anti-integrins

a technology of anti-integrins and compositions, applied in the field of therapeutic compositions and cancer treatment, can solve the problems of inability to fully inhibit tumors and/or metastases, and the prediction of anti-angiogenesis hypothesis has not yet been realized in the clinic, so as to enhance the delivery of therapeutics and increase vascular permeability

Inactive Publication Date: 2014-03-20
RGT UNIV OF CALIFORNIA
View PDF6 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a method of treating cancer by giving a combination of two antibodies: one that targets beta-1 integrin and another that targets VEGF receptor. This treatment can be delivered through injection or directly to the tumor bed after surgery. Other substances can also be used to increase the delivery of the antibodies to certain organs like the brain. The treatment can be repeated to achieve the desired effect.

Problems solved by technology

The technical problem addressed in this patent is the resistance to anti-angiogenesis therapy in the clinic, which is likely due to tumor cells using an alternative method for obtaining a vasculature. Existing therapeutic strategies have either heavily relied on the angiogenesis hypothesis or proposed combination therapeutic strategies that target only the angiogenic aspect of tumor vascularization. The patent proposes a new approach that targets both angiogenic and adhesion-based signaling of co-option to inhibit tumor and metastasis vascularization.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Methods and compositions for improving antiangiogenic therapy with Anti-integrins
  • Methods and compositions for improving antiangiogenic therapy with Anti-integrins
  • Methods and compositions for improving antiangiogenic therapy with Anti-integrins

Examples

Experimental program
Comparison scheme
Effect test

example 1

Hypoxia Associated with High Beta-1 Integrin Expression

[0092]Here it is shown that hypoxia, another common cellular stress in the setting of fast-growing cancers and after antiangiogenic therapy, is correlated with high beta1 expression in patient glioblastomamultiforme (GBM) specimens. To directly confirm this mechanism we subjected glioma cells to 6 to 48 h of 1% oxygen to simulate microenvironmental hypoxia. We observed a significant increase in beta1 integrin expression in glioma cells in vitro (FIG. 1). This is a rapid and reversible cellular response and was also demonstrated in breast and colorectal carcinoma cells. To verify that anti-angiogenic therapy can acutely increase beta1 expression in growing tumors in vivo we stained glioma tumors from mice taken within days of the last bevacizumab treatment. Marked increases in beta1 were observed in the treated tumors compared to controls, particularly in the hypoxic tumor core (FIG. 2).

example 2

Increased Beta 1 Integrin Expression Observed During Tumor Cell Proliferation

[0093]Further increases in beta1 expression in tumor cells in vitro were observed during tumor cell proliferation itself. There is an inverse correlation between cell confluence in vitro and level of beta1 in U87MG glioma cells (FIG. 3). In addition, expression of proliferation marker Ki-67 was positively correlated with beta1 expression in U87MG glioma cells as demonstrated by FACS. This is consistent with what others have observed in breast carcinoma cells. Finally, we visually observed significant increases in beta1 integrin expression in angiogenic vessels in human surgical specimens from primary GBM (FIG. 4). This increased beta 1 integrin expression is thought to be related to the association of beta1 to cellular proliferation observed in glioma cells, as discussed above. Thus, in addition to invasion and growth upon vessels, beta1 integrin appears to be intimately involved in tumor cell proliferation...

example 3

Beta 1 Integrin Involvement in Anti-VEGF Antibody Resistance in Tumor Cells

[0094]To test the hypothesis that beta1 integrin may be involved in bevacizumab resistance we used immunofluorescenthistochemistry for beta1 integrin in paired patient specimens of GBM taken before bevacizumab therapy and after development of acquired bevacizumab resistance. Clear increases in post-bevacizumab GBM tissues compared to untreated specimens was seen in 9 of 12 pairs (75%, FIG. 5).

[0095]To directly verify the increase in beta1 integrin expression in tumor cells after acquired bevacizumab resistance we analyzed cell lines derived from primary GBMs (first surgery) and from tissue isolated at least 30 d after development of resistance to antiangiogenic therapy. Indeed, beta1 integrin expression was an average of 13-fold higher in cells from the latter group compared to the former (FIG. 6).

[0096]To verify that the observed beta1 integrin upregulation was functional we stained adjacent patient tumor se...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

PropertyMeasurementUnit
Gene expression profileaaaaaaaaaa
Cell growthaaaaaaaaaa
Login to view more

Abstract

Described here are methods and compositions for treating tumors and metastases that improve anti-angiogenesis therapy. By inhibiting these mechanisms in a biological system with an anti-beta one integrin composition in combination with an anti-angiogenic composition, tumors and metastases may be deprived of an adequate blood supply, thereby resulting in tumor cell growth arrest and possibly regression, including tumor cell death. The present compositions comprise an anti-beta one integrin agent in combination with an anti-VEGF agent, in a pharmaceutical composition or compositions. Methods of treatment and of imaging are also described.

Description

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
Owner RGT UNIV OF CALIFORNIA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap