The impact of tumor receptor heterogeneity on the response to anti-angiogenic cancer treatment

Ding, Li; Finley, Stacey D.

doi:10.1039/c8ib00019k

Cited by 16 publications

(17 citation statements)

References 76 publications

(109 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The effective inhibition of tumor angiogenesis may arrest tumor progression and has shown synergistic effect in other cancer treatments 19 , 20 . As one targeted tumor therapy, anti-angiogenic regimen can actually benefit only a few patients due to the biological heterogeneity of tumors 21 , 22 . Molecular imaging using radio-labeled tumor-targeting probes can be used to select patients, dynamically assess response to therapy, and therefore predict efficacy of treatment 23 .…”

Section: Discussionmentioning

confidence: 99%

Synthesis and evaluation of ⁶⁸Ga-labeled dimeric cNGR peptide for PET imaging of CD13 expression with ovarian cancer xenograft

Yang¹,

Zhang²,

Zou³

et al. 2021

J. Cancer

View full text Add to dashboard Cite

Introduction: Previous studies have shown that peptides containing the asparagine-glycine-arginine (NGR) sequence can specifically bind to CD13 (aminopeptidase N) receptor, a tumor neovascular biomarker that is over-expressed on the surface of angiogenic blood vessels and various tumor cells, and it plays an important role in angiogenesis and tumor progression. In the present study, we aimed to evaluate the efficacy of a gallium-68 ( 68 Ga)-labeled dimeric cyclic NGR (cNGR) peptide as a new molecular probe that binds to CD13 in vitro and in vivo . Materials and Methods: A dimeric cNGR peptide conjugated with 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) was synthesized and labeled with 68 Ga. In vitro uptake and binding analyses of the 68 Ga- DOTA-c(NGR) 2 were performed in two ovarian tumor cell lines, ES2 and SKOV3, which had different CD13 expression patterns. An in vivo biodistribution study was performed in normal mice, and micro positron emission tomography (PET) imaging was conducted in nude mice bearing ES2 and SKOV3 tumors. Results: 68 Ga-DOTA-c(NGR) 2 was prepared with high radiochemical purity (>95%), and it was stable both in saline at room temperature and in bovine serum at 37°C for 3 h. In vitro studies showed that the uptake of 68 Ga-DOTA-c(NGR) 2 in ES2 cells was higher compared with SKOV3 cells, and such uptake could be blocked by the cold DOTA-c(NGR) 2 . Biodistribution studies demonstrated that 68 Ga-DOTA-c(NGR) 2 was rapidly cleared from blood and mainly excreted from the kidney. MicroPET imaging of ES2 tumor xenografts showed the focal uptake of 68 Ga-DOTA-c(NGR) 2 in tumors from 1 to 1.5 h post-injection. The high-contrast tumor visualization occurred at 1 h, corresponding to the highest tumor/background ratio of 10.30±0.26. The CD13-specific tumor targeting of the 68 Ga-DOTA-c(NGR) 2 was further supported by the reduced uptake of the probe in ES2 tumors by co-injection of the unlabeled cold peptide. In SKOV3 tumor models, the tumor was not obviously visible under the same imaging conditions. Conclusions: 68 Ga-DOTA-c(NGR) 2 was easily synthesized, and it showed favorable CD13-specific targeting ability by in vitro data and microPET imaging with ovarian cancer xenografts. Collectively, 68 Ga-DOTA-c(NGR) 2 might be a potential PET imaging probe for non-invasive evaluation of the CD13 receptor expression in tumors.

show abstract

Section: Discussionmentioning

confidence: 99%

Synthesis and evaluation of ⁶⁸Ga-labeled dimeric cNGR peptide for PET imaging of CD13 expression with ovarian cancer xenograft

Yang¹,

Zhang²,

Zou³

et al. 2021

J. Cancer

View full text Add to dashboard Cite

show abstract

“…These models were mainly used to illustrate the distribution of angiogenic factors and therapeutic agents in tumor tissue and in the whole body. 24,25 In addition, the ligand-receptor details are further linked to higher-level processes to study tumor angiogenesis and response to anti-VEGF treatment. For example, the VEGF ligand-receptor dynamics are linked with different cellular processes, including proliferation, apoptosis, and maturation, and influence cellular crosstalk and the development of vascular phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Mechanistic insights into the heterogeneous response to anti‐VEGF treatment in tumors

Ding

Finley

2021

Comp Sys Onco

Self Cite

View full text Add to dashboard Cite

Vascular endothelial growth factor (VEGF) is a strong promoter of angiogenesis in tumors, and anti‐VEGF treatment, such as a humanized antibody to VEGF, is clinically used as a monotherapy or in combination with chemotherapy to treat cancer patients. However, this approach is not effective in all patients or cancer types. To better understand the heterogeneous responses to anti‐VEGF and the synergy between anti‐VEGF and other anticancer therapies, we constructed a computational model characterizing angiogenesis‐mediated growth of in vivo mouse tumor xenografts. The model captures VEGF‐mediated cross‐talk between tumor cells and endothelial cells and is able to predict the details of molecular‐ and cellular‐level dynamics. The model predictions of tumor growth in response to anti‐VEGF closely match the quantitative measurements from multiple preclinical mouse studies. We applied the model to investigate the effects of VEGF‐targeted treatment on tumor cells and endothelial cells. We identified that tumors with lower tumor cell growth rate and higher carrying capacity have a stronger response to anti‐VEGF treatment. The predictions indicate that the variation of tumor cell growth rate can be a main reason for the experimentally observed heterogeneous response to anti‐VEGF. In addition, our simulation results suggest a new synergy mechanism where anticancer therapy can enhance anti‐VEGF simply through reducing the tumor cell growth rate. Overall, this work generates novel insights into the heterogeneous response to anti‐VEGF treatment and the synergy of anti‐VEGF with other therapies, providing a tool that be further used to test and optimize anticancer therapy.

show abstract

“…These models can be used to study strategies that regulate the distribution of angiogenic factors in tumor tissue. For example, Li and Finley constructed a compartmental whole-body model to study the effect of anti-angiogenic therapies targeting VEGF and TSP1 signaling in a simulated cancer patient cohort [ 18 ]. Also, models that study intracellular signaling [ 20 , 21 ] can help identify potential targets and explore their efficacy for pro- or anti-angiogenic therapies.…”

Section: Introductionmentioning

confidence: 99%

ERK and Akt exhibit distinct signaling responses following stimulation by pro-angiogenic factors

Song

Finley

2020

Cell Commun Signal

Self Cite

View full text Add to dashboard Cite

Background Angiogenesis plays an important role in the survival of tissues, as blood vessels provide oxygen and nutrients required by the resident cells. Thus, targeting angiogenesis is a prominent strategy in many different settings, including both tissue engineering and cancer treatment. However, not all of the approaches that modulate angiogenesis lead to successful outcomes. Angiogenesis-based therapies primarily target pro-angiogenic factors such as vascular endothelial growth factor-A (VEGF) or fibroblast growth factor (FGF) in isolation, and there is a limited understanding of how these promoters combine together to stimulate angiogenesis. Targeting one pathway could be insufficient, as alternative pathways may compensate, diminishing the overall effect of the treatment strategy. Methods To gain mechanistic insight and identify novel therapeutic strategies, we have developed a detailed mathematical model to quantitatively characterize the crosstalk of FGF and VEGF intracellular signaling. The model focuses on FGF- and VEGF-induced mitogen-activated protein kinase (MAPK) signaling to promote cell proliferation and the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway, which promotes cell survival and migration. We fit the model to published experimental datasets that measure phosphorylated extracellular regulated kinase (pERK) and Akt (pAkt) upon FGF or VEGF stimulation. We validate the model with separate sets of data. Results We apply the trained and validated mathematical model to characterize the dynamics of pERK and pAkt in response to the mono- and co-stimulation by FGF and VEGF. The model predicts that for certain ranges of ligand concentrations, the maximum pERK level is more responsive to changes in ligand concentration compared to the maximum pAkt level. Also, the combination of FGF and VEGF indicates a greater effect in increasing the maximum pERK compared to the summation of individual effects, which is not seen for maximum pAkt levels. In addition, our model identifies the influential species and kinetic parameters that specifically modulate the pERK and pAkt responses, which represent potential targets for angiogenesis-based therapies. Conclusions Overall, the model predicts the combination effects of FGF and VEGF stimulation on ERK and Akt quantitatively and provides a framework to mechanistically explain experimental results and guide experimental design. Thus, this model can be utilized to study the effects of pro- and anti-angiogenic therapies that particularly target ERK and/or Akt activation upon stimulation with FGF and VEGF.

show abstract

The impact of tumor receptor heterogeneity on the response to anti-angiogenic cancer treatment

Cited by 16 publications

References 76 publications

Synthesis and evaluation of ⁶⁸Ga-labeled dimeric cNGR peptide for PET imaging of CD13 expression with ovarian cancer xenograft

Synthesis and evaluation of ⁶⁸Ga-labeled dimeric cNGR peptide for PET imaging of CD13 expression with ovarian cancer xenograft

Mechanistic insights into the heterogeneous response to anti‐VEGF treatment in tumors

ERK and Akt exhibit distinct signaling responses following stimulation by pro-angiogenic factors

Contact Info

Product

Resources

About

The impact of tumor receptor heterogeneity on the response to anti-angiogenic cancer treatment

Cited by 16 publications

References 76 publications

Synthesis and evaluation of 68Ga-labeled dimeric cNGR peptide for PET imaging of CD13 expression with ovarian cancer xenograft

Synthesis and evaluation of 68Ga-labeled dimeric cNGR peptide for PET imaging of CD13 expression with ovarian cancer xenograft

Mechanistic insights into the heterogeneous response to anti‐VEGF treatment in tumors

ERK and Akt exhibit distinct signaling responses following stimulation by pro-angiogenic factors

Contact Info

Product

Resources

About

Synthesis and evaluation of ⁶⁸Ga-labeled dimeric cNGR peptide for PET imaging of CD13 expression with ovarian cancer xenograft

Synthesis and evaluation of ⁶⁸Ga-labeled dimeric cNGR peptide for PET imaging of CD13 expression with ovarian cancer xenograft