scholarly journals Monitoring vascular normalization: new opportunities for mitochondrial inhibitors in breast cancer

Oncoscience ◽  
2021 ◽  
pp. 1
Keyword(s):  
Breast Cancer ◽  
Vascular Normalization ◽  
Mitochondrial Inhibitors

scholarly journals Immuno-priming durvalumab with bevacizumab in HER2-negative advanced breast cancer: a pilot clinical trial

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Miguel Quintela-Fandino ◽  
Esther Holgado ◽  
Luis Manso ◽  
Serafin Morales ◽  
Begoña Bermejo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Clinical Benefit ◽  
Mononuclear Cells ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Vascular Normalization ◽  
Preclinical Research ◽  
Expression Studies ◽  
Gene Expression Studies

Abstract Background Preclinical research suggests that the efficacy of immune checkpoint inhibitors in breast cancer can be enhanced by combining them with antiangiogenics, particularly in a sequential fashion. We sought to explore the efficacy and biomarkers of combining the anti-PD-L1 durvalumab plus the antiangiogenic bevacizumab after bevacizumab monotherapy for advanced HER2-negative breast cancer. Methods Patients had advanced HER2-negative disease that progressed while receiving single-agent bevacizumab maintenance as a part of a previous chemotherapy plus bevacizumab regimen. Treatment consisted of bi-weekly durvalumab plus bevacizumab (10 mg/kg each i.v.). Peripheral-blood mononuclear cells (PBMCs) were obtained before the first durvalumab dose and every 4 weeks and immunophenotyped by flow-cytometry. A fresh pre-durvalumab tumor biopsy was obtained; gene-expression studies and immunohistochemical staining to assess vascular normalization and characterize the immune infiltrate were conducted. Patients were classified as “non-progressors” if they had clinical benefit (SD/PR/CR) at 4 months. The co-primary endpoints were the changes in the percentage T cell subpopulations in PBMCs in progressors versus non-progressors, and PFS/OS time. Results Twenty-six patients were accrued. Median PFS and OS were 3.5 and 11 months; a trend for a longer OS was detected for the hormone-positive subset (19.8 versus 7.4 months in triple-negatives; P = 0.11). Clinical benefit rate at 2 and 4 months was 60% and 44%, respectively, without significant differences between hormone-positive and triple-negative (P = 0.73). Non-progressors’ tumors displayed vascular normalization features as a result of previous bevacizumab, compared with generally abnormal patterns observed in progressors. Non-progressors also showed increased T-effector and T-memory signatures and decreased TREG signatures in gene expression studies in baseline—post-bevacizumab—tumors compared with progressors. Notably, analysis of PBMC populations before durvalumab treatment was concordant with the findings in tumor samples and showed a decreased percentage of circulating TREGs in non-progressors. Conclusions This study reporting on sequential bevacizumab+durvalumab in breast cancer showed encouraging activity in a heavily pre-treated cohort. The correlative studies agree with the preclinical rationale supporting an immunopriming effect exerted by antiangiogenic treatment, probably by reducing TREGs cells both systemically and in tumor tissue. The magnitude of this benefit should be addressed in a randomized setting. Trial registration (www.clinicaltrials.gov): NCT02802098. Registered on June 16, 2020.

scholarly journals Role of mitochondria in rescuing glycolytically inhibited subpopulation of triple negative but not hormone-responsive breast cancer cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Asmaa Reda ◽  
Alaa Refaat ◽  
Ahmed A. Abd-Rabou ◽  
Ali Mokhtar Mahmoud ◽  
Mohamed Adel ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Viability ◽  
Cell Survival ◽  
Triple Negative ◽  
Combined Treatment ◽  
Glucose Consumption ◽  
Mrna Levels ◽  
Mcf7 Cells ◽  
Mitochondrial Inhibitors ◽  
Er Positive

Abstract Triple-negative breast cancer (TNBC) subtype is among the most aggressive cancers with the worst prognosis and least therapeutic targetability while being more likely to spread and recur. Cancer transformations profoundly alter cellular metabolism by increasing glucose consumption via glycolysis to support tumorigenesis. Here we confirm that relative to ER-positive cells (MCF7), TNBC cells (MBA-MD-231) rely more on glycolysis thus providing a rationale to target these cells with glycolytic inhibitors. Indeed, iodoacetate (IA), an effective GAPDH inhibitor, caused about 70% drop in MDA-MB-231 cell viability at 20 μM while 40 μM IA was needed to decrease MCF7 cell viability only by 30% within 4 hours of treatment. However, the triple negative cells showed strong ability to recover after 24 h whereas MCF7 cells were completely eliminated at concentrations <10 μM. To understand the mechanism of MDA-MB-231 cell survival, we studied metabolic modulations associated with acute and extended treatment with IA. The resilient TNBC cell population showed a significantly greater count of cells with active mitochondria, lower apoptotic markers, normal cell cycle regulations, moderately lowered ROS, but increased mRNA levels of p27 and PARP1; all compatible with enhanced cell survival. Our results highlight an interplay between PARP and mitochondrial oxidative phosphorylation in TNBC that comes into play in response to glycolytic disruption. In the light of these findings, we suggest that combined treatment with PARP and mitochondrial inhibitors may provide novel therapeutic strategy against TNBC.

scholarly journals Immunohistochemistry study of tumor vascular normalization and anti-angiogenic effects of sunitinib versus bevacizumab prior to dose-dense doxorubicin/cyclophosphamide chemotherapy in HER2-negative breast cancer

2021 ◽  
Author(s):  
Kritika Yadav ◽  
Joline Lim ◽  
Joan Choo ◽  
Samuel Guan Wei Ow ◽  
Andrea Wong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Proliferation Index ◽  
Vascular Endothelial ◽  
Breast Cancer Patients ◽  
Tumor Vessel ◽  
Vascular Normalization ◽  
Pre Treatment ◽  
Dose Dense ◽  
Tumor Biopsies ◽  
Endothelial Growth Factor

Abstract Purpose Tumor angiogenesis controlled predominantly by vascular endothelial growth factor and its receptor (VEGF-VEGFR) interaction plays a key role in the growth and propagation of cancer cells. However, the newly formed network of blood vessels is disorganized and leaky. Pre-treatment with anti-angiogenic agents can “normalize” the tumor vasculature allowing effective intra-tumoral delivery of standard chemotherapy. Immunohistochemistry (IHC) analysis was applied to investigate and compare the vascular normalization and anti-angiogenic effects of two commonly used anti-angiogenic agents, Sunitinib and Bevacizumab, administered prior to chemotherapy in HER2-negative breast cancer patients. Methods This prospective clinical trial enrolled 38 patients into a sunitinib cohort and 24 into a bevacizumab cohort. All received 4 cycles of doxorubicin/cyclophosphamide chemotherapy and pre-treatment with either sunitinib or bevacizumab. Tumor biopsies were obtained at baseline, after cycle 1 (C1) and cycle 4 (C4) of chemotherapy. IHC was performed to assess the tumor vascular normalization index (VNI), lymphatic vessel density (LVD), Ki67 proliferation index and expression of tumor VEGFR2. Results In comparison to Bevacizumab, Sunitinib led to a significant increase in VNI post-C1 and C4 (p < 0.001 and 0.001) along with decrease in LVD post-C1 (p = 0.017). Both drugs when combined with chemotherapy resulted in significant decline in tumor proliferation after C1 and C4 (baseline vs post-C4 Ki67 index p = 0.006 for Sunitinib vs p = 0.021 for Bevacizumab). Bevacizumab resulted in a significant decrease in VEGFR2 expression post-C1 (p = 0.004). Conclusion Sunitinib, in comparison to Bevacizumab showed a greater effect on tumor vessel modulation and lymphangiogenesis suggesting that its administration prior to chemotherapy might result in improved drug delivery. Trial registry ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).

scholarly journals Immunohistochemistry Study of Tumor Vascular Normalization and Anti-angiogenic Effects of Sunitinib Versus Bevacizumab Prior to Dose Dense Doxorubicin/cyclophosphamide Chemotherapy in HER2 Negative Breast Cancer

2021 ◽  
Author(s):  
Kritika Yadav ◽  
Joline Lim ◽  
Joan Choo ◽  
Samuel Guan Wei Ow ◽  
Andrea Wong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Vasculature ◽  
Proliferation Index ◽  
Vascular Endothelial ◽  
Tumor Vessel ◽  
Vascular Normalization ◽  
Pre Treatment ◽  
Dose Dense ◽  
Tumor Biopsies ◽  
Endothelial Growth Factor

Abstract PurposeTumor angiogenesis controlled predominantly by vascular endothelial growth factor and its receptor (VEGF-VEGFR) interaction plays a key role in the growth and propagation of cancer cells. However, the newly formed network of blood vessels is disorganized and leaky. Pre-treatment with anti-angiogenic agents can “normalize” the tumor vasculature allowing effective intra-tumoral delivery of standard chemotherapy.Immunohistochemistry (IHC) analysis was applied to investigate and compare the vascular normalization and anti-angiogenic effects of two commonly used anti-angiogenic agents, Sunitinib and Bevacizumab, administered prior to chemotherapy in HER2 negative breast cancer patients.MethodsThis prospective clinical trial enrolled 38 patients into a sunitinib cohort and 24 into a bevacizumab cohort. All received 4 cycles of doxorubicin/cyclophosphamide chemotherapy and pre-treatment with either sunitinib or bevacizumab. Tumor biopsies were obtained at baseline, after cycle 1 (C1) and cycle 4 (C4) of chemotherapy. IHC was performed to assess the tumor vascular normalization index (VNI), lymphatic vessel density (LVD), Ki67 proliferation index and expression of tumor VEGFR2. ResultsIn comparison to Bevacizumab, Sunitinib led to a significant increase in VNI post C1 and C4 (p <0.001 and 0.001) along with decrease in LVD post C1 (p= 0.017). Both drugs when combined with chemotherapy resulted in significant decline in tumor proliferation after C1 and C4 (baseline vs post C4 Ki67 index p=0.006 for Sunitinib vs p=0.021 for Bevacizumab). Bevacizumab resulted in a significant decrease in VEGFR2 expression post C1 (p=0.004). ConclusionSunitinib, in comparison to Bevacizumab showed a greater effect on tumor vessel modulation and lymphangiogenesis suggesting that its administration prior to chemotherapy might result in improved drug delivery.Clinical trial registrationClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).

scholarly journals Visualization nanozyme based on tumor microenvironment “unlocking” for intensive combination therapy of breast cancer

2020 ◽  
Vol 6 (48) ◽  
pp. eabc8733
Author(s):  
Zhiyi Wang ◽  
Ziyuan Li ◽  
Zhaoli Sun ◽  
Shuren Wang ◽  
Zeeshan Ali ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Combination Therapy ◽  
Near Infrared ◽  
Infrared Region ◽  
Vascular Normalization ◽  
Normal Tissues ◽  
Natural Enzyme ◽  
Imaging Performance

Nanozymes as artificial enzymes that mimicked natural enzyme–like activities have received great attention in cancer therapy. However, it remains a great challenge to design nanozymes that precisely exert its activity in tumor without producing off-target toxicity to surrounding normal tissues. Here, we report a synergetic enhancement strategy through the combination between nanozyme and tumor vascular normalization to destruct tumors, which was based on tumor microenvironment (TME) “unlocking.” This nanozyme that we developed not only has photothermal properties but also can produce reactive oxygen species efficiently under the stimulation of TME. Moreover, this nanozyme also showed remarkable imaging performance in fluorescence imaging in the second near-infrared region and magnetic resonance imaging for visualization tracing in vivo. The process of combination therapy showed remarkable therapeutic effect for breast cancer. This study provides a therapeutic strategy by the cooperation between multifunctional nanozyme and tumor vascular normalization for intensive combination therapy of breast cancer.

scholarly journals PDGF-D Improves Drug Delivery and Efficacy via Vascular Normalization, But Promotes Lymphatic Metastasis by Activating CXCR4 in Breast Cancer

2011 ◽  
Vol 17 (11) ◽  
pp. 3638-3648 ◽  
Author(s):  
Jieqiong Liu ◽  
Shan Liao ◽  
Yuhui Huang ◽  
Rekha Samuel ◽  
Tony Shi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Delivery ◽  
Lymphatic Metastasis ◽  
Vascular Normalization

scholarly journals Optical Redox Imaging Differentiates Triple-Negative Breast Cancer Subtypes

2021 ◽  
pp. 253-258
Author(s):  
Jinxia Jiang ◽  
Min Feng ◽  
Annemarie Jacob ◽  
Lin Z. Li ◽  
He N. Xu
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Response Patterns ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Mitochondrial Inhibitors ◽  
Tnbc Cell

AbstractTriple-negative breast cancer (TNBC) is a highly diverse group of cancers with limited treatment options, responsible for about 15% of all breast cancers. TNBC cells differ from each other in many ways such as gene expression, metabolic activity, tumorigenicity, and invasiveness. Recently, many research and clinical efforts have focused on metabolically targeted therapy for TNBC. Metabolic characterization of TNBC cell lines can facilitate the assessment of therapeutic effects and assist in metabolic drug development. Herein, we used optical redox imaging (ORI) techniques to characterize TNBC subtypes metabolically. We found that various TNBC cell lines had differing redox statuses (levels of reduced nicotinamide adenine dinucleotide (NADH), oxidized flavin adenine dinucleotide (FAD), and the redox ratio (FAD/(NADH+FAD)). We then metabolically perturbed the cells with mitochondrial inhibitors and an uncoupler and performed ORI accordingly. As expected, we observed that these TNBC cell lines had similar response patterns to the metabolic perturbations. However, they exhibited differing redox plasticity. These results suggest that subtypes of TNBC cells are different metabolically and that ORI can serve as a sensitive technique for the metabolic profiling of TNBC cells.

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