Concurrent administration of anti-HER2 therapy and radiotherapy: Systematic review

Mignot, Fabien; Ajgal, Zahra; Xu, Haoping; Géraud, Arthur; Chen, Jia Yi; Mégnin-Chanet, Frédérique; Kirova, Youlia

doi:10.1016/j.radonc.2017.07.006

Cited by 40 publications

(28 citation statements)

References 65 publications

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“…Radiation may result in a more potent anti-tumour effect when combined with anti-HER2 therapy. Further exploration of concurrent administration of T-DM1 with radiotherapy is warranted in GI cancers [89] . The challenges of combining ADCs with other modalities includes choice of ADC with other cytotoxic agents, dose of compounds, toxicity of combination and scheduling/sequencing of combinations.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Antibody drug conjugate development in gastrointestinal cancers: hopes and hurdles from clinical trials

Wu¹,

Kilpatrick²,

Chau³

2018

CDR

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Gastrointestinal (GI) cancers represent the leading cause of cancer-related mortality worldwide. Antibody drug conjugates (ADCs) are a rapidly growing new class of anti-cancer agents which may improve GI cancer patient survival. ADCs combine tumour-antigen specific antibodies with cytotoxic drugs to deliver tumour cell specific chemotherapy. Currently, only two ADCs [brentuximab vedotin and trastuzumab emtansine (T-DM1)] have been Food and Drug Administration approved for the treatment of lymphoma and metastatic breast cancer, respectively. Clinical research evaluating ADCs in GI cancers has shown limited success. In this review, we will retrace the relevant clinical trials investigating ADCs in GI cancers, especially ADCs targeting human epidermal growth receptor 2, mesothelin, guanylyl cyclase C, carcinogenic antigen-related cell adhesion molecule 5 (also known as CEACAM5) and other GI malignancy specific targets. We will review potential hurdles for their success and provide new perspective for future treatment.

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Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Antibody drug conjugate development in gastrointestinal cancers: hopes and hurdles from clinical trials

Wu¹,

Kilpatrick²,

Chau³

2018

CDR

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“…Human epidermal growth factor receptor 2 positive (HER2+) breast cancer is characterized by overexpression of the HER2/neu receptor and represents 15-20% of breast cancer cases [1]. Trastuzumab, a monoclonal antibody targeted to the HER2 receptor, is used clinically in both neoadjuvant and adjuvant standard-of-care treatment, and is often combined with radiation in the adjuvant setting to eliminate residual disease and prevent recurrence [2][3][4]. Preclinical studies have shown that overexpression of HER2 is a contributing factor to radiation resistance, and treatment with anti-HER2 therapy could potentially act as a radiosensitizer [5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Quantifying the effects of combination trastuzumab and radiation therapy in human epidermal growth factor receptor 2 positive breast cancer

Bloom

Song

Virostko

et al. 2020

Preprint

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Background: Trastuzumab, a clinical antibody targeted to the human epidermal growth factor receptor 2 (HER2), has been shown to sensitize cells to radiation in vitro. Current studies lack longitudinal evaluation of cellular response and in vivo data is limited. The purpose of this study is to quantify the effects of combination trastuzumab and radiation therapy in vitro and in vivo over time to determine if there is a synergistic interaction. Methods: EGFP expressing BT474, SKBR3 and MDA-MB-231 cell lines were treated with 0.1 ng/ml of trastuzumab, 5 or 10 Gy of radiation, or combination treatment, and imaged using fluorescence live cell microscopy for one week. The Bliss independence model was used to quantify the effects of combination treatment. HER2+ tumor bearing mice (female NU/J) (N=34) were treated with saline, 10 mg/kg of trastuzumab, 5 or 10 Gy of radiation, or combination treatment. Tumor size was measured three times per week for four weeks via caliper measurements. Additional mice (N=13) were treated with 10 mg/kg of trastuzumab, 5 Gy of radiation, or combination treatment. Tumors were harvested at one week and evaluated with immunohistochemistry for inflammation (CD45), vascularity (CD31 and α-SMA), and hypoxia (pimonidazole). Results: Altering the order of therapies did not significantly affect BT474 cell proliferation in vitro (P>0.05). The interaction index calculations revealed additive effects of trastuzumab and radiation treatment in all three cell lines in vitro. In vivo results revealed significant differences in tumor response between mice treated with 5 and 10 Gy single agent radiation (P < 0.001); however, no difference was seen in the combination groups when trastuzumab was added to the radiation regimen (P=0.56), indicating a lower dose of radiation could be used without decreasing therapeutic efficacy. Histology results revealed increases in inflammation (CD45+) in mice receiving trastuzumab (P<0.05). Conclusions: Longitudinal evaluation of cell proliferation in vitro showed additive effects of combination therapy. In vivo results show a potential to achieve the same efficacy of treatment with reduced radiation when also administering trastuzumab. Further evaluation of tumor microenvironmental alterations during treatment could identify mechanisms of increased therapeutic efficacy in this regimen.

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“…18,19 ERBB2 (receptor tyrosine-protein kinase erbB-2) is a member of the epidermal growth factor receptor that promotes cell proliferation and opposes apoptosis, and therefore must be tightly regulated to prevent uncontrolled cell growth. 20 In human study, elevated positive proteins of neoplastic ESR1, TP53, ERBB2 were observed in OGS samples, followed by abnormal cancer antigen contents in blood samples. Based on the literature and human data, we further conducted the pharmacological experiments of FN OGS using a tumour-bearing nude mouse model.…”

Section: Discussionmentioning

confidence: 94%

Anti‐cancer targets of formononetin and molecular mechanisms in osteosarcoma: Findings of bioinformatic and experimental assays

Zhao³

et al. 2019

J Cellular Molecular Medi

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In current study, a bioinformatic‐based network pharmacology was used to identify the osteosarcoma ( OGS )‐pathological targets and formononetin ( FN )‐treated targets before the main core predictive biotargets were screened. In addition, all core targets were selected through a number of bioinformatic databases, followed by identification of predominant biological processes and signalling pathways of FN anti‐ OGS . Further, top three core targets of FN anti‐ OGS were determined as oestrogen receptor 1 ( ESR 1), tumour protein p53 ( TP 53), receptor tyrosine‐protein kinase erbB‐2 ( ERBB 2) respectively. In clinical biochemical data, the plasma samples of OGS showed the increased trends of alkaline phosphatase, triglyceride, blood glucose, lactate dehydrogenase, high‐sensitive C‐reactive protein and some immune cell counts when referenced to medical criteria. In clinicopathological examination, histological OGS sections resulted in increased positive cell counts of neoplastic ESR 1, TP 53, ERBB 2. To further validate these corn proteins in experimental study in vivo, FN ‐treated tumour‐bearing nude mice showed intracellular reductions of ESR 1, TP 53, ERBB 2 positive expressions, accompanied with visibly reduced tumour weights. Collectively, our bioinformatic and experimental findings disclosed main core targets, biological processes and signalling pathways of FN anti‐ OGS . Interestingly, the top core targets were representatively validated following FN treatment in vivo. Therefore, we reasoned that these predictive targets might be the potential biomarkers for screening and treating osteosarcoma.

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Concurrent administration of anti-HER2 therapy and radiotherapy: Systematic review

Cited by 40 publications

References 65 publications

Antibody drug conjugate development in gastrointestinal cancers: hopes and hurdles from clinical trials

Antibody drug conjugate development in gastrointestinal cancers: hopes and hurdles from clinical trials

Quantifying the effects of combination trastuzumab and radiation therapy in human epidermal growth factor receptor 2 positive breast cancer

Anti‐cancer targets of formononetin and molecular mechanisms in osteosarcoma: Findings of bioinformatic and experimental assays

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