Dataset Information

Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model.

ABSTRACT:

Background

Patients with metastatic HER2/neu-positive (HER2/neu?+) breast cancer (BC) often experience treatment resistance, disease recurrences and metastases. Thus, new approaches for improving the treatment of HER2/neu?+?BC to prevent metastatic dissemination are urgently needed. Our previous studies have shown that losartan, an angiotensin receptor blocker, increases tumor perfusion and decreases hypoxia in a number of tumor models. Hypoxia reduces the efficacy of radiation and increases metastases. We therefore hypothesized that by modifying tumor stroma and increasing oxygenation, losartan will improve the outcome of radiotherapy and inhibit disease progression in a highly metastatic HER2/neu?+?murine BC model.

Methods

We established a metastatic HER2/neu?+?murine BC line (MCa-M3C) and used it to generate mammary fat pad isografts in syngeneic female FVB/N mice. Starting on day 3 after orthotopic tumor implantation, we administered a 7-day losartan treatment (40 mg/kg BW, gavage daily); or a 7-day losartan treatment followed by 20 Gy single dose local irradiation (S-IR) on day 10 (tumor size?~?100 mm³), or 20 Gy local fractionated (5?×?4 Gy daily) irradiation (F-IR) on days 10-14. We analyzed tumor-growth delay (TGD), development of spontaneous lung metastases, animal survival, tumor vascular density, and tumor hypoxia.

Results

Treatments with S-IR, F-IR, Losartan?+?S-IR, or Losartan?+?F-IR resulted in a significantly increased TGD (8-16 days) in MCa-M3C tumors versus controls. However, the combination of Losartan?+?S-IR and Losartan?+?F-IR further enhanced tumor response to radiation alone by increasing TGD an additional 5 to 8 days for both single and fractionated dose irradiation (P?ConclusionsCombining losartan with local irradiation significantly enhanced tumor response, at least in part via reduced tumor hypoxia presumably due to increased tumor perfusion. Our findings suggest that combining losartan with radiotherapy is a potential new treatment strategy for local control and inhibiting metastasis in HER2?+?BC.

SUBMITTER: Li W

PROVIDER: S-EPMC7934382 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model.

Li Wende W Li Sen S Chen Ivy X IX Liu Yujiao Y Ramjiawan Rakesh R RR Leung Chi-Ho CH Gerweck Leo E LE Fukumura Dai D Loeffler Jay S JS Jain Rakesh K RK Duda Dan G DG Huang Peigen P

Radiation oncology (London, England) 20210304 1

<h4>Background</h4>Patients with metastatic HER2/neu-positive (HER2/neu +) breast cancer (BC) often experience treatment resistance, disease recurrences and metastases. Thus, new approaches for improving the treatment of HER2/neu + BC to prevent metastatic dissemination are urgently needed. Our previous studies have shown that losartan, an angiotensin receptor blocker, increases tumor perfusion and decreases hypoxia in a number of tumor models. Hypoxia reduces the efficacy of radiation and incre ...[more]

PMID: 33663521

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Project description:BackgroundHER2/neu-positive breast cancer cells have recently been shown to use a unique Warburg-like metabolism for survival and aggressive behavior. These cells exhibit increased fatty acid synthesis and storage compared to normal breast cells or other tumor cells. Disruption of this synthetic process results in apoptosis. Since the addition of physiological doses of exogenous palmitate induces cell death in HER2/neu-positive breast cancer cells, the pathway is likely operating at its limits in these cells. We have studied the response of HER2/neu-positive breast cancer cells to physiological concentrations of exogenous palmitate to identify lipotoxicity-associated consequences of this physiology. Since epidemiological data show that a diet rich in saturated fatty acids is negatively associated with the development of HER2/neu-positive cancer, this cellular physiology may be relevant to the etiology and treatment of the disease. We sought to identify signaling pathways that are regulated by physiological concentrations of exogenous palmitate specifically in HER2/neu-positive breast cancer cells and gain insights into the molecular mechanism and its relevance to disease prevention and treatment.MethodsTranscriptional profiling was performed to assess programs that are regulated in HER2-normal MCF7 and HER2/neu-positive SKBR3 breast cancer cells in response to exogenous palmitate. Computational analyses were used to define and predict functional relationships and identify networks that are differentially regulated in the two cell lines. These predictions were tested using reporter assays, fluorescence-based high content microscopy, flow cytometry and immunoblotting. Physiological effects were confirmed in HER2/neu-positive BT474 and HCC1569 breast cancer cell lines.ResultsExogenous palmitate induces functionally distinct transcriptional programs in HER2/neu-positive breast cancer cells. In the lipogenic HER2/neu-positive SKBR3 cell line, palmitate induces a G2 phase cell cycle delay and CHOP-dependent apoptosis as well as a partial activation of the ER stress response network via XBP1 and ATF6. This response appears to be a general feature of HER2/neu-positive breast cancer cells but not cells that overexpress only HER2/neu. Exogenous palmitate reduces HER2 and HER3 protein levels without changes in phosphorylation and sensitizes HER2/neu-positive breast cancer cells to treatment with the HER2-targeted therapy trastuzumab.ConclusionsSeveral studies have shown that HER2, FASN and fatty acid synthesis are functionally linked. Exogenous palmitate exerts its toxic effects in part through inducing ER stress, reducing HER2 expression and thereby sensitizing cells to trastuzumab. These data provide further evidence that HER2 signaling and fatty acid metabolism are highly integrated processes that may be important for disease development and progression.

Project description:Abstract Breast cancer brain metastases (BCBM) are a major cause of morbidity and mortality, despite multimodal management including surgery, radiotherapy, and systemic therapies. There is an urgent need to develop novel, efficacious alternatives. Neratinib is an orally bioavailable, irreversible pan-HER tyrosine kinase inhibitor that is FDA-approved in the extended adjuvant treatment setting for HER2-positive, early breast cancer (NCT00878709). Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate with reported single-agent activity against HER2-positive BCBM. Here, we used HER2-positive orthotopic patient derived xenograft (PDX) models of BCBM to test if combining neratinib with T-DM1 could improve tumor response. PDX cells are labelled with luciferase to allow tumor growth measurement in vivo. We found that neratinib is able to reduce phosphorylated HER2 in an orthotopic PDX tumor derived from HER2-positive BCBM, indicating that neratinib can cross the BBB and inhibit HER2 activation in BCBM PDX tissues. However, in both HER2-positive DF-BM354 and DF-BM355 PDX models, single agent neratinib did not block orthotopic tumor growth compared to vehicle control as monitored by bioluminescence measurements. In contrast, combined treatment of neratinib with T-DM1 significantly reduced tumor growth compared to single agent treatment with neratinib or T-DM1 at earlier time points in both models. At later time points, the combined treatment is comparable to T-DM1 alone in DF-BM354 model, but significantly prolong the survival of mice bearing DF-BM355 tumors. These data warrant further testing of neratinib alone and in combination with T-DM1 in additional BCBM PDX models to better understand drivers of resistance and susceptibility to HER2-inhibitors in HER2-positive BCBMs. Furthermore, they support the launch of a prospective clinical trial (NCT01494662) to test the efficacy and tolerability of T-DM1 in combination with neratinib in patients with progressive HER2-positive BCBM.

Dataset Information

Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model.

Background

Methods

Results

Publications

Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model.

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