Combination of anthracyclines and anti-CD47 therapy inhibit invasive breast cancer growth while preventing cardiac toxicity by regulation of autophagy

Feliz-Mosquea, Yismeilin R.; Christensen, Ashley A.; Wilson, Ana; Westwood, Brian; Varagić, Jasmina; Meléndez, Giselle C.; Schwartz, Anthony; Chen, Qingrong; Griner, Lesley Mathews; Guha, Rajarshi; Thomas, Craig J.; Ferrer, Marc; Merino, María J.; Cook, Katherine L.; Roberts, D. A.; Soto-Pantoja, David R.

doi:10.1007/s10549-018-4884-x

Cited by 51 publications

(51 citation statements)

References 54 publications

(73 reference statements)

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“…Increased expression of CD47 by tumor cells inhibits their phagocytosis, a crucial way in which they evade immune surveillance [19]. Many preclinical studies have shown that abrogation of the SIRPα-CD47 interaction, especially when combined with tumor targeting antibodies or chemo/radiotherapy, promotes cancer cell death and improves survival [19][20][21][22][23][24][25][26][27]. Various biologic agents targeting the SIRPα-CD47 axis, including monoclonal antibodies and decoy receptors, are in early clinical development as cancer immunotherapies [28][29][30][31].…”

Section: Introductionmentioning

confidence: 99%

A homogeneous SIRPα-CD47 cell-based, ligand-binding assay: Utility for small molecule drug development in immuno-oncology

et al. 2020

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CD47 is an immune checkpoint protein that downregulates both the innate and adaptive antitumor immune response via its counter receptor SIRPα. Biologics, including humanized CD47 monoclonal antibodies and decoy SIRPα receptors, that block the SIRPα-CD47 interaction, are currently being developed as cancer immunotherapy agents. However, adverse side effects and limited penetration of tumor tissue associated with their structure and large size may impede their clinical application. We recently developed a quantitative high throughput screening assay platform to identify small molecules that disrupt the binding of SIRPα and CD47 as an alternative approach to these protein-based therapeutics. Here, we report on the development and optimization of a cell-based binding assay to validate active small molecules from our biochemical screening effort. This assay has a low volume, high capacity homogenous format that relies on laser scanning cytometry (LSC) and associated techniques to enhance signal to noise measurement of cell surface binding. The LSC assay is specific, concentration dependent, and validated for the two major human SIRPα variants (V1 and V2), with results that parallel those of our biochemical data as well as published studies. We also utilized the LSC assay to confirm published studies showing that the inhibition of amino-terminal pyroglutamate formation on CD47 using the glutaminyl cyclase inhibitor SEN177 disrupts SIRPα binding. The SIRPα-CD47 interaction could be quantitatively measured in live and fixed tumor cells. Use of fixed cells reduces the burden of cell maintenance and provides stable cell standards to control for inter-and intra-assay variations. We also demonstrate the utility of the assay to characterize the activity of the first reported small molecule antagonists of the SIRPα-CD47 interaction. This assay will support the screening of thousands of compounds to identify or validate active small molecules as hits, develop structure activity relationships and assist in the optimization of hits to leads by a typical iterative medicinal chemistry campaign.

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Section: Introductionmentioning

confidence: 99%

A homogeneous SIRPα-CD47 cell-based, ligand-binding assay: Utility for small molecule drug development in immuno-oncology

et al. 2020

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“…In a mouse model of breast cancer, Feliz‐Mosquea et al . () found significantly reduced metastasis after doxorubicin and CD47 mAb combination therapy.…”

Section: Discussionmentioning

confidence: 90%

“…Combination therapy of doxorubicin and CD47 mAb has shown success in different cancers (Feliz-Mosquea et al, 2018;Iribarren et al, 2019;Li et al, 2018;Wu et al, 2018) but their efficacy in osteosarcoma remains unknown. To our knowledge, our study is the first to evaluate the efficacy of combination therapy with doxorubicin in osteosarcomas.…”

Section: Discussionmentioning

confidence: 99%

“…Suppression of CD47 chemosensitized hepatocellular carcinoma through blockade of CTSS/PAR2 signaling (Lee et al, 2014;Lo et al, 2016). In a different study, it has been shown that targeting CD47 enhanced the effect of doxorubicin chemotherapy in vivo by reducing tumor growth and metastatic spread by activation of an antitumor innate immune response (Feliz-Mosquea et al, 2018;Iribarren et al, 2019). In contrast, Hermann et al showed that CD7 mAb treatment did not further enhance macrophagemediated phagocytosis of anthracycline pretreated rhabdomyosarcoma cells (Herrmann et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell ‘don't eat me’ signals off and ‘eat me’ signals on

et al. 2019

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The long‐term survival of osteosarcoma patients with metastatic or recurrent disease remains dismal, and new therapeutic options are urgently needed. The purpose of our study was to compare the efficacy of CD47 mAb plus doxorubicin combination therapy in mouse models of osteosarcoma with CD47 mAb and doxorubicin monotherapy. Forty‐eight NOD scid gamma (NSG) mice with intratibial MNNG/HOS tumors received CD47 mAb, doxorubicin, combination therapy, or control IgG treatment. Twenty‐four mice (n = 6 per group) underwent pre‐ and post‐treatment magnetic resonance imaging (MRI) scans with the macrophage marker ferumoxytol, bioluminescence imaging, and histological analysis. Tumor ferumoxytol enhancement, tumor flux, and tumor‐associated macrophages (TAM) density were compared between different groups using a one‐way ANOVA. Twenty‐four additional NSG mice underwent survival analyses with Kaplan–Meier curves and a log‐rank (Mantel–Cox) test. Intratibial osteosarcomas demonstrated significantly stronger ferumoxytol enhancement and significantly increased TAM quantities after CD47 mAb plus doxorubicin combination therapy compared to CD47 mAb (P = 0.02) and doxorubicin monotherapy (P = 0.001). Tumor‐bearing mice treated with CD47 mAb plus doxorubicin combination therapy demonstrated significantly reduced tumor size and prolonged survival compared to control groups that received CD47 mAb (P = 0.03), doxorubicin monotherapy (P = 0.01), and control IgG (P = 0.001). In conclusion, CD47 mAb plus doxorubicin therapy demonstrates an additive therapeutic effect in mouse models of osteosarcomas, which can be monitored with an immediately clinically applicable MRI technique.

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“…The interaction between SIRPα on DCs with CD47 on T cells is important for regulating the priming of naive T cells, which then differentiate into T helper cells, or induction of antigen-specific cytotoxic T cell responses by DCs [15]. Current focus on immunotherapy had been targeted toward inhibiting CD47-SIRPα interaction via anti-CD47 or anti-SIRPα antibodies [16].…”

Section: Introductionmentioning

confidence: 99%

The Immunotherapeutic Effect of SIRPα-Silenced DCs against Cervical Cancer

Zhou

Liang

et al. 2020

Journal of Immunology Research

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Signal regulatory protein α (SIRPα), a transmembrane protein that is predominantly expressed in dendritic cells (DCs) or macrophages, interacts with CD47 that is overexpressed in almost all types of tumor cells. The interaction between SIRPα and CD47 leads to a negative signal that prevents the phenotypic and functional maturation of DC and inhibits phagocytosis. The SIRPα knockdown in DCs that were pulsed with a modified HPV16E7 (HPV16mE7) protein with enhanced antigenicity and reduced transformation activity results in increased cytokine (TNF-α/IL-12/IL-6) secretion, IFN-γ secretion by T lymphocytes, and in vitro/in vivo tumoricidal activity against cervical cancer cells. Taken together, these results suggest that SIRPα-silenced DC vaccination presented potential therapeutic implications against cervical cancer.

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Combination of anthracyclines and anti-CD47 therapy inhibit invasive breast cancer growth while preventing cardiac toxicity by regulation of autophagy

Cited by 51 publications

References 54 publications

A homogeneous SIRPα-CD47 cell-based, ligand-binding assay: Utility for small molecule drug development in immuno-oncology

A homogeneous SIRPα-CD47 cell-based, ligand-binding assay: Utility for small molecule drug development in immuno-oncology

Improving the efficacy of osteosarcoma therapy: combining drugs that turn cancer cell ‘don't eat me’ signals off and ‘eat me’ signals on

The Immunotherapeutic Effect of SIRPα-Silenced DCs against Cervical Cancer

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