Inhibition of Established Micrometastases by Targeted Drug Delivery via Cell Surface–Associated GRP78

Miao, Yu; Eckhardt, Bedrich L.; Cao, Yuan; Pasqualini, Renata; Argani, Pedram; Arap, Wadih; Ramsay, Robert G.; Anderson, Robin L.

doi:10.1158/1078-0432.ccr-12-2991

Cited by 66 publications

(58 citation statements)

References 50 publications

(73 reference statements)

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“…GRP78 has been targeted previously for anticancer treatment (42,43). Indeed, our group has reported GRP78 overexpression in a limited set of matched primary/metastatic tumors from patients with prostate and breast cancer, supporting the likelihood of systemic targeting of surface GRP78 in primary and metastatic disease settings (44,45).…”

Section: Discussionmentioning

confidence: 62%

Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

Dobroff

D’Angelo

Eckhardt

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.inflammatory breast cancer | ligand-directed theranostics | molecular imaging | gene therapy | AAVP B reast cancer remains a major cause of cancer death in women (1), and one of its most lethal presentations is inflammatory breast carcinoma (IBC), a clinicopathological diagnosis characterized by diffuse erythema/edema involving the skin of the breast (a sign classically known as "peau d'orange") caused by tumor emboli within the dermal lymphatics. Although IBC comprises <5% of breast cancer cases, the tumor accounts for more than 10% of breast cancer mortality in the United States (2, 3). IBC is considered aggressive because it evolves rapidly-over days to weeks rather than months-with most patients presenting with lymph node involvement and more than 30% of patients having distant metastases at diagnosis (4, 5). Although IBC, like non-IBC breast cancers, is a heterogeneous disease and can occur as any of the five molecular subtypes, the IBC is most commonly ErbB2 overexpressing or triple negative (6), thus rendering a large armamentarium of targeted drugs ineffective. Finally, IBC generally presents with high-grade histology, elevated cell proliferation rate, and angiolymphatic invasion (5, 7). Indeed, the hallmark lymphatic invasion dictates the requirement for initial systemic treatment of IBC, because micrometastatic disease likely has occurred even in the Significance Inflammatory breast cancer (IBC) is defined clinically and pathologically. Dermal lymphatic invasion is typical but is neither necessary nor sufficient for diagnosis; sentinel lymph node biopsy is contraindicated, challenging multidisciplinar...

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Section: Discussionmentioning

confidence: 62%

Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

Dobroff

D’Angelo

Eckhardt

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…[8][9][10] Indeed, synthetic peptides containing cell-surface GRP78-binding motifs conjugated to proapoptotic peptide suppressed primary tumor growth as well as established micrometastasis in mice. 11,12 Furthermore, a natural human IgM antibody targeting cell-surface GRP78, PAT-SM6, induces apoptosis in primary human multiple myeloma cells. 13 In this work, we report that ISM is a novel proapoptotic ligand for cell-surface GRP78.…”

mentioning

confidence: 99%

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Zhang

et al. 2014

Cell Death Differ

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Isthmin (ISM) is a secreted 60-kDa protein that potently induces endothelial cell (EC) apoptosis. It suppresses tumor growth and angiogenesis in mice when stably overexpressed in cancer cells. Although avb5 integrin serves as a low-affinity receptor for ISM, the mechanism by which ISM mediates antiangiogenesis and apoptosis in ECs remain to be fully resolved. In this work, we report the identification of cell-surface glucose-regulated protein 78 kDa (GRP78) as a high-affinity receptor for ISM (K d ¼ 8.6 nM). We demonstrated that ISM-GRP78 interaction triggers apoptosis not only in activated ECs but also in cancer cells expressing high level of cell-surface GRP78. Normal cells and benign tumor cells tend to express low level of cell-surface GRP78 and are resistant to ISM-induced apoptosis. Upon binding to GRP78, ISM is internalized into ECs through clathrin-dependent endocytosis that is essential for its proapoptotic activity. Once inside the cell, ISM co-targets with GRP78 to mitochondria where it interacts with ADP/ATP carriers on the inner membrane and blocks ATP transport from mitochondria to cytosol, thereby causing apoptosis. Hence, ISM is a novel proapoptotic ligand that targets cell-surface GRP78 to trigger apoptosis by inducing mitochondrial dysfunction. The restricted and high-level expression of cell-surface GRP78 on cancer cells and cancer ECs make them uniquely susceptible to ISM-targeted apoptosis. Indeed, systemic delivery of recombinant ISM potently suppressed subcutaneous 4T1 breast carcinoma and B16 melanoma growth in mice by eliciting apoptosis selectively in the cancer cells and cancer ECs. Together, this work reveals a novel ISM-GRP78 apoptosis pathway and demonstrates the potential of ISM as a cancer-specific and dual-targeting anticancer agent.

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“…26,27 Inhibition of cell surface GRP78 inhibited the tumor invasion and metastasis in hepatocellular carcinoma and colorectal cancer cell. [28][29][30] Nowadays, cell surface GRP78 is regarded as a potential target for the targeted therapy of many human cancers. [31][32][33] In this paper, we show that bovine serum albumin (BSA) NPs conjugated with the monoclonal antibody against GRP78 (mAb GRP78) could inhibit the adhesion, invasion, and metastasis of hepatocellular carcinoma SMMC-7721, in which GRP78 is overexpressed.…”

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confidence: 99%

Nanoparticles inhibit cancer cell invasion and enhance antitumor efficiency by targeted drug delivery via cell surface-related GRP78

Zhao¹,

Li²,

Shi³

et al. 2014

IJN

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Nanoparticles (NPs) which target specific agents could effectively recognize the target cells and increase the stability of chemical agents by encapsulation. As such, NPs have been widely used in cancer treatment research. Recently, over 90% of treatment failure cases in patients with metastatic cancer were attributed to resistance to chemotherapy. Surface-exposed glucose-regulated protein of 78 kDa (GRP78) is expressed highly on many tumor cell surfaces in many human cancers and is related to the regulation of invasion and metastasis. Herein, we report that NPs conjugated with antibody against GRP78 (mAb GRP78-NPs) inhibit the adhesion, invasion, and metastasis of hepatocellular carcinoma (HCC) and promote drug delivery of 5-fluorouracil into GRP78 high-expressed human hepatocellular carcinoma cells. Our new findings suggest that mAb GRP78-NPs could enhance drug accumulation by effectively transporting NPs into cell surface GRP78-overexpressed human hepatocellular carcinoma cells and then inhibit cell proliferation and viability and induce cell apoptosis by regulating caspase-3. In brief, mAb GRP78-NPs effectively inhibit cancer cell invasion and enhance antitumor efficiency by targeted drug delivery.

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Inhibition of Established Micrometastases by Targeted Drug Delivery via Cell Surface–Associated GRP78

Cited by 66 publications

References 50 publications

Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

Isthmin targets cell-surface GRP78 and triggers apoptosis via induction of mitochondrial dysfunction

Nanoparticles inhibit cancer cell invasion and enhance antitumor efficiency by targeted drug delivery via cell surface-related GRP78

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