Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors

Mandelin, Jami; Cardó-Vila, Marina; Driessen, Wouter H. P.; Mathew, Paul; Navone, Nora M.; Lin, Sue-Hwa; Logothetis, Christopher J.; Rietz, Anna Cecilia; Dobroff, Andrey S.; Proneth, Bettina; Sidman, Richard L.; Pasqualini, Renata; Arap, Wadih

doi:10.1073/pnas.1500128112

Cited by 56 publications

(37 citation statements)

References 55 publications

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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: 60%

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: 60%

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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“…To evaluate potential "theranostic" (a merging of the terms therapeutic and diagnostic) strategies for AVPC, we exploited SNTRVAP, a peptide motif isolated by screening of combinatorial phage display libraries in the MDA-PCa-118b patient tumor-derived xenograft (PDX) in vivo (9,10) (Fig. 1).…”

Section: Significancementioning

confidence: 99%

“…Altered glucose metabolism of cancer cells, as well as glucose starvation in poorly vascularized tumors, are associated with GRP78 overexpression and translocation to the cell surface (12)(13)(14). Overexpression of GRP78 has been correlated with poor survival in patients with breast (15)(16)(17) and prostate cancer (10,(18)(19)(20). Its tumor-specific localization and stress-response attributes make cell surface GRP78 an attractive candidate receptor for ligand-directed strategies in solid tumor management (10,21).…”

Section: Significancementioning

confidence: 99%

Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer

Ferrara

Staquicini

Driessen

et al. 2016

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

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Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/ phage (AAVP) particles in mice bearing MDA-PCa-118b, a patientderived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicideinducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, liganddirected theranostics for translational applications in AVPC.aggressive variant prostate cancer | ligand-directed theranostics | molecular imaging | gene therapy | AAVP P rostate cancer, the most common carcinoma in men and a major cause of morbidity and mortality (1), is a clinically heterogenous disease. Although a majority of prostate cancers are highly responsive to androgen receptor (AR)-directed therapies, a subset is relatively resistant to these therapies and carries a dismal prognosis (2-5). At the extreme of this spectrum are the small-cell or neuroendocrine carcinomas, a predominantly AR-negative histological variant of the disease that is associated with atypical clinical features (such as visceral metastases, predominantly lytic bone metastases, low levels of prostate-specific antigen relative to tumor burden, bulky primary tumors, and high levels of lactic dehydrongenase and carcinoembryonic antigen) and responds to platinum-based chemotherapies (6). Although small-cell or neuorendocrine carcinomas of the prostate are rare at initial diagnosis, they are increasingly recognized in the castration-resistant phases of disease progression. Moreover, a larger group of morphologically heterogeneous prostate cancers share the clinical features of the small-cell neuroendocrine carcinomas and, likely, their underlying biology (7, 8); these have been grouped under the term aggressive variant prostate carcinomas (AVPC). The molecular underpinnings of the AVPC are likely shared with subsets of other Significance Aggressive variant prost...

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“…This approach has been used in various applications, such as in the mapping and mimicking of epitopes, the identification of new receptors and natural ligands, high-affinity antibodies and analogs, the isolation of specific antigens binding to bioactive compounds, the production of novel enzyme inhibitors and DNA-binding proteins, and the probing of cellular and tissue-specific processes. Phage display has been successfully applied for the identification of peptides with a high specificity for target tumor neovasculature or a variety of human tumor cells (16,(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

Section: Biotechnology Methods For Identification Of New Ligands: Dismentioning

confidence: 99%

Identification of Ligands and Translation to Clinical Applications

et al. 2017

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Technologic advances in molecular biology and biotechnology are increasingly being used for the development of new tumor-targeting tracers. In oncology, major progress has recently been achieved with peptidic and proteinaceous compounds. The development of new biocompatible molecules relies on the identification and validation of new target structures in close conjunction with the application of novel techniques. The identification of lead compounds by these techniques is followed by the screening of various derivatives of these molecules. Hence, high-throughput methods that generate vast libraries of epitopes have been applied. These libraries are screened to identify the few variants that bind with a high affinity to the target structure. A key feature of this strategy is the large number of candidate molecules that can be identified. Further evaluation and optimization of these molecules requires characterization of structure-function relationships and subsequent improvement with respect to binding, internalization, and biodistribution through a rational design of corresponding analogs.

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Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors

Cited by 56 publications

References 55 publications

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

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

Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer

Identification of Ligands and Translation to Clinical Applications

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