The binding characteristics of a cyclic nonapeptide, c(CGRRAGGSC), in LNCaP human prostate cancer cells

Gu, Cheng; Lü, Ling; He, Yangang; Jiang, Jianwei; Yang, Zhifu; Wu, Qinghua

doi:10.3892/ol.2012.769

Cited by 3 publications

(3 citation statements)

References 19 publications

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“…One selected peptide motif, GRRAGGS, was identified from a prostate biopsy sample that exhibited sequence homology to interleukin 11 (IL-11). Our group as well as others confirmed IL-11 binds to its cognate receptor, IL-11Rα [41, 90, 91], which is overexpressed during tumor progression and metastases in a large cohort of prostate cancer patients [42]. Similar to prostate cancer, expression of IL-11 and IL-11Rα are significantly higher in breast cancer samples compared to healthy mammary tissue [92].…”

Section: Targeting Strategiessupporting

confidence: 62%

Ligand-targeted theranostic nanomedicines against cancer

Yao¹,

D’Angelo²,

Butler

et al. 2016

Journal of Controlled Release

169

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Nanomedicines have significant potential for cancer treatment. Although the majority of nanomedicines currently tested in clinical trials utilize simple, biocompatible liposome-based nanocarriers, their widespread use is limited by non-specificity and low target site concentration and thus, do not provide a substantial clinical advantage over conventional, systemic chemotherapy. In the past 20 years, we have identified specific receptors expressed on the surfaces of tumor endothelial and perivascular cells, tumor cells, the extracellular matrix and stromal cells using combinatorial peptide libraries displayed on bacteriophage. These studies corroborate the notion that unique receptor proteins such as IL-11Rα, GRP78, EphA5, among others, are differentially overexpressed in tumors and present opportunities to deliver tumor-specific therapeutic drugs. By using peptides that bind to tumor-specific cell-surface receptors, therapeutic agents such as apoptotic peptides, suicide genes, imaging dyes or chemotherapeutics can be precisely and systemically delivered to reduce tumor growth in vivo, without harming healthy cells. Given the clinical applicability of peptide-based therapeutics, targeted delivery of nanocarriers loaded with therapeutic cargos seems plausible. We propose a modular design of a functionalized protocell in which a tumor-targeting moiety, such as a peptide or recombinant human antibody single chain variable fragment (scFv), is conjugated to a lipid bilayer surrounding a silica-based nanocarrier core containing a protected therapeutic cargo. The functionalized protocell can be tailored to a specific cancer subtype and treatment regimen by exchanging the tumor-targeting moiety and/or therapeutic cargo or used in combination to create unique, theranostic agents. In this review, we summarize the identification of tumor-specific receptors through combinatorial phage display technology and the use of antibody display selection to identify recombinant human scFvs against these tumor-specific receptors. We compare the characteristics of different types of simple and complex nanocarriers, and discuss potential types of therapeutic cargos and conjugation strategies. The modular design of functionalized protocells may improve the efficacy and safety of nanomedicines for future cancer therapy.

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Section: Targeting Strategiessupporting

confidence: 62%

Ligand-targeted theranostic nanomedicines against cancer

Yao¹,

D’Angelo²,

Butler

et al. 2016

Journal of Controlled Release

169

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“…Human IL‐11Rα was overexpressed and had expression profiles similar to those of IL‐11Rα and cluster of differentiation 31 (CD31 [also called platelet endothelial cell adhesion molecule]), with colocalization during tumor progression and metastases in a large cohort of prostate cancer patients; specific drug binding to IL‐11Rα and dose‐dependent apoptosis induction of prostate cancer cells is mediated through a receptor‐interacting site within IL‐11. 9 Independent groups have confirmed this ligand‐receptor system by characterizing the binding of CGRRAGGSC …”

Section: Introductionmentioning

confidence: 93%

“…9 Independent groups have confirmed this ligand-receptor system by characterizing the binding of CGRRAGGSC. 10,11 On the basis of these findings, we designed a liganddirected agent, bone metastasis-targeting peptidomimetic-11 (BMTP-11), which consists of the CGRRAGGSC motif synthesized in tandem to D (KLA-KLAK) 2 , an apoptosis-inducing motif that is active on cell internalization and has been validated in preclinical models of cancer, obesity, and retinopathies. 8,[12][13][14][15][16][17] Here, we report preclinical studies of BMTP-11 across rodent and nonhuman primate species and a phase 0 BMTP-11 trial in patients with castrate-resistant prostate cancer.…”

Section: Introductionmentioning

confidence: 99%

Targeting the interleukin‐11 receptor α in metastatic prostate cancer: A first‐in‐man study

Pasqualini

Millikan

Christianson

et al. 2015

Cancer

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BACKGROUNDReceptors in tumor blood vessels are attractive targets for ligand-directed drug discovery and development. The authors have worked systematically to map human endothelial receptors (“vascular zip codes”) within tumors through direct peptide library selection in cancer patients. Previously, they selected a ligand-binding motif to the interleukin-11 receptor alpha (IL-11Rα) in the human vasculature.METHODSThe authors generated a ligand-directed, peptidomimetic drug (bone metastasis-targeting peptidomimetic-11 [BMTP-11]) for IL-11Rα–based human tumor vascular targeting. Preclinical studies (efficacy/toxicity) included evaluating BMTP-11 in prostate cancer xenograft models, drug localization, targeted apoptotic effects, pharmacokinetic/pharmacodynamic analyses, and dose-range determination, including formal (good laboratory practice) toxicity across rodent and nonhuman primate species. The initial BMTP-11 clinical development also is reported based on a single-institution, open-label, first-in-class, first-in-man trial (National Clinical Trials number NCT00872157) in patients with metastatic, castrate-resistant prostate cancer.RESULTSBMTP-11 was preclinically promising and, thus, was chosen for clinical development in patients. Limited numbers of patients who had castrate-resistant prostate cancer with osteoblastic bone metastases were enrolled into a phase 0 trial with biology-driven endpoints. The authors demonstrated biopsy-verified localization of BMTP-11 to tumors in the bone marrow and drug-induced apoptosis in all patients. Moreover, the maximum tolerated dose was identified on a weekly schedule (20-30 mg/m2). Finally, a renal dose-limiting toxicity was determined, namely, dose-dependent, reversible nephrotoxicity with proteinuria and casts involving increased serum creatinine.CONCLUSIONSThese biologic endpoints establish BMTP-11 as a targeted drug candidate in metastatic, castrate-resistant prostate cancer. Within a larger discovery context, the current findings indicate that functional tumor vascular ligand-receptor targeting systems may be identified through direct combinatorial selection of peptide libraries in cancer patients. Cancer 2015;121:2411–2421. © 2015 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.The authors report on the development of a new ligand-directed peptidomimetic (termed bone metastasis-targeting peptidomimetic-11) for interleukin-11 receptor-based human vascular targeting, including the translation from preclinical studies to a first-in-class, first-in-man clinical trial in patients with metastatic, castrate-resistant prostate cancer.

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