Inhibition of CXCR4 by CTCE-9908 inhibits breast cancer metastasis to lung and bone

Richert, Monica M.; Vaidya, Kedar S.; Mills, Caroline N.; Wong, Donald; Korz, Walter; Hurst, Douglas R.; Welch, Danny R.

doi:10.3892/or_00000282

Cited by 44 publications

(7 citation statements)

References 37 publications

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“…CTCE-9908 inhibits human breast tumor cells growth in mouse xenografts impairing the CXCR4–VEGF loop and lowering tumor VEGF levels (Hassan et al, 2011) and affects breast, prostate and esophageal cancer metastasization in murine models (Wong and Korz, 2008; Richert et al, 2009). Phase I/II clinical trials of this compound, in patients with hepatocellular carcinoma, are currently under evaluation (Wong and Korz, 2008).…”

Section: Targeting Cxcl12–cxcr4/cxcr7 Axis In Cancer: Rationalementioning

confidence: 99%

CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment

Würth

Bajetto

Harrison

et al. 2014

Front. Cell. Neurosci.

114

128

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Chemokines are crucial autocrine and paracrine players in tumor development. In particular, CXCL12, through its receptors CXCR4 and CXCR7, affects tumor progression by controlling cancer cell survival, proliferation and migration, and, indirectly, via angiogenesis or recruiting immune cells. Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults and despite current multimodal therapies it remains almost incurable. The aggressive and recurrent phenotype of GBM is ascribed to high growth rate, invasiveness to normal brain, marked angiogenesis, ability to escape the immune system and resistance to standard of care therapies. Tumor molecular and cellular heterogeneity severely hinders GBM therapeutic improvement. In particular, a subpopulation of chemo- and radio-therapy resistant tumorigenic cancer stem–like cells (CSCs) is believed to be the main responsible for tumor cell dissemination to the brain. GBM cells display heterogeneous expression levels of CXCR4 and CXCR7 that are overexpressed in CSCs, representing a molecular correlate for the invasive potential of GBM. The microenvironment contribution in GBM development is increasingly emphasized. An interplay exists between CSCs, differentiated GBM cells, and the microenvironment, mainly through secreted chemokines (e.g., CXCL12) causing recruitment of fibroblasts, endothelial, mesenchymal and inflammatory cells to the tumor, via specific receptors such as CXCR4. This review covers recent developments on the role of CXCL12/CXCR4–CXCR7 networks in GBM progression and the potential translational impact of their targeting. The biological and molecular understanding of the heterogeneous GBM cell behavior, phenotype and signaling is still limited. Progress in the identification of chemokine-dependent mechanisms that affect GBM cell survival, trafficking and chemo-attractive functions, opens new perspectives for development of more specific therapeutic approaches that include chemokine-based drugs.

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Section: Targeting Cxcl12–cxcr4/cxcr7 Axis In Cancer: Rationalementioning

confidence: 99%

CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment

Würth

Bajetto

Harrison

et al. 2014

Front. Cell. Neurosci.

114

128

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“…CTCE-9908 shows a potent inhibitory activity in metastasis . Higher doses (25 mg/kg/mouse or more) than those used in these studies − , may be necessary to inhibit metastasis. These findings strongly suggest that the antimetastatic effect of CTCE-KLAK is due to the cytotoxic ability of the KLAK motif.…”

Section: Discussionmentioning

confidence: 86%

“…For example, CTCE-9908 is a 17 amino acid peptide that consists of a dimer for the first eight amino acids of SDF-1α. CTCE-9908 competitively inhibits the interaction between the CXCR4 receptor and its ligand SDF-1α. − CTCE-9908 blocks the function of CXCR4, thus suppressing tumor growth and metastasis in different mouse tumor models. − …”

Section: Introductionmentioning

confidence: 99%

CXCR4-Targeted Necrosis-Inducing Peptidomimetic for Treating Breast Cancer

2023

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Triple-negative breast cancer is an aggressive subtype with a high recurrence rate, potential for metastasis, and a poor prognosis. The chemokine receptor, CXCR4, is a promising molecular target in breast cancer therapy. Here, we have developed a CXCR4-targeted antitumor peptidomimetic (named CTCE-KLAK), which is a fusion of the CXCR4 receptor antagonist CTCE-9908 and the D-form of proapoptotic peptide (KLAKLAK)2, for the treatment of breast cancer. First, we investigated the in vitro antitumor activity of CTCE-KLAK against various breast cancer cells and noncancerous mammary epithelial cells. CTCE-KLAK showed cell-selective cytotoxicity and induced rapid necrotic cell death in breast cancer cells but not in normal cells. In contrast, unconjugated peptides such as the carboxylate analogues of CTCE-9908 and D(KLAKLAK)2 were not cytotoxic to these cells. The tumor selectivity of CTCE-KLAK for cytotoxic activity depends on its internalization into tumor cells. There was no cleavage of caspase-3, caspase-7, or PARP1 in CTCE-KLAK-treated cells. In addition, cell death by CTCE-KLAK was not prevented by z-VAD-fmk, a pan-caspase inhibitor that inhibits cisplatin-induced cell death. These data indicate that the CTCE-KLAK conjugate is a cell-selective inducer of necrosis. Furthermore, we evaluated the in vivo antitumor activity of CTCE-KLAK in the 4T1 mouse metastatic breast cancer model. Intravenous administration of CTCE-KLAK significantly inhibited tumor growth and lung metastasis. Together, these findings suggest that the necrosis-inducing peptidomimetic CTCE-KLAK is a promising CXCR4-targeted agent for treating triple-negative breast cancer.

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“…OBs constitutively express CXCL12 and attract CXCR4-expressing tumor cells (14). Using mouse models, it has been shown that breast, lung, and prostate cancer cells overexpressing CXCR4 and CXCR7 increased their ability to extravasate and colonize bone (15, 16), and CXCR4 inhibition decreased bone and lung metastases (17, 18). Integrins and cadherins are other crucial factors for the interactions between DTCs and niches (16, 19).…”

Section: Dtcs Colonize Bone Marrow and Activate The Bone Metastatic Vmentioning

confidence: 99%

The Uncovered Role of Immune Cells and NK Cells in the Regulation of Bone Metastasis

Roato

Vitale

2019

Front. Endocrinol.

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Bone is one of the main metastatic sites of solid tumors like breast, lung, and prostate cancer. Disseminated tumor cells (DTCs) and cancer stem cells (CSCs) represent the main target to counteract bone metastatization. These cells often localize in bone marrow (BM) at level of pre-metastatic niche: they can remain dormant for years or directly grow and create bone lesion, according to the different stimulations received in BM. The immune system in bone marrow is dampened and represents an appealing site for DTCs/CSCs. NK cells have an important role in controlling tumor progression, but their involvement in bone metastasis formation is an interesting and not fully investigated issue. Indeed, whether NK cells can interfere with CSC formation, kill them at the site of primary tumor, during circulation or in the pre-metastic niche needs to be elucidated. This review focuses on different aspects that regulate DTC/CSC life in bone and how NK cells potentially control bone metastasis formation.

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Inhibition of CXCR4 by CTCE-9908 inhibits breast cancer metastasis to lung and bone

Cited by 44 publications

References 37 publications

CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment

CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment

CXCR4-Targeted Necrosis-Inducing Peptidomimetic for Treating Breast Cancer

The Uncovered Role of Immune Cells and NK Cells in the Regulation of Bone Metastasis

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