Epigenetic Modulation Enhances the Therapeutic Effect of Anti–IL-13Rα2 Antibody in Human Mesothelioma Xenografts

Cancer/testis (CT) antigens are potential immunotherapeutic targets in cancer. However, the expression of particular antigens is limited to a subset of tumors of a given type. Thus, there is a need to identify antigens with complementary expression patterns for effective therapeutic intervention. In this study, we searched for genes that were distinctly expressed at a higher level in lung tumor tissue and the testes compared to other non-tumor tissues and identified members of the VCX/Y gene family as novel CT antigens. VCX3A, a member of the VCX/Y gene family, was expressed at the protein level in approximately 20% of lung adenocarcinomas and 35% of squamous cell carcinomas, but not expressed in normal lung tissues. Among CT antigens with concordant mRNA and protein expression levels, four CT antigens, XAGE1, VCX, IL13RA2, and SYCE1, were expressed, alone or in combination, in about 80% of lung adenocarcinoma tumors. The CT antigen VCX/Y gene family broadens the spectrum of CT antigens expressed in lung adenocarcinomas for clinical applications.

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“…5A). XAGE1 (39) and IL13RA2 (40) are known to be induced by 5-Aza-dC. Our data indicate that similar epigenetic regulation occurs in VCX/Y genes.…”

Section: Discussionsupporting

confidence: 54%

A Search for Novel Cancer/Testis Antigens in Lung Cancer Identifies VCX/Y Genes, Expanding the Repertoire of Potential Immunotherapeutic Targets

et al. 2014

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“…We described the overexpression of IL13Ra2 in 66% of tumor samples from patients with colon cancer, which was associated to late stages of progression (metastasis in lymph nodes or liver) and poor outcome of patients with colorectal cancer (2). IL13Ra2 is overexpressed in a variety of human tumor types, such as colon, glioblastoma, renal cell carcinoma, pancreatic, melanoma, head and neck, mesothelioma, and ovarian, where it has been proposed as biomarker and potential therapeutic target (2)(3)(4)(5)(6)(7)(8)(9)(10). In glioblastoma multiforme, IL13Ra2 expression occurs in 75% of tumors and is associated with poor prognosis (3).…”

Section: Introductionmentioning

confidence: 99%

IL13 Receptor α2 Signaling Requires a Scaffold Protein, FAM120A, to Activate the FAK and PI3K Pathways in Colon Cancer Metastasis

et al. 2015

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IL13 signaling through its receptor IL13Ra2 plays a critical role in colon cancer invasion and liver metastasis, but the mechanistic features of this process are obscure. In this study, we identified a scaffold protein, FAM120A (C9ORF10), as a signaling partner in this process. FAM120A was overexpressed in human colon cancer cell lines and 55% of human colon cancer specimens. IL13Ra2-FAM120A coimmunoprecipitation experiments revealed further signaling network associations that could regulate the activity of IL13Ra2, including FAK, SRC, PI3K, G-protein-coupled receptors, and TRAIL receptors. In addition, FAM120A associated with kinesins and motor proteins involved in cargo movement along microtubules. IL13Ra2-triggered activation of the FAK and PI3K/AKT/mTOR pathways was mediated by FAM120A, which also recruited PI3K and functioned as a scaffold protein to enable phosphorylation and activation of PI3K by Src family kinases. FAM120A silencing abolished IL13-induced cell migration, invasion, and survival. Finally, antibody blockade of IL13Ra2 or FAM120A silencing precluded liver colonization in nude mice or metastasis. In conclusion, we identified FAM120A in the IL13/IL13Ra2 signaling pathway as a key mediator of invasion and liver metastasis in colon cancer. Cancer Res; 75(12); 2434-44. Ó2015 AACR.

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“…We established several mAbs specific for EPHA2 by immunizing BALB/c mice with the previously described A375 human melanoma cell line (23). In order to examine the specificity of the mAbs to EPHA2, we performed immunoprecipitation and siRNA transfection.…”

Section: Resultsmentioning

confidence: 99%

An Agonistic Antibody to EPHA2 Exhibits Antitumor Effects on Human Melanoma Cells

et al. 2018

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Abstract. Background/Aim: EPH receptor A2 (EPHA2) is highly expressed in aggressive types of human cancer, and is expected to be an excellent target molecule for antibody treatments. In this study, we investigated the therapeutic potential of antibody to EPHA2 against melanoma in vitro. Materials and Methods: We generated three monoclonal antibodies (mAbs) to EPHA2 and examined cell-surface expression by flow cytometry. To investigate the ability to inhibit tumor cell migration therapy with mAbs to EPHA2, we performed a wound scratch assay and invasion assay. We investigated the therapeutic effects of immunotoxins consisting of toxin-conjugated EPHA2 mAbs. Results: All human melanoma cell lines studied expressed EPHA2. Like natural ligand ephrin-A1, one of EPHA2 mAbs, SHM16, inhibited metastatic behavior of cells, such as migration and invasion. In addition, drastic growth inhibition and cytotoxicity were found using immunotoxin-conjugated SHM16. Conclusion: These observations indicate a promising role for EPHA2 as a target in antibody treatments for melanoma, and demonstrate the potential therapeutic effects of an agonistic antibody to EPHA2.Melanoma is the most aggressive type of skin cancer. While melanoma accounts for fewer than 5% of all skin cancer cases, it is responsible for the large majority of deaths due to skin cancer. The type of treatment will depend not only on stage and location of the melanoma, but also on the patient's overall health. When melanoma has not grown deeper than the epidermis, it is usually treated by surgery (wide excision). When this is not possible, therapeutic options including injections of Bacille Calmette-Guerin (BCG) vaccine, interferon, or interleukin-2 (IL2) directly into the melanoma, radiation therapy, and chemotherapy (1, 2). The treatment of widespread melanoma has changed in recent years as newer forms of immunotherapy and molecularly-targeted drugs have been shown to be more effective than chemotherapy (3-6).Receptor tyrosine kinases (RTKs) transmit signals that regulate cell proliferation and differentiation, promote cell migration and survival, and modulate cell metabolism. They play critical roles in a wide range of biological processes, including embryonic development, growth of an organism, angiogenesis, synaptic plasticity, and oncogenesis (7-9). EPH receptors, the largest subfamily of RTKs, are involved in many biological processes including angiogenesis, tissue-border formation, cell migration, and axon guidance (10, 11). EPH receptors and their ephrin ligands are important mediators of cell-to-cell communication that regulate cell attachment to the extracellular matrix, cell shape and cell motility. They have been studied extensively for their roles in the developmental process. In recent years, EPH receptors and ephrins have been found to be integral players in cancer formation and progression. EPH receptor A2 (EPHA2) and ephrin-A1 are especially known to be involved in the development and maintenance of many types of solid tumors (12)(13)(14).EPHA2 was ori...

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Epigenetic Modulation Enhances the Therapeutic Effect of Anti–IL-13Rα2 Antibody in Human Mesothelioma Xenografts

Cited by 26 publications

References 36 publications

A Search for Novel Cancer/Testis Antigens in Lung Cancer Identifies VCX/Y Genes, Expanding the Repertoire of Potential Immunotherapeutic Targets

A Search for Novel Cancer/Testis Antigens in Lung Cancer Identifies VCX/Y Genes, Expanding the Repertoire of Potential Immunotherapeutic Targets

IL13 Receptor α2 Signaling Requires a Scaffold Protein, FAM120A, to Activate the FAK and PI3K Pathways in Colon Cancer Metastasis

An Agonistic Antibody to EPHA2 Exhibits Antitumor Effects on Human Melanoma Cells

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