Delta‐like 3 localizes to neuroendocrine cells and plays a pivotal role in gastrointestinal neuroendocrine malignancy

Matsuo, Kentaro; Taniguchi, Kohei; Hamamoto, Hiroki; Ito, Yuko; Futaki, Sugiko; Inomata, Yosuke; Shima, Takafumi; Asakuma, Mitsuhiro; Lee, Sang‐Woong; Tanaka, Keitaro; Okuda, Jun; Kondo, Yoichi; Uchiyama, Kazuhisa

doi:10.1111/cas.14157

Cited by 20 publications

(23 citation statements)

References 25 publications

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“…According to the DLL3-expression profile, the DLL3/CD3 ITE has the potential to be developed in additional indications with high unmet medical need, such as glioma (33), medullary thyroid cancer (34), gastrointestinal neuroendocrine malignancies (35), dispersed neuroendocrine tumors of the pancreas (34), small cell bladder cancer (36), Merkel-cell carcinoma (37), and neuroendocrine prostate cancer (38).…”

Section: Discussionmentioning

confidence: 99%

A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer

Hipp

Voynov

Drobits-Handl

et al. 2020

Clinical Cancer Research

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Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy-resistant recurrence in the majority of patients. To effectively treat SCLC, we have developed a unique and novel IgG-like T-cell engaging bispecific antibody (ITE) that potently redirects T-cells to specifically lyse SCLC cells expressing Delta-like ligand 3 (DLL3), an antigen that is frequently expressed on the cell surface of SCLC cells, with no to very little detectable expression in normal tissues. Experimental Design: The antitumor activity and mode of action of DLL3/CD3 ITE was evaluated in vitro using SCLC cell lines and primary human effector cells and in vivo in an SCLC xenograft model reconstituted with human CD3 þ T-cells. Results: Selective binding of DLL3/CD3 ITE to DLL3-positive tumor cells and T-cells induces formation of an immunological synapse resulting in tumor cell lysis and activation of T-cells. In a human T-cell engrafted xenograft model, the DLL3/CD3 ITE leads to an increase in infiltration of T-cells into the tumor tissue resulting in apoptosis of the tumor cells and tumor regression. Consistent with the mode of action, the DLL3/CD3 ITE treatment led to upregulation of PD-1, PD-L1, and LAG-3. Conclusions: This study highlights the ability of the DLL3/CD3 ITE to induce strictly DLL3-dependent T-cell redirected lysis of tumor cells and recruitment of T-cells into noninflamed tumor tissues leading to tumor regression in a preclinical in vivo model. These data support clinical testing of the DLL3/CD3 ITE in patients with SCLC.

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Section: Discussionmentioning

confidence: 99%

A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer

Hipp

Voynov

Drobits-Handl

et al. 2020

Clinical Cancer Research

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“…6,7 In tumors, a range of DLL3 functions have been described (Figure 2). DLL3 is not expressed on the surface of normal cells, but is highly expressed on the surface of tumor cells, particularly those with histopathologic features of neuro-or neuro-endocrine origin, including IDH wild-type and mutant gliomas, 55,56 neuroendocrine lung cancer, 28 neuroendocrine prostate cancer (NEPC), 111 gastrointestinal neuroendocrine cancer (GI-NEC) 112 and small cell bladder cancer (SCBC). 113 DLL3 is upregulated at the transcriptional level in neuroendocrine tumors by the ASCL1 oncogenic driver, and is predominantly expressed in metastatic and aggressive disease phenotypes.…”

Section: Dll3mentioning

confidence: 99%

“…56 In GI-NEC, SCLC and SCBC, DLL3 shows a cytoplasmic distribution in tumor cells (reported as Golgi apparatus-localized in a single SCLC study 114 ) but how this influences Notch signaling is unknown. 27,28,112,113,[115][116][117] In LLC cells, DLL3 localizes to the cell nuclei, inhibiting Notch signaling at the transcriptional level. Akt signaling is activated by DLL3, which promotes LLC cell survival and reduces cell apoptosis.…”

Section: Dll3mentioning

confidence: 99%

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

Xiu

Liu

Kuang

2020

OTT

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Delta-like ligands (DLLs) control Notch signaling. DLL1, DLL3 and DLL4 are frequently deregulated in cancer and influence tumor growth, the tumor vasculature and tumor immunity, which play different roles in cancer progression. DLLs have attracted intense research interest as anti-cancer therapeutics. In this review, we discuss the role of DLLs in cancer and summarize the emerging DLL-relevant targeting methods to aid future studies.

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“…. Detailed protocol information is described in our previous reports (26,27). Anti-phospho-histone H2A.X (Ser139) antibody (EMD Millipore) was used.…”

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

“…Western blot analysis. Detailed protocol information is described in our previous reports (26)(27)(28). The primary antibodies used were as follows: anti-phospho-histone H2A.X (Merck Millipore; 1:1,000) and anti-β-actin (Cell Signaling Technology, Inc.; 1:1,000).…”

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

γ‑H2AX as a potential indicator of radiosensitivity in colorectal cancer cells

et al. 2020

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Preoperative radiotherapy improves local disease control and disease-free survival in patients with advanced rectal cancer; however, a reliable predictive biomarker for the effectiveness of irradiation has yet to be elucidated. Phosphorylation of H2A histone family member X (H2AX) to γ-H2AX is induced by DNA double-strand breaks and is associated with the development of colorectal cancer (CRC). The current study aimed to clarify the relationship between γ-H2AX expression and CRC radiosensitivity in vitro and in vivo. H2AX levels were analyzed in datasets obtained from cohort studies and γ-H2AX expression was investigated by performing immunohistochemistry and western blotting using clinical CRC samples from patients without any preoperative therapy. In addition, the CRC cell lines WiDr and DLD-1 were subjected to irradiation and/or small interfering RNA-H2AX, after which the protein levels of γ-H2AX were examined in samples obtained from patients undergoing preoperative chemoradiotherapy. To quantify the observable effect of treatment on cancer cells, outcomes were graded as follows: 1, mild; 2, moderate; and 3, marked, with defined signatures of cellular response. Datasets obtained from cohort studies demonstrated that H2AX mRNA levels were significantly upregulated and associated with distal metastasis and microsatellite instability in CRC tissues, in contrast to that of normal tissues. In addition, γ-H2AX was overexpressed in clinical samples. In vitro, following irradiation, γ-H2AX expression levels increased and cell viability decreased in a time-dependent manner. Combined irradiation and γ-H2AX knockdown reduced the viability of each cell line when compared with irradiation or γ-H2AX knockdown alone. Furthermore, among clinical CRC samples from patients undergoing preoperative chemoradiotherapy, levels of γ-H2AX in the grade 1 group were significantly higher than those in grade 2 or grade 3. In conclusion, γ-H2AX may serve as a novel predictive marker and target for preoperative radiotherapy effectiveness in patients with CRC.

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Delta‐like 3 localizes to neuroendocrine cells and plays a pivotal role in gastrointestinal neuroendocrine malignancy

Cited by 20 publications

References 25 publications

A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer

A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

γ‑H2AX as a potential indicator of radiosensitivity in colorectal cancer cells

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