Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer

Puca, Loredana; Gavyert, Katie; Sailer, Verena; Conteduca, Vincenza; Dardenne, Étienne; Sigouros, Michael; Isse, Kumiko; Kearney, Megan; Vosoughi, Aram; Fernandez, Luisa; Pan, Heng; Motanagh, Samaneh; Hess, Judy; Donoghue, Adam; Sboner, Andrea; Wang, Yuzhuo; Dittamore, Ryan; Rickman, David S.; Nanus, David M.; Tagawa, Scott T.; Elemento, Olivier; Mosquera, Juan Miguel; Saunders, Laura R.; Beltran, Himisha

doi:10.1126/scitranslmed.aav0891

Cited by 133 publications

(121 citation statements)

References 45 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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“…Currently, all human PCa organoids are derived from patients with advanced metastatic antiandrogen resistant PCa; hence, most of these lines are anti-androgen resistant and suitable for identifying new treatments. As proof-of-concept, delta-like 3 (DLL3) has been identified as a therapeutic target using patient-derived NEPC organoids that are targetable with rovalpituzumab tesirine 13 . This method is suitable for these types of experiments and is also suitable for prostate organoids from normal benign tissue, primary prostate cancer, and CTCs.…”

Section: Discussionmentioning

confidence: 99%

Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses

Pappas

Choi

Sawyers

et al. 2019

JoVE

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Presented here is a protocol to study pharmacodynamics, stem cell potential, and cancer differentiation in prostate epithelial organoids. Prostate organoids are androgen responsive, threedimensional (3D) cultures grown in a defined medium that resembles the prostatic epithelium. Prostate organoids can be established from wild-type and genetically engineered mouse models, benign human tissue, and advanced prostate cancer. Importantly, patient derived organoids closely resemble tumors in genetics and in vivo tumor biology. Moreover, organoids can be genetically manipulated using CRISPR/Cas9 and shRNA systems. These controlled genetics make the organoid culture attractive as a platform for rapidly testing the effects of genotypes and mutational profiles on pharmacological responses. However, experimental protocols must be specifically adapted to the 3D nature of organoid cultures to obtain reproducible results. Described here are detailed protocols for performing seeding assays to determine organoid formation capacity. Subsequently, this report shows how to perform drug treatments and analyze pharmacological response via viability measurements, protein isolation, and RNA isolation. Finally, the protocol describes how to prepare organoids for xenografting and subsequent in vivo growth assays using subcutaneous grafting. These protocols yield highly reproducible data and are widely applicable to 3D culture systems.

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“…NcT03392064) are also in progress. compared with dLL4 and NOTcH3, dLL3 is an ideal target for Adcs, bsAbs and cAR-Ts, because dLL3 is upregulated in ScLc and other neuroendocrine tumors, repressing Notch signaling and reciprocally upregulating REST to maintain the neuroendocrine phenotype (41,170,180).…”

Section: Therapeutics Targeting Notch Signaling Cascadesmentioning

confidence: 99%

Precision medicine for human cancers with Notch signaling dysregulation (Review)

Katoh¹,

2019

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NOTcH1, NOTcH2, NOTcH3 and NOTcH4 are transmembrane receptors that transduce juxtacrine signals of the delta-like canonical Notch ligand (dLL)1, dLL3, dLL4, jagged canonical Notch ligand (JAG)1 and JAG2. canonical Notch signaling activates the transcription of BMI1 proto-oncogene polycomb ring finger, cyclin D1, CD44, cyclin dependent kinase inhibitor 1A, hes family bHLH transcription factor 1, hes related family bHLH transcription factor with YRPW motif 1, MYC, NOTCH3, RE1 silencing transcription factor and transcription factor 7 in a cellular context-dependent manner, while non-canonical Notch signaling activates NF-κB and Rac family small GTPase 1. Notch signaling is aberrantly activated in breast cancer, non-small-cell lung cancer and hematological malignancies, such as T-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, Notch signaling is inactivated in small-cell lung cancer and squamous cell carcinomas. Loss-of-function NOTCH1 mutations are early events during esophageal tumorigenesis, whereas gain-of-function NOTCH1 mutations are late events during T-cell leukemogenesis and B-cell lymphomagenesis. Notch signaling cascades crosstalk with fibroblast growth factor and WNT signaling cascades in the tumor microenvironment to maintain cancer stem cells and remodel the tumor microenvironment. The Notch signaling network exerts oncogenic and tumor-suppressive effects in a cancer stage-or (sub)type-dependent manner. Small-molecule γ-secretase inhibitors (AL101, MRK-560, nirogacestat and others) and antibody-based biologics targeting Notch ligands or receptors [ABT-165, AMG 119, rovalpituzumab tesirine (Rova-T) and others] have been developed as investigational drugs. The dLL3-targeting antibody-drug conjugate (Adc) Rova-T, and dLL3-targeting chimeric antigen receptor-modified T cells (CAR-Ts), AMG 119, are promising anti-cancer therapeutics, as are other Adcs or cARTs targeting tumor necrosis factor receptor superfamily member 17, cd19, cd22, cd30, cd79B, cd205, claudin 18.2, fibroblast growth factor receptor (FGFR)2, FGFR3, receptor-type tyrosine-protein kinase FLT3, HER2, hepatocyte growth factor receptor, NEcTIN4, inactive tyrosine-protein kinase 7, inactive tyrosine-protein kinase transmembrane receptor ROR1 and tumor-associated calcium signal transducer 2. Adcs and cARTs could alter the therapeutic framework for refractory cancers, especially diffuse-type gastric cancer, ovarian cancer and pancreatic cancer with peritoneal dissemination. Phase III clinical trials of Rova-T for patients with small-cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch-related knowledge-base and optimize Notch-targeted therapy for patients with cancer.

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Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer

Cited by 133 publications

References 45 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

Prostate Organoid Cultures as Tools to Translate Genotypes and Mutational Profiles to Pharmacological Responses

Precision medicine for human cancers with Notch signaling dysregulation (Review)

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