Neuroendocrine tumors: current therapies, notch signaling, and cancer stem cells

Crabtree, Judy S.; Miele, Lucio

doi:10.20517/2394-4722.2016.30

Cited by 5 publications

(2 citation statements)

References 167 publications

(224 reference statements)

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“…Large cell neuroendocrine carcinoma organoids produced a peripheral palisading pattern displayed in large cell neuroendocrine carcinoma tissues and maintained the expression of CK7 34 and a stem cell marker CD133 35,36 , but failed to recapitulate expression of neuroendocrine marker CD56 34 and syneptophysin in our culture condition. Small cell lung carcinoma organoids displayed typical small cell morphology of densely packed small round tumour cells with scanty cytoplasm and granular nuclei 28 , and diagnostic markers of small cell carcinoma seen in the corresponding cancer tissues, such as CD56 37 , synaptophysin 37 , and TTF-1 expression 28 (Fig.…”

Section: Resultsmentioning

confidence: 79%

Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening

et al. 2019

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Lung cancer shows substantial genetic and phenotypic heterogeneity across individuals, driving a need for personalised medicine. Here, we report lung cancer organoids and normal bronchial organoids established from patient tissues comprising five histological subtypes of lung cancer and non-neoplastic bronchial mucosa as in vitro models representing individual patient. The lung cancer organoids recapitulate the tissue architecture of the primary lung tumours and maintain the genomic alterations of the original tumours during long-term expansion in vitro. The normal bronchial organoids maintain cellular components of normal bronchial mucosa. Lung cancer organoids respond to drugs based on their genomic alterations: a BRCA2-mutant organoid to olaparib, an EGFR-mutant organoid to erlotinib, and an EGFR-mutant/MET-amplified organoid to crizotinib. Considering the short length of time from organoid establishment to drug testing, our newly developed model may prove useful for predicting patient-specific drug responses through in vitro patient-specific drug trials.

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Section: Resultsmentioning

confidence: 79%

Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening

et al. 2019

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“…We modeled the efficacy of a potent and selective covalent‐binding small molecule inhibitor of LSD1 (ORY‐1001) in small‐cell lung cancer (SCLC). LSD1 (also known as KDM1A) is a lysine‐specific histone demethylase enzyme whose epigenetic function is associated with promoting a neuroendocrine phenotype, a quality of certain stem cell populations, which is known to be pro‐proliferation, prosurvival, and prometastatic . Furthermore, LSD1 is overexpressed in many cancers and is associated with poor prognosis .…”

Section: Experimental Data Used For Model Trainingmentioning

confidence: 99%

Predicting In Vivo Efficacy from In Vitro Data: Quantitative Systems Pharmacology Modeling for an Epigenetic Modifier Drug in Cancer

Bouhaddou

Lunardi

et al. 2020

Clinical Translational Sci

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Reliably predicting in vivo efficacy from in vitro data would facilitate drug development by reducing animal usage and guiding drug dosing in human clinical trials. However, such prediction remains challenging. Here, we built a quantitative pharmacokinetic/pharmacodynamic (PK/PD) mathematical model capable of predicting in vivo efficacy in animal xenograft models of tumor growth while trained almost exclusively on in vitro cell culture data sets. We studied a chemical inhibitor of LSD1 (ORY‐1001), a lysine‐specific histone demethylase enzyme with epigenetic function, and drug‐induced regulation of target engagement, biomarker levels, and tumor cell growth across multiple doses administered in a pulsed and continuous fashion. A PK model of unbound plasma drug concentration was linked to the in vitro PD model, which enabled the prediction of in vivo tumor growth dynamics across a range of drug doses and regimens. Remarkably, only a change in a single parameter—the one controlling intrinsic cell/tumor growth in the absence of drug—was needed to scale the PD model from the in vitro to in vivo setting. These findings create a framework for using in vitro data to predict in vivo drug efficacy with clear benefits to reducing animal usage while enabling the collection of dense time course and dose response data in a highly controlled in vitro environment.

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DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms

et al. 2022

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Introduction Neuroendocrine neoplasms (NEN) are heterogeneous malignancies that can arise at almost any anatomical site and are classified as biologically distinct well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Current systemic therapies for advanced disease, including targeted therapies, chemotherapy, and immunotherapy, are associated with limited duration of response. New therapeutic targets are needed. One promising target is delta-like ligand 3 (DLL3), an inhibitory ligand of the Notch receptor whose overexpression on the surface of NEN is associated with tumorigenesis. Methods This article is a narrative review that highlights the role of DLL3 in NEN progression and prognosis, the potential for therapeutic targeting of DLL3, and ongoing studies of DLL3-targeting therapies. Classification, incidence, pathogenesis, and current management of NEN are reviewed to provide biological context and illustrate the unmet clinical needs. Discussion DLL3 is overexpressed in many NENs, implicated in tumor progression, and is typically associated with poor clinical outcomes, particularly in patients with NEC. Targeted therapies using DLL3 as a homing beacon for cytotoxic activity mediated via several different mechanisms (eg, antibody-drug conjugates, T-cell engager molecules, CAR-Ts) have shown promising clinical activity in small-cell lung cancer (SCLC). DLL3 may be a clinically actionable target across NEN. Conclusions Current treatment options for NEN do not provide sustained responses. DLL3 is expressed on the cell surface of many NEN types and is associated with poor clinical outcomes. Initial clinical studies targeting DLL3 therapeutically in SCLC have been promising, and additional studies are expanding this approach to the broader group of NEN.

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Neuroendocrine tumors: current therapies, notch signaling, and cancer stem cells

Cited by 5 publications

References 167 publications

Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening

Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening

Predicting In Vivo Efficacy from In Vitro Data: Quantitative Systems Pharmacology Modeling for an Epigenetic Modifier Drug in Cancer

DLL3 as an Emerging Target for the Treatment of Neuroendocrine Neoplasms

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