Small-Cell Lung Cancer: An Update on Targeted Therapies

Joshi, Monika; Ayoola, Ayodele; Belani, Chandra P.

doi:10.1007/978-1-4614-6176-0_18

Cited by 39 publications

(36 citation statements)

References 67 publications

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“…The observed durable responses after SC16LD6.5 exposure are consistent with the effective targeting of TICs, in contrast with the SOC C/E, which neither affected the frequency of TICs nor provided durable responses. We hypothesize that the frequent and rapid relapse observed clinically among SCLC patients despite strong initial debulking responses to C/E is consistent with the inability of SOC to affect TIC frequency (4). …”

Section: Discussionmentioning

confidence: 61%

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A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo

et al. 2015

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The high-grade pulmonary neuroendocrine tumors, small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), remain among the most deadly malignancies. Therapies that effectively target and kill tumor-initiating cells (TICs) in these cancers should translate to improved patient survival. Patient-derived xenograft (PDX) tumors serve as excellent models to study tumor biology and characterize TICs. Increased expression of delta-like 3 (DLL3) was discovered in SCLC and LCNEC PDX tumors and confirmed in primary SCLC and LCNEC tumors. DLL3 protein is expressed on the surface of tumor cells but not in normal adult tissues. A DLL3-targeted antibody-drug conjugate (ADC), SC16LD6.5, comprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin, induced durable tumor regression in vivo across multiple PDX models. Serial transplantation experiments executed with limiting dilutions of cells provided functional evidence confirming that the lack of tumor recurrence after SC16LD6.5 exposure resulted from effective targeting of DLL3-expressing TICs. In vivo efficacy correlated with DLL3 expression, and responses were observed in PDX models initiated from patients with both limited and extensive-stage disease and were independent of their sensitivity to standard-of-care chemotherapy regimens. SC16LD6.5 effectively targets and eradicates DLL3-expressing TICs in SCLC and LCNEC PDX tumors and is a promising first-in-class ADC for the treatment of high-grade pulmonary neuroendocrine tumors.

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Section: Discussionmentioning

confidence: 61%

“…Both SCLC and LCNEC remain among the most deadly malignancies because no new therapeutic options have emerged for these indications in more than 30 years (3, 4). SCLC survival is measured in months, with a 5-year survival rate <5%.…”

Section: Introductionmentioning

confidence: 99%

A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo

et al. 2015

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“…11, 12 However, despite several clinical trials, effective targeted therapies for SCLC are not currently available. 13 Because curative intent resections are seldom performed for SCLC, there is a paucity of tumor materials for the performance of translational research. Biological and preclinical studies of SCLC largely depend on the availability of modest sized banks of human cell lines.…”

Section: Introductionmentioning

confidence: 99%

The Comparative Pathology of Genetically Engineered Mouse Models for Neuroendocrine Carcinomas of the Lung

Gazdar

Savage

Johnson

et al. 2015

Journal of Thoracic Oncology

105

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Introduction Because small cell lung carcinomas (SCLC) are seldom resected, human materials for study are limited. Thus, genetically engineered mouse models (GEMMs) for SCLC and other high-grade lung neuroendocrine (NE) carcinomas are crucial for translational research. Methods The pathologies of five GEMMs were studied in detail and consensus diagnoses reached by four lung cancer pathology experts. Hematoxylin and Eosin and immunostained slides of over 100 mice were obtained from the originating and other laboratories and digitalized. The GEMMs included the original Rb/p53 double knockout (Berns laboratory) and triple knockouts from the Sage, MacPherson and Jacks laboratories (double knockout model plus loss of p130 (Sage laboratory) or loss of Pten (MacPherson and Jacks laboratories). In addition, a GEMM with constitutive co-expression of SV40 large T antigen (Tag) and Ascl1 under the Scgb1a1 promoter from the Linnoila laboratory was included. Results The lung tumors in all of the models had common as well as distinct pathological features. All three conditional knockout models resulted in multiple pulmonary tumors arising mainly from the central compartment (large bronchi) with foci of in situ carcinoma and NE cell hyperplasia. They consisted of inter- and intra-tumor mixtures of SCLC and large cell NE cell carcinoma (LCNEC) in varying proportions. Occasional adeno- or large cell carcinomas were also seen. Extensive vascular and lymphatic invasion and metastases to the mediastinum and liver were noted, mainly of SCLC histology. In the Rb/p53/Pten triple knockout model from the MacPherson and Jacks laboratories and in the constitutive SV40/Tag model many peripherally arising NSCLC tumors having varying degrees of NE marker expression were present (NSCLC-NE tumors). The resultant histological phenotypes were influenced by the introduction of specific genetic alterations, by inactivation of one or both alleles of specific genes, by time from Cre activation and by targeting of lung cells or NE cell subpopulations. Conclusion The five GEMM models studied are representative for the entire spectrum of human high-grade NE carcinomas and are also useful for the study of multistage pathogenesis and the metastatic properties of these tumors. They represent one of the most advanced forms of currently available GEMM models for the study of human cancer.

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“…It spreads on visceral pleura and chest wall. Typically LCNECs do not produce clinical symptoms of hormone excess [65][66][67][68][69][70].…”

Section: Reviewmentioning

confidence: 99%

Neuroendocrine neoplasms and somatostatin receptor subtypes expression

Hankus

Tomaszewska

2016

Nucl. Med. Rev.

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Neuroendocrine neoplasms (NENs) show wide spectrum of clinical course -from benign biological potential to recurrences and rapidly progressive disease. Somatostatin analogs that bind to somatostatin receptor are part of the therapy; detection and evaluation of activation of somatostatin receptor subtypes are part of the process of new therapy induction. When using RT-PCR method and immunohistochemistry, it is possible to detect more than two SSTR subtypes in majority or all neuroendocrine neoplasms regardless tumor origin. Generally with some exceptions, from the viewpoint of tumor grade -apart the site of origin, there is a tendency to decrease the percentage of SSTRs expression; 100% (G1, 2)-85.7% (G3) for SSTR 1; 81.8% (G1, 2)-61.9% (G3) for SSTR 2; 54.5% (G1, 2)-52.4% (G3) for SSTR 3; 9% (G1, 2)-4.8% (G3) for SSTR 5. Different studies indicate significant differences in the expression of SSTR 1 and 2A and 2B between NEC G3 small cell type and non-small cell type.Further research on SSTRs expression in NEN could serve as base to development and improvement of somatostatin analogs' pharmacotherapy in patients with unsatisfactory course.

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Small-Cell Lung Cancer: An Update on Targeted Therapies

Cited by 39 publications

References 67 publications

A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo

A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo

The Comparative Pathology of Genetically Engineered Mouse Models for Neuroendocrine Carcinomas of the Lung

Neuroendocrine neoplasms and somatostatin receptor subtypes expression

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