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Kenro Kusumi - One of the best experts on this subject based on the ideXlab platform.
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cyclical expression of the notch wnt regulator nrarp requires modulation by DLL3 in somitogenesis
Developmental Biology, 2009Co-Authors: William F. Sewell, Duncan B. Sparrow, Sally L. Dunwoodie, Dorian M. Gonzalez, Eric F. Rappaport, Kenro Kusumi, Allanceson SmithAbstract:Abstract Delta-like 3 (DLL3) is a divergent ligand and modulator of the Notch signaling pathway only identified so far in mammals. Null mutations of DLL3 disrupt cycling expression of Notch targets Hes1, Hes5, and Lfng, but not of Hes7. Compared with Dll1 or Notch1, the effects of DLL3 mutations are less severe for gene expression in the presomitic mesoderm, yet severe segmentation phenotypes and vertebral defects result in both human and mouse. Reasoning that DLL3 specifically disrupts key regulators of somite cycling, we carried out functional analysis to identify targets accounting for the segmental phenotype. Using microdissected embryonic tissue from somitic and presomitic mesodermal tissue, we identified new genes enriched in these tissues, including Limch1, Rhpn2, and A130022J15Rik. Surprisingly, we only identified a small number of genes disrupted by the DLL3 mutation. These include Uncx, a somite gene required for rib and vertebral patterning, and Nrarp, a regulator of Notch/Wnt signaling in zebrafish and a cycling gene in mouse. To determine the effects of DLL3 mutation on Nrarp, we characterized the cycling expression of this gene from early (8.5 dpc) to late (10.5 dpc) somitogenesis. Nrarp displays a distinct pattern of cycling phases when compared to Lfng and Axin2 (a Wnt pathway gene) at 9.5 dpc but appears to be in phase with Lfng by 10.5 dpc. Nrarp cycling appears to require DLL3 but not Lfng modulation. In DLL3 null embryos, Nrarp displayed static patterns. However, in Lfng null embryos, Nrarp appeared static at 8.5 dpc but resumed cycling expression by 9.5 and dynamic expression at 10.5 dpc stages. By contrast, in Wnt3a null embryos, Nrarp expression was completely absent in the presomitic mesoderm. Towards identifying the role of DLL3 in regulating somitogenesis, Nrarp emerges as a potentially important regulator that requires DLL3 but not Lfng for normal function.
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Cyclical expression of the Notch/Wnt regulator Nrarp requires modulation by DLL3 in somitogenesis
Developmental Biology, 2009Co-Authors: William F. Sewell, Duncan B. Sparrow, Sally L. Dunwoodie, Allanceson J. Smith, Dorian M. Gonzalez, Eric F. Rappaport, Kenro KusumiAbstract:Abstract Delta-like 3 (DLL3) is a divergent ligand and modulator of the Notch signaling pathway only identified so far in mammals. Null mutations of DLL3 disrupt cycling expression of Notch targets Hes1, Hes5, and Lfng, but not of Hes7. Compared with Dll1 or Notch1, the effects of DLL3 mutations are less severe for gene expression in the presomitic mesoderm, yet severe segmentation phenotypes and vertebral defects result in both human and mouse. Reasoning that DLL3 specifically disrupts key regulators of somite cycling, we carried out functional analysis to identify targets accounting for the segmental phenotype. Using microdissected embryonic tissue from somitic and presomitic mesodermal tissue, we identified new genes enriched in these tissues, including Limch1, Rhpn2, and A130022J15Rik. Surprisingly, we only identified a small number of genes disrupted by the DLL3 mutation. These include Uncx, a somite gene required for rib and vertebral patterning, and Nrarp, a regulator of Notch/Wnt signaling in zebrafish and a cycling gene in mouse. To determine the effects of DLL3 mutation on Nrarp, we characterized the cycling expression of this gene from early (8.5 dpc) to late (10.5 dpc) somitogenesis. Nrarp displays a distinct pattern of cycling phases when compared to Lfng and Axin2 (a Wnt pathway gene) at 9.5 dpc but appears to be in phase with Lfng by 10.5 dpc. Nrarp cycling appears to require DLL3 but not Lfng modulation. In DLL3 null embryos, Nrarp displayed static patterns. However, in Lfng null embryos, Nrarp appeared static at 8.5 dpc but resumed cycling expression by 9.5 and dynamic expression at 10.5 dpc stages. By contrast, in Wnt3a null embryos, Nrarp expression was completely absent in the presomitic mesoderm. Towards identifying the role of DLL3 in regulating somitogenesis, Nrarp emerges as a potentially important regulator that requires DLL3 but not Lfng for normal function.
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Molecular analysis of congenital scoliosis: a candidate gene approach.
Human Genetics, 2005Co-Authors: Melissa K. Maisenbacher, Megan L. O'brien, Ji Soo Han, Michael R. Tracy, Erol B, Alyssa A. Schaffer, John P. Dormans, Elaine H. Zackai, Kenro KusumiAbstract:The etiology of congenital scoliosis is largely unknown. The severe vertebral disorder, spondylocostal dysostosis type 1, is associated with a homozygous delta-like 3 (DLL3) mutation. Scoliosis has been observed in a heterozygous DLL3 carrier, raising the possibility of its involvement in congenital scoliosis. We present the first molecular study of congenital scoliosis by analysis of the candidate gene DLL3 and demonstrate one novel missense variant. However, no novel or previously described mutations are present in our cohort, indicating that DLL3 mutations may not be a major cause of congenital scoliosis. Additionally, we have evaluated patients with congenital scoliosis not diagnosed with a known syndrome and identified a significant number of associated renal and cardiac anomalies and familial incidence of idiopathic scoliosis in this group.
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Gene expression pattern Dynamic expression patterns of the pudgy/spondylocostal dysostosis gene DLL3 in the developing nervous system
2001Co-Authors: Kenro Kusumi, Sally L. Dunwoodie, Robb KrumlaufAbstract:AbstractDefects in the Notch pathway ligand DLL3 have been identified in the mouse pudgy (DLL3 pu ) and human spondylocostal dysostosis (SD,MIM 277300) mutations. Although these mutations are primarily associated with segmental defects in the axial skeleton and somiticpatterning, they also exhibit cranial neurological defects. Therefore we have looked at the expression of DLL3 in the developing mousenervous system. The expression of Notch ligands and receptors shares common features at 10.75 dpc in the rhombic lips and dorsal hindbrain.Temporal analysis of DLL3 expression from 9.0 to 11.0 dpc reveals that it is strongly expressed in laminar columns linked with regions ofneuronal differentiation and hindbrain segmentation. Transverse sections show that DLL3 is expressed in territories where commissuralneurons are formed. We have also looked at neuronal patterning in the mid-hindbrain region in DLL3 pu mutants. q 2001 Elsevier ScienceIreland Ltd. All rights reserved. Keywords: Notch signaling; DLL3; Pudgy; Spondylocostal dysostosis; Neural patterning; Mouse mutant; Neurogenesis; Hindbrain
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Dynamic expression patterns of the pudgy/spondylocostal dysostosis gene DLL3 in the developing nervous system.
Mechanisms of Development, 2001Co-Authors: Kenro Kusumi, Sally L. Dunwoodie, Robb KrumlaufAbstract:Abstract Defects in the Notch pathway ligand DLL3 have been identified in the mouse pudgy (DLL3pu) and human spondylocostal dysostosis (SD, MIM 277300) mutations. Although these mutations are primarily associated with segmental defects in the axial skeleton and somitic patterning, they also exhibit cranial neurological defects. Therefore we have looked at the expression of DLL3 in the developing mouse nervous system. The expression of Notch ligands and receptors shares common features at 10.75 dpc in the rhombic lips and dorsal hindbrain. Temporal analysis of DLL3 expression from 9.0 to 11.0 dpc reveals that it is strongly expressed in laminar columns linked with regions of neuronal differentiation and hindbrain segmentation. Transverse sections show that DLL3 is expressed in territories where commissural neurons are formed. We have also looked at neuronal patterning in the mid-hindbrain region in DLL3pu mutants.
Sally L. Dunwoodie - One of the best experts on this subject based on the ideXlab platform.
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A cell autonomous role for the Notch ligand Delta-like 3 in αβ T-cell development.
Immunology & Cell Biology, 2010Co-Authors: Gerard F. Hoyne, Gavin Chapman, Yovina Sontani, S.e. Pursglove, Sally L. DunwoodieAbstract:Notch signalling is critical to help direct T-cell lineage commitment in early T-cell progenitors and in the development of ab T-cells. Epithelial and stromal cell populations in the thymus express the Notch DSL (Delta, Serrate and Lag2)ligands Delta-like 1 (Dll1), Delta-like 4 (Dll4), Jagged 1 and Jagged 2, and induce Notch signalling in thymocytes that express the Notch receptor. At present there is nothing known about the role of the Delta-like 3 (DLL3) ligand in the immune system. Here we describe a novel cell autonomous role for DLL3 in ab T-cell development. We show that DLL3 cannot activate Notch when expressed in trans but like other Notch ligands it can inhibit Notch signalling when expressed in cis with the receptor. The loss of DLL3 leads to an increase in Hes5 expression in double positive thymocytes and their increased production of mature CD4 + and CD8 + T cells. Studies using competitive irradiation chimeras proved that DLL3 acts in a cell autonomous manner to regulate positive selection but not negative selection of autoreactive T cells. Our results indicate that DLL3 has a unique function during T-cell development that is distinct from the role played by the other DSL ligands of Notch and is in keeping with other recent studies indicating that Dll1 and DLL3 ligands have non-overlapping roles during embryonic development. Immunology and Cell Biology advance online publication, 14 December 2010; doi:10.1038/icb.2010.154
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Notch inhibition by the ligand Delta-Like 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis
Human Molecular Genetics, 2010Co-Authors: Gavin Chapman, Elisabeth Kremmer, Duncan B. Sparrow, Sally L. DunwoodieAbstract:Mutations in the DELTA-LIKE 3 (DLL3) gene cause the congenital abnormal vertebral segmentation syndrome, spondylocostal dysostosis (SCD). DLL3 is a divergent member of the DSL family of Notch ligands that does not activate signalling in adjacent cells, but instead inhibits signalling when expressed in the same cell as the Notch receptor. Targeted deletion of DLL3 in the mouse causes a developmental defect in somite segmentation, and consequently vertebral formation is severely disrupted, closely resembling human SCD. In contrast to the canonical Notch signalling pathway, very little is known about the mechanism of cis-inhibition by DSL ligands. Here, we report that DLL3 is not presented on the surface of presomitic mesoderm (PSM) cells in vivo, but instead interacts with Notch1 in the late endocytic compartment. This suggests for the first time a mechanism for DLL3-mediated cis-inhibition of Notch signalling, with DLL3 targeting newly synthesized Notch1 for lysosomal degradation prior to post-translational processing and cell surface presentation of the receptor. An inhibitory role for DLL3 in vivo is further supported by the juxtaposition of DLL3 protein and Notch1 signalling in the PSM. Defining a mechanism for cis-inhibition of Notch signalling by DLL3 not only contributes greatly to our understanding of this ligand's function during the formation of the vertebral column, but also provides a paradigm for understanding how other ligands of Notch cis-inhibit signalling.
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cyclical expression of the notch wnt regulator nrarp requires modulation by DLL3 in somitogenesis
Developmental Biology, 2009Co-Authors: William F. Sewell, Duncan B. Sparrow, Sally L. Dunwoodie, Dorian M. Gonzalez, Eric F. Rappaport, Kenro Kusumi, Allanceson SmithAbstract:Abstract Delta-like 3 (DLL3) is a divergent ligand and modulator of the Notch signaling pathway only identified so far in mammals. Null mutations of DLL3 disrupt cycling expression of Notch targets Hes1, Hes5, and Lfng, but not of Hes7. Compared with Dll1 or Notch1, the effects of DLL3 mutations are less severe for gene expression in the presomitic mesoderm, yet severe segmentation phenotypes and vertebral defects result in both human and mouse. Reasoning that DLL3 specifically disrupts key regulators of somite cycling, we carried out functional analysis to identify targets accounting for the segmental phenotype. Using microdissected embryonic tissue from somitic and presomitic mesodermal tissue, we identified new genes enriched in these tissues, including Limch1, Rhpn2, and A130022J15Rik. Surprisingly, we only identified a small number of genes disrupted by the DLL3 mutation. These include Uncx, a somite gene required for rib and vertebral patterning, and Nrarp, a regulator of Notch/Wnt signaling in zebrafish and a cycling gene in mouse. To determine the effects of DLL3 mutation on Nrarp, we characterized the cycling expression of this gene from early (8.5 dpc) to late (10.5 dpc) somitogenesis. Nrarp displays a distinct pattern of cycling phases when compared to Lfng and Axin2 (a Wnt pathway gene) at 9.5 dpc but appears to be in phase with Lfng by 10.5 dpc. Nrarp cycling appears to require DLL3 but not Lfng modulation. In DLL3 null embryos, Nrarp displayed static patterns. However, in Lfng null embryos, Nrarp appeared static at 8.5 dpc but resumed cycling expression by 9.5 and dynamic expression at 10.5 dpc stages. By contrast, in Wnt3a null embryos, Nrarp expression was completely absent in the presomitic mesoderm. Towards identifying the role of DLL3 in regulating somitogenesis, Nrarp emerges as a potentially important regulator that requires DLL3 but not Lfng for normal function.
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Cyclical expression of the Notch/Wnt regulator Nrarp requires modulation by DLL3 in somitogenesis
Developmental Biology, 2009Co-Authors: William F. Sewell, Duncan B. Sparrow, Sally L. Dunwoodie, Allanceson J. Smith, Dorian M. Gonzalez, Eric F. Rappaport, Kenro KusumiAbstract:Abstract Delta-like 3 (DLL3) is a divergent ligand and modulator of the Notch signaling pathway only identified so far in mammals. Null mutations of DLL3 disrupt cycling expression of Notch targets Hes1, Hes5, and Lfng, but not of Hes7. Compared with Dll1 or Notch1, the effects of DLL3 mutations are less severe for gene expression in the presomitic mesoderm, yet severe segmentation phenotypes and vertebral defects result in both human and mouse. Reasoning that DLL3 specifically disrupts key regulators of somite cycling, we carried out functional analysis to identify targets accounting for the segmental phenotype. Using microdissected embryonic tissue from somitic and presomitic mesodermal tissue, we identified new genes enriched in these tissues, including Limch1, Rhpn2, and A130022J15Rik. Surprisingly, we only identified a small number of genes disrupted by the DLL3 mutation. These include Uncx, a somite gene required for rib and vertebral patterning, and Nrarp, a regulator of Notch/Wnt signaling in zebrafish and a cycling gene in mouse. To determine the effects of DLL3 mutation on Nrarp, we characterized the cycling expression of this gene from early (8.5 dpc) to late (10.5 dpc) somitogenesis. Nrarp displays a distinct pattern of cycling phases when compared to Lfng and Axin2 (a Wnt pathway gene) at 9.5 dpc but appears to be in phase with Lfng by 10.5 dpc. Nrarp cycling appears to require DLL3 but not Lfng modulation. In DLL3 null embryos, Nrarp displayed static patterns. However, in Lfng null embryos, Nrarp appeared static at 8.5 dpc but resumed cycling expression by 9.5 and dynamic expression at 10.5 dpc stages. By contrast, in Wnt3a null embryos, Nrarp expression was completely absent in the presomitic mesoderm. Towards identifying the role of DLL3 in regulating somitogenesis, Nrarp emerges as a potentially important regulator that requires DLL3 but not Lfng for normal function.
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Divergent functions and distinct localization of the Notch ligands DLL1 and DLL3 in vivo.
Journal of Cell Biology, 2007Co-Authors: Insa Geffers, Karin Schuster-gossler, Katrin Serth, Elisabeth Kremmer, Gavin Chapman, Robert Jaekel, Ralf Cordes, Duncan B. Sparrow, Sally L. Dunwoodie, Thomas KleinAbstract:The Notch ligands Dll1 and DLL3 are coexpressed in the presomitic mesoderm of mouse embryos. Despite their coexpression, mutations in Dll1 and DLL3 cause strikingly different defects. To determine if there is any functional equivalence, we replaced Dll1 with DLL3 in mice. DLL3 does not compensate for Dll1; DLL1 activates Notch in Drosophila wing discs, but DLL3 does not. We do not observe evidence for antagonism between DLL1 and DLL3, or repression of Notch activity in mice or Drosophila. In vitro analyses show that differences in various domains of DLL1 and DLL3 individually contribute to their biochemical nonequivalence. In contrast to endogenous DLL1 located on the surface of presomitic mesoderm cells, we find endogenous DLL3 predominantly in the Golgi apparatus. Our data demonstrate distinct in vivo functions for DLL1 and DLL3. They suggest that DLL3 does not antagonize DLL1 in the presomitic mesoderm and warrant further analyses of potential physiological functions of DLL3 in the Golgi network.
Kumiko Isse - One of the best experts on this subject based on the ideXlab platform.
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Delta-like Protein 3 Expression and Targeting in Merkel Cell Carcinoma.
The Oncologist, 2020Co-Authors: Hao Xie, Frederic J. Kaye, Kumiko Isse, Yan Sun, Johanna Ramoth, Dorothy French, Thomas J. Flotte, Yan Luo, Laura Saunders, Aaron S. MansfieldAbstract:Purpose Delta-like protein 3 (DLL3) is being developed as a predictive biomarker for DLL3-targeting antibody-drug conjugate and other therapies. Given the neuroendocrine features of Merkel cell carcinoma (MCC), we sought to evaluate DLL3 expression and its role in MCC. Experimental design Formalin-fixed and paraffin-embedded MCC cases were consecutively selected. Immunohistochemistry was performed for DLL3 (SC16.65 antibody) and polyomavirus large T-antigen (sc-136172 antibody). Slides were read out for percentage of positive tumor cells. Cox proportional hazards model was applied to assess the association between DLL3 expression and overall survival (OS). A patient with a DLL3-expressing MCC was treated with rovalpituzumab tesirine (Rova-T) in the "other tumor" cohort of NCT02709889 and assessed for response. Results The median H-score of DLL3 expression of 65 patients included was 60 (interquartile range, 30-100). Fifty-eight cases (89%) had ≥1% tumor cells positive for DLL3 expression with any intensity, of which the median DLL3 expression was 50% (interquartile range, 25%-70%). Thirty-four cases (52%) had ≥50% tumor cells positive for DLL3 expression with any intensity. Higher H-score of DLL3 expression was associated with higher polyomavirus nuclear expression (p = .003) when it was dichotomized to negative versus positive. H-score of DLL3 expression did not predict OS of patients with MCC (p = .4) after being adjusted for common clinicopathological factors. A patient treated with Rova-T for refractory metastatic MCC achieved partial response. Conclusions DLL3 overexpression is very common in MCC by immunohistochemistry. The response to treatment suggests that DLL3 expression may have predictive relevance for DLL3-targeting therapies in MCC. Implications for practice Delta-like protein 3 (DLL3) is being developed as a predictive biomarker to identify patients for treatment with DLL3-targeting agents. Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. It was found that DLL3 overexpression is very common in MCC by immunohistochemistry and significantly associated with Merkel cell polyomavirus expression. Despite the lack of prognostic significance in this cohort, DLL3 expression may have predictive relevance for DLL3-targeting therapies in MCC. The high levels of DLL3 expression in a subset of MCC may potentially be used to select patients to receive DLL3-targeting therapies.
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delta like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer
Science Translational Medicine, 2019Co-Authors: Loredana Puca, Kumiko Isse, Verena Sailer, Katie Gavyert, Vincenza Conteduca, Etienne Dardenne, Michael Sigouros, Megan Kearney, Aram Vosoughi, Luisa FernandezAbstract:Histologic transformation to small cell neuroendocrine prostate cancer occurs in a subset of patients with advanced prostate cancer as a mechanism of treatment resistance. Rovalpituzumab tesirine (SC16LD6.5) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) and was initially developed for small cell lung cancer. We found that DLL3 is expressed in most of the castration-resistant neuroendocrine prostate cancer (CRPC-NE) (36 of 47, 76.6%) and in a subset of castration-resistant prostate adenocarcinomas (7 of 56, 12.5%). It shows minimal to no expression in localized prostate cancer (1 of 194) and benign prostate (0 of 103). DLL3 expression correlates with neuroendocrine marker expression, RB1 loss, and aggressive clinical features. DLL3 in circulating tumor cells was concordant with matched metastatic biopsy (87%). Treatment of DLL3-expressing prostate cancer xenografts with a single dose of SC16LD6.5 resulted in complete and durable responses, whereas DLL3-negative models were insensitive. We highlight a patient with neuroendocrine prostate cancer with a meaningful clinical and radiologic response to SC16LD6.5 when treated on a phase 1 trial. Overall, our findings indicate that DLL3 is preferentially expressed in CRPC-NE and provide rationale for targeting DLL3 in patients with DLL3-positive metastatic prostate cancer.
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Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target.
Clinical Cancer Research, 2018Co-Authors: Vadim S. Koshkin, Kumiko Isse, Laura R Saunders, Paul Elson, Cristina Magi-galluzzi, Jesse K. Mckenney, Jorge A. Garcia, Jordan P. Reynolds, Evan Bishop, Aysegul BalyimezAbstract:Purpose: Transcriptomic profiling can shed light on the biology of SCBC, nominating biomarkers and novel therapeutic targets. Experimental Design: Sixty-three SCBC patients had small cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody-drug conjugate (ADC). Results: Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most "normal-like" pattern of gene expression had longer OS compared to the other 3 clusters while patients with the most "metastasis-like" pattern had the shortest OS (p=0.047). Expression of DLL3, PDL1, ASCL1 and CD56 was confirmed by IHC in 68%, 30%, 52% and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on >10% and CD56 expression on >30% of tumor cells were both prognostic of shorter OS (p=0.03 each). A DLL3-targeting ADC showed durable anti-tumor efficacy in a SCBC PDX model. Conclusions: Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.
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Abstract 1947: Rovalpituzumab tesirine as a therapeutic agent for neuroendocrine prostate cancer
Experimental and Molecular Therapeutics, 2018Co-Authors: Loredana Puca, Kumiko Isse, Katie Gavyert, Etienne Dardenne, Michael Sigouros, Verena Sailor, David M. Nanus, Scott T. Tagawa, Juan Miguel Mosquera, Laura SaundersAbstract:Background: Delta-like protein 3 (DLL3) is expressed on the surface of small cell lung cancer (SCLC) tumor-initiating cells, and the DLL3 targeted antibody-drug conjugate, Rovalpituzumab tesirine (Rova-T™; SC16LD6.5), has shown promise for patients with SCLC. Neuroendocrine prostate cancer (NEPC) is an emerging late stage subtype of castration resistant prostate cancer with limited therapeutic options. Based on clinical and molecular similarities with SCLC, we investigated expression of DLL3 and the use of Rovalpituzumab tesirine in NEPC xenografts. Methods: We evaluated mRNA and/or protein expression of DLL3 in a cohort of 361 patients (552 samples) ranging from benign prostate (BEN), localized prostate adenocarcinoma (PCA), castration resistant adenocarcinoma (CRPC), and castration resistant NEPC and correlated with pathologic and genomic features. mRNA was assessed by RNAseq. Protein was assessed by immunohistochemistry (DLL3 SP347 antibody). Prostate cancer cell lines were engrafted in mice and treated with SC16LD6.5 in vivo. Results: DLL3 was expressed at the mRNA and/or protein level in 0/132 Benign (0%), 1/254 (0.4%) PCA, 10/90 (11.1%) CRPC and 47/76 (61.8%) NEPC samples. DLL3 IHC was of higher intensity in NEPC and co-localized with classical neuroendocrine (NE) markers. DLL3 was amongst the most differentially expressed genes by RNA-seq in NEPC versus CRPC (p= Conclusions: DLL3 is expressed on the surface of the majority of NEPC cases evaluated and is not expressed in primary prostate cancer or benign tissues. Modulation of DLL3 expression does not appear to affect AR or NEPC signaling in cell lines. SC16LD6.5 (Rova-T) demonstrates preferential preclinical activity in NEPC that express DLL3 compared to CRPC-adenocarcinoma that are DLL3 negative, in vivo. A Phase 1 Basket trial investigating Rova-T is now open with a dedicated NEPC arm (NCT02709889). Citation Format: Loredana Puca, Verena Sailor, Katie Gavyert, Etienne Dardenne, Kumiko Isse, Michael Sigouros, David M. Nanus, Scott T. Tagawa, Juan Miguel Mosquera, Laura Saunders, Himisha Beltran. Rovalpituzumab tesirine as a therapeutic agent for neuroendocrine prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1947.
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prevalence of delta like protein 3 expression in patients with small cell lung cancer
Lung Cancer, 2018Co-Authors: Kentaro Tanaka, Kumiko Isse, Tomomichi Fujihira, Mitsuhiro Takenoyama, Laura R Saunders, Sheila Bheddah, Yoichi Nakanishi, Isamu OkamotoAbstract:Abstract Objectives Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC) positive for this protein. However, the prevalence of DLL3 expression and its association with patient ethnicity and other characteristics have remained unclear. Materiais and methods Tumor samples from 63 patients with SCLC were subjected to immunohistochemical staining for DLL3. The relation of patient characteristics including sex, age, disease stage, and smoking history to DLL3 expression status was analyzed. Results and conlusions Fifty-two patients (83%) were positive for DLL3 expression, with 20 patients (32%) being positive in at least 50% of cancer cells (DLL3-high). DLL3 expression was not associated with any of the patient characteristics examined. In addition, overall survival did not differ between DLL3-high and DLL3-low patients. Our results reveal that DLL3 is expressed in tumor specimens from most patients with SCLC, and they should inform the undertaking of clinical trials of Rova-T including an ongoing phase I study (NCT03086239) in Japan as well as global phase III trials (NCT03061812 and NCT03033511).
Laura R Saunders - One of the best experts on this subject based on the ideXlab platform.
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Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target.
Clinical Cancer Research, 2018Co-Authors: Vadim S. Koshkin, Kumiko Isse, Laura R Saunders, Paul Elson, Cristina Magi-galluzzi, Jesse K. Mckenney, Jorge A. Garcia, Jordan P. Reynolds, Evan Bishop, Aysegul BalyimezAbstract:Purpose: Transcriptomic profiling can shed light on the biology of SCBC, nominating biomarkers and novel therapeutic targets. Experimental Design: Sixty-three SCBC patients had small cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess in vivo efficacy of DLL3-targeting antibody-drug conjugate (ADC). Results: Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most "normal-like" pattern of gene expression had longer OS compared to the other 3 clusters while patients with the most "metastasis-like" pattern had the shortest OS (p=0.047). Expression of DLL3, PDL1, ASCL1 and CD56 was confirmed by IHC in 68%, 30%, 52% and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on >10% and CD56 expression on >30% of tumor cells were both prognostic of shorter OS (p=0.03 each). A DLL3-targeting ADC showed durable anti-tumor efficacy in a SCBC PDX model. Conclusions: Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of DLL3 mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated in vivo efficacy superior to chemotherapy in a PDX model of SCBC.
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prevalence of delta like protein 3 expression in patients with small cell lung cancer
Lung Cancer, 2018Co-Authors: Kentaro Tanaka, Kumiko Isse, Tomomichi Fujihira, Mitsuhiro Takenoyama, Laura R Saunders, Sheila Bheddah, Yoichi Nakanishi, Isamu OkamotoAbstract:Abstract Objectives Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC) positive for this protein. However, the prevalence of DLL3 expression and its association with patient ethnicity and other characteristics have remained unclear. Materiais and methods Tumor samples from 63 patients with SCLC were subjected to immunohistochemical staining for DLL3. The relation of patient characteristics including sex, age, disease stage, and smoking history to DLL3 expression status was analyzed. Results and conlusions Fifty-two patients (83%) were positive for DLL3 expression, with 20 patients (32%) being positive in at least 50% of cancer cells (DLL3-high). DLL3 expression was not associated with any of the patient characteristics examined. In addition, overall survival did not differ between DLL3-high and DLL3-low patients. Our results reveal that DLL3 is expressed in tumor specimens from most patients with SCLC, and they should inform the undertaking of clinical trials of Rova-T including an ongoing phase I study (NCT03086239) in Japan as well as global phase III trials (NCT03061812 and NCT03033511).
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An open-label study of rovalpituzumab tesirine in patients with DLL3-expressing advanced solid tumors.
Journal of Clinical Oncology, 2017Co-Authors: Edward Kavalerchik, Laura R Saunders, Sheila Bheddah, Satwant Lally, Tae H. Han, Scott J. DyllaAbstract:TPS2597Background: Delta-like protein 3 (DLL3) is an inhibitory ligand of the Notch receptor family. It is highly expressed in high-grade neuroendocrine carcinoma (NEC), such as small cell lung cancer (SCLC) and large cell NEC (LCNEC), but is not expressed in normal tissue. DLL3 is expressed in melanoma, glioblastoma (GBM), neuroendocrine prostate, medullary thyroid carcinoma (MTC), and other solid cancers. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3, composed of a DLL3-specific IgG1 monoclonal antibody joined to a toxic DNA cross-linking agent by a cleavable linker. Rova-T binds to DLL3 on target-expressing cells, is internalized and cleaved, releasing the toxin to induce cell death. A Phase 1 study of Rova-T in SCLC showed encouraging antitumor activity in DLL3-high patients (pts), and was well-tolerated (Rudin et al., Lancet Oncol, 2016). As novel therapies are needed for multiple cancers that express DLL3, Rova-T may be effective in these tumors. Methods: This is a P...
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Rovalpituzumab tesirine (Rova-T) as a therapeutic agent for Neuroendocrine Prostate Cancer (NEPC).
Journal of Clinical Oncology, 2017Co-Authors: Loredana Puca, Kumiko Isse, Laura R Saunders, Verena Sailer, Michael Sigouros, David M. Nanus, Scott T. Tagawa, Juan Miguel Mosquera, Kaitlyn Gayvert, Himisha BeltranAbstract:5029Background: TheNotch ligand Delta like ligand 3 (DLL3) is aberrantly expressed on the cell surface of small cell lung cancer (SCLC), and the DLL3-antibody drug conjugate, Rova-T, has shown prom...
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Metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas (NECs) as novel indications for rovalpituzumab tesirine: A delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC).
Journal of Clinical Oncology, 2016Co-Authors: Stanford Peng, Laura R Saunders, Sheila Bheddah, Samuel A. Williams, Rahul Aggarwal, Jill E. Shea, Eun Y. Lee, Jiaoti Huang, Allison Zemek, Teri A. LongacreAbstract:11611Background: DLL3 is highly expressed in tumor-initiating cells (TIC) in small cell lung cancer (SCLC), where the DLL3-targeted ADC rovalpituzumab tesirine (Rova-T; SC16LD6.5) is able to eradic...
Sheila Bheddah - One of the best experts on this subject based on the ideXlab platform.
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prevalence of delta like protein 3 expression in patients with small cell lung cancer
Lung Cancer, 2018Co-Authors: Kentaro Tanaka, Kumiko Isse, Tomomichi Fujihira, Mitsuhiro Takenoyama, Laura R Saunders, Sheila Bheddah, Yoichi Nakanishi, Isamu OkamotoAbstract:Abstract Objectives Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC) positive for this protein. However, the prevalence of DLL3 expression and its association with patient ethnicity and other characteristics have remained unclear. Materiais and methods Tumor samples from 63 patients with SCLC were subjected to immunohistochemical staining for DLL3. The relation of patient characteristics including sex, age, disease stage, and smoking history to DLL3 expression status was analyzed. Results and conlusions Fifty-two patients (83%) were positive for DLL3 expression, with 20 patients (32%) being positive in at least 50% of cancer cells (DLL3-high). DLL3 expression was not associated with any of the patient characteristics examined. In addition, overall survival did not differ between DLL3-high and DLL3-low patients. Our results reveal that DLL3 is expressed in tumor specimens from most patients with SCLC, and they should inform the undertaking of clinical trials of Rova-T including an ongoing phase I study (NCT03086239) in Japan as well as global phase III trials (NCT03061812 and NCT03033511).
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Abstract 3093: Expression of DLL3 in metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas as potential indications for rovalpituzumab tesirine (Rova-T; SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody d
Experimental and Molecular Therapeutics, 2017Co-Authors: Laura Saunders, Kumiko Isse, Sheila Bheddah, Verena Sailer, Loredana Puca, Samuel A. Williams, Sarah Fong, Marybeth A. Pysz, Himisha Beltran, Juan M. MosqueraAbstract:Expression of DLL3 was examined in additional tumor types, as it was found to be highly expressed in tumor-initiating cells (TIC) in small cell lung cancer (SCLC), where a DLL3-targeted antibody drug conjugate (ADC), rovalpituzumab tesirine (Rova-T; SC16LD6.5; Saunders et al. 2015 Sci Transl Med 7:302ra136)) exerted clinically meaningful anti-tumor effects in a phase I trial (Spigel et al. 2016 Lancet Oncology; In Press). DLL3 expression was profiled by qRT-PCR, ELISA and immunohistochemistry in multiple tumor types. Patient-derived xenografts (PDX) from melanoma and ovarian small cell carcinoma were established and used for efficacy studies to determine the ability of Rova-T to impact tumor growth and TIC frequency. DLL3 expression was seen in metastatic melanoma (55%), low grade gliomas (90%), glioblastoma (70%), medullary thyroid cancer (65%), carcinoids (33%), dispersed neuroendocrine tumors in the pancreas (9%), bladder (57%) and prostate (24%), testicular cancer (90%), and lung adenocarcinomas with neuroendocrine features (80%). Unlike SCLC, where DLL3 does not predict clinical outcome on standard therapies, DLL3 expression negatively correlates with overall survival in melanoma and small cell bladder cancer. In mice bearing DLL3 positive melanoma PDX, treatment with a single dose of Rova-T resulted in effective and durable responses (>100 days), which correlated with a significant impact on TIC frequency. Similarly, in mice bearing DLL3-positive ovarian small cell PDX, a single dose of Rova-T resulted in effective and durable responses (>100 days). Our results show that DLL3 is expressed in many neuroendocrine tumors (lung, ovarian, prostate, bladder, etc), metastatic melanoma, medullary thyroid cancer, low-grade gliomas and glioblastoma. Given pre-clinical results showing efficacy of Rova-T in melanoma and ovarian small cell carcinoma, as well as encouraging clinical data with Rova-T in patients with recurrent/refractory SCLC, clinical evaluation of Rova-T in DLL3-positive melanoma, glioblastoma, medullary thyroid cancer and other high-grade neuroendocrine carcinomas is warranted. A “basket” trial enrolling patients with DLL3-positive solid tumors is now recruiting patients (NCT02709889). Citation Format: Laura R. Saunders, Samuel A. Williams, Sheila Bheddah, Kumiko Isse, Sarah Fong, Marybeth A. Pysz, Himisha Beltran, Loredana Puca, Verena Sailer, Juan M. Mosquera, Yu Yin, Jiaoti Huang, Andrew J. Armstrong, Jorge Garcia, Cristina Magi-Galluzzi, Vadim Koshkin, Petros Grivas, Farhad Kosari, John Cheville, Justin C. Moser, Thomas J. Flotte, Thorvardur Halfdanarson, Aaron Mansfield, Konstantinos N. Leventakos, Julian R. Molina, Douglas W. Ball, Barry D. Nelkin, Jill E. Shea, Courtney L. Scaife, Scott J. Dylla. Expression of DLL3 in metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas as potential indications for rovalpituzumab tesirine (Rova-T; SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody drug conjugate (ADC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3093. doi:10.1158/1538-7445.AM2017-3093
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An open-label study of rovalpituzumab tesirine in patients with DLL3-expressing advanced solid tumors.
Journal of Clinical Oncology, 2017Co-Authors: Edward Kavalerchik, Laura R Saunders, Sheila Bheddah, Satwant Lally, Tae H. Han, Scott J. DyllaAbstract:TPS2597Background: Delta-like protein 3 (DLL3) is an inhibitory ligand of the Notch receptor family. It is highly expressed in high-grade neuroendocrine carcinoma (NEC), such as small cell lung cancer (SCLC) and large cell NEC (LCNEC), but is not expressed in normal tissue. DLL3 is expressed in melanoma, glioblastoma (GBM), neuroendocrine prostate, medullary thyroid carcinoma (MTC), and other solid cancers. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3, composed of a DLL3-specific IgG1 monoclonal antibody joined to a toxic DNA cross-linking agent by a cleavable linker. Rova-T binds to DLL3 on target-expressing cells, is internalized and cleaved, releasing the toxin to induce cell death. A Phase 1 study of Rova-T in SCLC showed encouraging antitumor activity in DLL3-high patients (pts), and was well-tolerated (Rudin et al., Lancet Oncol, 2016). As novel therapies are needed for multiple cancers that express DLL3, Rova-T may be effective in these tumors. Methods: This is a P...
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Noninvasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer
Cancer Research, 2017Co-Authors: Sai Kiran Sharma, Kumiko Isse, Jacob Pourat, Dalya Abdel-atti, Sean Carlin, Alessandra Piersigilli, Alexander J. Bankovich, Eric E. Gardner, Omar Hamdy, Sheila BheddahAbstract:The Notch ligand DLL3 has emerged as a novel therapeutic target expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas. Rovalpituzumab teserine (Rova-T; SC16LD6.5) is a first-in-class DLL3-targeted antibody-drug conjugate with encouraging initial safety and efficacy profiles in SCLC in the clinic. Here we demonstrate that tumor expression of DLL3, although orders of magnitude lower in surface protein expression than typical oncology targets of immunoPET, can serve as an imaging biomarker for SCLC. We developed 89Zr-labeled SC16 antibody as a companion diagnostic agent to facilitate selection of patients for treatment with Rova-T based on a noninvasive interrogation of the in vivo status of DLL3 expression using PET imaging. Despite low cell-surface abundance of DLL3, immunoPET imaging with 89Zr-labeled SC16 antibody enabled delineation of subcutaneous and orthotopic SCLC tumor xenografts as well as distant organ metastases with high sensitivity. Uptake of the radiotracer in tumors was concordant with levels of DLL3 expression and, most notably, DLL3 immunoPET yielded rank-order correlation for response to SC16LD6.5 therapy in SCLC patient-derived xenograft models. Cancer Res; 77(14); 3931-41. ©2017 AACR.
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Metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas (NECs) as novel indications for rovalpituzumab tesirine: A delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC).
Journal of Clinical Oncology, 2016Co-Authors: Stanford Peng, Laura R Saunders, Sheila Bheddah, Samuel A. Williams, Rahul Aggarwal, Jill E. Shea, Eun Y. Lee, Jiaoti Huang, Allison Zemek, Teri A. LongacreAbstract:11611Background: DLL3 is highly expressed in tumor-initiating cells (TIC) in small cell lung cancer (SCLC), where the DLL3-targeted ADC rovalpituzumab tesirine (Rova-T; SC16LD6.5) is able to eradic...