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Article: Functional Characterisation of the ATOH1 Molecular Subtype Indicates a Pro-Metastatic Role in Small Cell Lung Cancer.

bioRxiv : the preprint server for biology

2024

Abstract: Molecular subtypes of Small Cell Lung Cancer (SCLC) have been described based on differential expression of transcription factors (TFs) ...

Abstract	Molecular subtypes of Small Cell Lung Cancer (SCLC) have been described based on differential expression of transcription factors (TFs)
Language	English
Publishing date	2024-02-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.16.580247
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Article ; Online: Expanding Therapeutic Opportunities for Extrapulmonary Neuroendocrine Carcinoma.

Frizziero, Melissa / Kilgour, Elaine / Simpson, Kathryn L / Rothwell, Dominic G / Moore, David A / Frese, Kristopher K / Galvin, Melanie / Lamarca, Angela / Hubner, Richard A / Valle, Juan W / McNamara, Mairéad G / Dive, Caroline

Clinical cancer research : an official journal of the American Association for Cancer Research

2022 Volume 28, Issue 10, Page(s) 1999–2019

Abstract: Poorly differentiated neuroendocrine carcinomas (PD-NEC) are rare cancers garnering interest as they become more commonly encountered in the clinic. This is due to improved diagnostic methods and the increasingly observed phenomenon of "NE lineage ... ...

Abstract	Poorly differentiated neuroendocrine carcinomas (PD-NEC) are rare cancers garnering interest as they become more commonly encountered in the clinic. This is due to improved diagnostic methods and the increasingly observed phenomenon of "NE lineage plasticity," whereby nonneuroendocrine (non-NE) epithelial cancers transition to aggressive NE phenotypes after targeted treatment. Effective treatment options for patients with PD-NEC are challenging for several reasons. This includes a lack of targetable, recurrent molecular drivers, a paucity of patient-relevant preclinical models to study biology and test novel therapeutics, and the absence of validated biomarkers to guide clinical management. Although advances have been made pertaining to molecular subtyping of small cell lung cancer (SCLC), a PD-NEC of lung origin, extrapulmonary (EP)-PD-NECs remain understudied. This review will address emerging SCLC-like, same-organ non-NE cancer-like and tumor-type-agnostic biological vulnerabilities of EP-PD-NECs, with the potential for therapeutic exploitation. The hypotheses surrounding the origin of these cancers and how "NE lineage plasticity" can be leveraged for therapeutic purposes are discussed. SCLC is herein proposed as a paradigm for supporting progress toward precision medicine in EP-PD-NECs. The aim of this review is to provide a thorough portrait of the current knowledge of EP-PD-NEC biology, with a view to informing new avenues for research and future therapeutic opportunities in these cancers of unmet need.
MeSH term(s)	Biomarkers, Tumor/therapeutic use ; Carcinoma, Neuroendocrine/diagnosis ; Carcinoma, Neuroendocrine/drug therapy ; Carcinoma, Neuroendocrine/genetics ; Humans ; Infant, Newborn ; Lung/pathology ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Neuroendocrine Tumors/drug therapy ; Neuroendocrine Tumors/pathology ; Small Cell Lung Carcinoma/pathology
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2022-01-27
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-21-3058
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Article ; Online: Risk factors of stunting and wasting in Somali pre-school age children: results from the 2019 Somalia micronutrient survey.

Donkor, William E S / Mbai, Joshua / Sesay, Fatmata / Ali, Sundus Ibrahim / Woodruff, Bradley A / Hussein, Shuaib Mohamoud / Mohamud, Kheyriya Mohamed / Muse, Ahmed / Mohamed, Warsame Said / Mohamoud, Abdullahi Muse / Mohamud, Farhan Mohamed / Petry, Nicolai / Galvin, Melanie / Wegmüller, Rita / Rohner, Fabian / Katambo, Yvonne / Wirth, James P

BMC public health

2022 Volume 22, Issue 1, Page(s) 264

Abstract: Background: Stunting and wasting in children less than 5 years of age are two key indicators of child malnutrition. Reducing their prevalence is a priority of the global public health community and for Somalia, a country suffering complex humanitarian ... ...

Abstract	Background: Stunting and wasting in children less than 5 years of age are two key indicators of child malnutrition. Reducing their prevalence is a priority of the global public health community and for Somalia, a country suffering complex humanitarian emergencies such as drought, flooding, conflict and large-scale displacements. Methods: Data from the nationally representative cross-sectional Somalia Micronutrient Survey (SMS 2019) on 1947 children were analyzed to assess the prevalence and potential risk factors of stunting and wasting. Bivariate and multivariable analyses were conducted separately for children 0-5 months and 6-59 months, and population attributable fractions were calculated using adjusted risk ratios produced by Poisson regression models. Results: Among the 1947 children, the prevalence of stunting and wasting were 17.2% (95% CI: 15.0, 19.6) and 11.0% (95% CI: 9.3, 12.9), respectively. Among children 6-59 months of age, those residing in severely food insecure households had a higher risk of stunting (adjusted risk ratio [aRR] 1.47; CI: 1.12, 1.93) compared to those in food secure households. This risk of stunting was also higher in children with inflammation (aRR 1.75; CI: 1.35, 2.25) and iron deficiency (ID) (aRR 2.09; CI: 1.58, 2.80). For wasting, a dose-response relationship was found with household wealth, with the risk of wasting increasing significantly as the household wealth quintile decreased. On the other hand, the risk of wasting was lower in iron-deficient children (aRR 0.69; CI: 0.49, 0.98) than in iron-replete children. Among children 0-5 months of age no variables remained statistically significantly associated with stunting in the multivariable analysis. Wasting, however, was more common in children with recent diarrhea (aRR 3.51; CI: 1.68, 7.36). Conclusions: Nutritional status of children in Somalia may be improved by prevention of diarrhea and other infections and improvements in household food security.
MeSH term(s)	Child ; Child, Preschool ; Cross-Sectional Studies ; Diarrhea/complications ; Growth Disorders/prevention & control ; Humans ; Infant ; Iron ; Micronutrients ; Prevalence ; Risk Factors ; Somalia/epidemiology ; Trace Elements ; Wasting Syndrome/etiology
Chemical Substances	Micronutrients ; Trace Elements ; Iron (E1UOL152H7)
Language	English
Publishing date	2022-02-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041338-5
ISSN	1471-2458 ; 1471-2458
ISSN (online)	1471-2458
ISSN	1471-2458
DOI	10.1186/s12889-021-12439-4
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Article ; Online: Community management of acute malnutrition (CMAM) programme in Pakistan effectively treats children with uncomplicated severe wasting.

Aguayo, Víctor M / Badgaiyan, Nina / Qadir, Syed Saeed / Bugti, Ali Nasir / Alam, Muhammad Mazhar / Nishtar, Noureen / Galvin, Melanie

Maternal & child nutrition

2018 Volume 14 Suppl 4, Page(s) e12623

Abstract: Severe wasting is the most widespread form of severe acute malnutrition, affecting an estimated 17 million children globally. This analysis assesses the effectiveness of Pakistan's community management of acute malnutrition (CMAM) programme. We conducted ...

Abstract	Severe wasting is the most widespread form of severe acute malnutrition, affecting an estimated 17 million children globally. This analysis assesses the effectiveness of Pakistan's community management of acute malnutrition (CMAM) programme. We conducted a retrospective case series analysis of 32,458 children aged 6-59 months who were admitted to the programme with a mid-upper arm circumference (MUAC) < 115 mm (January 1-December 31, 2014). We found that at admission, 59.6% of the children were girls and 87.4% were in the age group 6-23 months old. While in the programme, 120 children (0.4%) died, 3,456 (10.6%) defaulted, and 28,882 (89.0%) were discharged after a mean length of stay of 69.3 ± 25.7 days. Children's mean weight gain while in the programme was 3.2 ± 2.7 g/kg body weight/day. At discharge, 28,499 children (98.7% of discharged) had recovered (MUAC ≥ 125 mm). The odds of death were significantly higher among children with weight-for-height (WHZ) < -3 and/or height-for-age (HAZ) < -2 at admission. The odds of recovery on the basis of MUAC ≥125 mm were higher among children with HAZ ≥ -2 at admission. The odds of recovery on the basis of WHZ ≥ -2 were significantly higher among children with WHZ ≥ -3 and/or HAZ < -2 at admission. Pakistan's CMAM programme is effective in achieving good survival and recovery rates. Population-level impact could be increased by giving priority to children 6-23 months old and children with multiple anthropometric failure and by scaling up CMAM in the provinces and areas where the risk, prevalence, and/or burden of severe acute malnutrition is highest.
MeSH term(s)	Anthropometry ; Body Weight ; Child ; Community Health Services ; Female ; Humans ; Infant ; Length of Stay ; Male ; Pakistan/epidemiology ; Retrospective Studies ; Severe Acute Malnutrition/diagnosis ; Severe Acute Malnutrition/epidemiology ; Severe Acute Malnutrition/therapy ; Wasting Syndrome/diagnosis ; Wasting Syndrome/epidemiology ; Wasting Syndrome/therapy
Language	English
Publishing date	2018-11-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2175105-5
ISSN	1740-8709 ; 1740-8695
ISSN (online)	1740-8709
ISSN	1740-8695
DOI	10.1111/mcn.12623
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Article ; Online: Brief report on the clinical characteristics of patients whose samples generate small cell lung cancer circulating tumour cell derived explants.

Vickers, Alexander J / Frese, Kristopher / Galvin, Melanie / Carter, Mathew / Franklin, Lynsey / Morris, Karen / Pierce, Jacqueline / Descamps, Tine / Blackhall, Fiona / Dive, Caroline / Carter, Louise

Lung cancer (Amsterdam, Netherlands)

2020 Volume 150, Page(s) 216–220

Abstract: Introduction: Small cell lung cancer (SCLC) has a dismal prognosis. Circulating tumour cells (CTCs) can be used to generate CTC derived explants (CDX) for the study of SCLC biology and the development of novel therapeutics. We investigated whether there ...

Abstract	Introduction: Small cell lung cancer (SCLC) has a dismal prognosis. Circulating tumour cells (CTCs) can be used to generate CTC derived explants (CDX) for the study of SCLC biology and the development of novel therapeutics. We investigated whether there are demographic or clinical predictors of the success of CDX generation, and whether CDX models are representative of the SCLC patient population. Methods: This was a single centre, retrospective analysis of SCLC patients who had participated in the CHEMORES Study. Paired blood samples were donated for CTC enumeration and CDX generation attempt at pre-treatment baseline, disease progression and intervening timepoints. Clinical and demographic data was collected from electronic records, and analysed for differences between patients whose samples did and did not generate a CDX. Results: 231 paired blood samples were taken from 147 patients. 45 CDX were generated from 34 patients. CTC number was significantly higher in blood samples which successfully generated a CDX than those which didn't, at both baseline (p=<0.0001) and progression (p = 0.0001). The group with successful blood samples had a poorer performance status (p = 0.0067), and a higher proportion of patients with chemorefractory disease (p = 0.0077). Both progression free survival (PFS) (p = 0.0132) and overall survival (p=< 0.0001) were significantly shorter for patients with successful samples. Conclusions: Patients whose samples generate CDX models may have a higher disease burden and more aggressive disease. Thus, insights gained by study of SCLC CDX may have a significant impact, particularly in the SCLC subpopulation with the greatest clinical need.
MeSH term(s)	Biomarkers, Tumor ; Humans ; Lung Neoplasms ; Neoplastic Cells, Circulating ; Prognosis ; Retrospective Studies ; Small Cell Lung Carcinoma
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2020-11-05
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632771-0
ISSN	1872-8332 ; 0169-5002
ISSN (online)	1872-8332
ISSN	0169-5002
DOI	10.1016/j.lungcan.2020.11.002
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Zs.A 2135: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The Rare YAP1 Subtype of SCLC Revisited in a Biobank of 39 Circulating Tumor Cell Patient Derived Explant Models: A Brief Report.

Pearsall, Sarah M / Humphrey, Sam / Revill, Mitchell / Morgan, Derrick / Frese, Kristopher K / Galvin, Melanie / Kerr, Alastair / Carter, Mathew / Priest, Lynsey / Blackhall, Fiona / Simpson, Kathryn L / Dive, Caroline

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

2020 Volume 15, Issue 12, Page(s) 1836–1843

Abstract: Introduction: Recent consensus defines four SCLC subtypes on the basis of transcription factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is associated with "neuroendocrine (NE)-low" cells among SCLC cell lines and patient ... ...

Abstract	Introduction: Recent consensus defines four SCLC subtypes on the basis of transcription factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is associated with "neuroendocrine (NE)-low" cells among SCLC cell lines and patient samples. We evaluated YAP1 in 39 patients with phenotypically diverse circulating tumor cell-derived explant (CDX) models and revisited YAP1 in terms of prevalence, cell phenotype, and intertumor and intratumor heterogeneity. Methods: YAP1 transcript and protein expression were assessed by RNA sequencing and immunohistochemistry or multiplexed immunofluorescence of NE and non-NE CDX subpopulations. Physically separated NE and non-NE CDX ex vivo culture lysates were Western blotted for YAP1, NE marker SYP, and AXL. Results: RNA sequencing normalized for the four subtype transcription factors identified YAP1 expression in 14 of 39 CDX. A total of 10 CDX expressed YAP1 protein, and eight had strong YAP1 expression confined to rare non-NE cell clusters. This was confirmed in ex vivo CDX cultures in which adherent non-NE cells lacking SYP expression expressed YAP1. However, in two CDX, weaker cellular YAP1 expression was observed, widely dispersed in SYP-positive NE cells. Conclusions: YAP1 was predominantly expressed in non-NE cell clusters in SCLC CDX, but two of 39 CDX expressed YAP1 in NE cells. CDX22P, with relatively high YAP1 expression, is an ASCL1 NE subtype with a low NE score and an outlier within this subtype in our CDX biobank. These descriptive data reveal subtly different YAP1 expression profiles, paving the way for functional studies to compare YAP1 signaling in non-NE and low NE cell contexts for potentially personalized therapeutic approaches.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Biological Specimen Banks ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/genetics ; Neoplastic Cells, Circulating ; Transcription Factors/genetics ; YAP-Signaling Proteins
Chemical Substances	Adaptor Proteins, Signal Transducing ; Transcription Factors ; YAP-Signaling Proteins ; YAP1 protein, human
Language	English
Publishing date	2020-07-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2432037-7
ISSN	1556-1380 ; 1556-0864
ISSN (online)	1556-1380
ISSN	1556-0864
DOI	10.1016/j.jtho.2020.07.008
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Zs.A 6664: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer.

Schenk, Maximilian W / Humphrey, Sam / Hossain, A S Md Mukarram / Revill, Mitchell / Pearsall, Sarah / Lallo, Alice / Brown, Stewart / Bratt, Samuel / Galvin, Melanie / Descamps, Tine / Zhou, Cong / Pearce, Simon P / Priest, Lynsey / Greenhalgh, Michelle / Chaturvedi, Anshuman / Kerr, Alastair / Blackhall, Fiona / Dive, Caroline / Frese, Kristopher K

Nature communications

2021 Volume 12, Issue 1, Page(s) 6652

Abstract: Small cell lung cancer (SCLC) has a 5-year survival rate of <7%. Rapid emergence of acquired resistance to standard platinum-etoposide chemotherapy is common and improved therapies are required for this recalcitrant tumour. We exploit six paired pre- ... ...

Abstract	Small cell lung cancer (SCLC) has a 5-year survival rate of <7%. Rapid emergence of acquired resistance to standard platinum-etoposide chemotherapy is common and improved therapies are required for this recalcitrant tumour. We exploit six paired pre-treatment and post-chemotherapy circulating tumour cell patient-derived explant (CDX) models from donors with extensive stage SCLC to investigate changes at disease progression after chemotherapy. Soluble guanylate cyclase (sGC) is recurrently upregulated in post-chemotherapy progression CDX models, which correlates with acquired chemoresistance. Expression and activation of sGC is regulated by Notch and nitric oxide (NO) signalling with downstream activation of protein kinase G. Genetic targeting of sGC or pharmacological inhibition of NO synthase re-sensitizes a chemoresistant CDX progression model in vivo, revealing this pathway as a mediator of chemoresistance and potential vulnerability of relapsed SCLC.
MeSH term(s)	Animals ; Cyclic GMP-Dependent Protein Kinases/metabolism ; Disease Models, Animal ; Disease Progression ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Enzyme Inhibitors/therapeutic use ; Etoposide/therapeutic use ; Gene Expression Regulation, Neoplastic ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mice ; Neoplastic Cells, Circulating/metabolism ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type II/antagonists & inhibitors ; Receptors, Notch/metabolism ; Signal Transduction/genetics ; Small Cell Lung Carcinoma/drug therapy ; Small Cell Lung Carcinoma/metabolism ; Small Cell Lung Carcinoma/pathology ; Soluble Guanylyl Cyclase/genetics ; Soluble Guanylyl Cyclase/metabolism
Chemical Substances	Enzyme Inhibitors ; Receptors, Notch ; Nitric Oxide (31C4KY9ESH) ; Etoposide (6PLQ3CP4P3) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Cyclic GMP-Dependent Protein Kinases (EC 2.7.11.12) ; Soluble Guanylyl Cyclase (EC 4.6.1.2)
Language	English
Publishing date	2021-11-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-26823-6
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Article ; Online: cfDNA methylome profiling for detection and subtyping of small cell lung cancers.

Chemi, Francesca / Pearce, Simon P / Clipson, Alexandra / Hill, Steven M / Conway, Alicia-Marie / Richardson, Sophie A / Kamieniecka, Katarzyna / Caeser, Rebecca / White, Daniel J / Mohan, Sumitra / Foy, Victoria / Simpson, Kathryn L / Galvin, Melanie / Frese, Kristopher K / Priest, Lynsey / Egger, Jacklynn / Kerr, Alastair / Massion, Pierre P / Poirier, John T /

Brady, Gerard / Blackhall, Fiona / Rothwell, Dominic G / Rudin, Charles M / Dive, Caroline

Nature cancer

2022 Volume 3, Issue 10, Page(s) 1260–1270

Abstract: Small cell lung cancer (SCLC) is characterized by morphologic, epigenetic and transcriptomic heterogeneity. Subtypes based upon predominant transcription factor expression have been defined that, in mouse models and cell lines, exhibit potential ... ...

Abstract	Small cell lung cancer (SCLC) is characterized by morphologic, epigenetic and transcriptomic heterogeneity. Subtypes based upon predominant transcription factor expression have been defined that, in mouse models and cell lines, exhibit potential differential therapeutic vulnerabilities, with epigenetically distinct SCLC subtypes also described. The clinical relevance of these subtypes is unclear, due in part to challenges in obtaining tumor biopsies for reliable profiling. Here we describe a robust workflow for genome-wide DNA methylation profiling applied to both patient-derived models and to patients' circulating cell-free DNA (cfDNA). Tumor-specific methylation patterns were readily detected in cfDNA samples from patients with SCLC and were correlated with survival outcomes. cfDNA methylation also discriminated between the transcription factor SCLC subtypes, a precedent for a liquid biopsy cfDNA-methylation approach to molecularly subtype SCLC. Our data reveal the potential clinical utility of cfDNA methylation profiling as a universally applicable liquid biopsy approach for the sensitive detection, monitoring and molecular subtyping of patients with SCLC.
MeSH term(s)	Animals ; Mice ; Cell-Free Nucleic Acids/genetics ; Small Cell Lung Carcinoma/diagnosis ; Epigenome/genetics ; DNA Methylation/genetics ; Lung Neoplasms/diagnosis ; Transcription Factors/genetics
Chemical Substances	Cell-Free Nucleic Acids ; Transcription Factors
Language	English
Publishing date	2022-08-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2662-1347
ISSN (online)	2662-1347
DOI	10.1038/s43018-022-00415-9
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Article ; Online: Lineage Plasticity in SCLC Generates Non-Neuroendocrine Cells Primed for Vasculogenic Mimicry.

Pearsall, Sarah M / Williamson, Stuart C / Humphrey, Sam / Hughes, Ellyn / Morgan, Derrick / García Marqués, Fernando J / Awanis, Griselda / Carroll, Rebecca / Burks, Laura / Shue, Yan Ting / Bermudez, Abel / Frese, Kristopher K / Galvin, Melanie / Carter, Mathew / Priest, Lynsey / Kerr, Alastair / Zhou, Cong / Oliver, Trudy G / Humphries, Jonathan D /

Humphries, Martin J / Blackhall, Fiona / Cannell, Ian G / Pitteri, Sharon J / Hannon, Gregory J / Sage, Julien / Dive, Caroline / Simpson, Kathryn L

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

2023 Volume 18, Issue 10, Page(s) 1362–1385

Abstract: Introduction: Vasculogenic mimicry (VM), the process of tumor cell transdifferentiation to endow endothelial-like characteristics supporting de novo vessel formation, is associated with poor prognosis in several tumor types, including SCLC. In ... ...

Abstract	Introduction: Vasculogenic mimicry (VM), the process of tumor cell transdifferentiation to endow endothelial-like characteristics supporting de novo vessel formation, is associated with poor prognosis in several tumor types, including SCLC. In genetically engineered mouse models (GEMMs) of SCLC, NOTCH, and MYC co-operate to drive a neuroendocrine (NE) to non-NE phenotypic switch, and co-operation between NE and non-NE cells is required for metastasis. Here, we define the phenotype of VM-competent cells and molecular mechanisms underpinning SCLC VM using circulating tumor cell-derived explant (CDX) models and GEMMs. Methods: We analyzed perfusion within VM vessels and their association with NE and non-NE phenotypes using multiplex immunohistochemistry in CDX, GEMMs, and patient biopsies. We evaluated their three-dimensional structure and defined collagen-integrin interactions. Results: We found that VM vessels are present in 23/25 CDX models, 2 GEMMs, and in 20 patient biopsies of SCLC. Perfused VM vessels support tumor growth and only NOTCH-active non-NE cells are VM-competent in vivo and ex vivo, expressing pseudohypoxia, blood vessel development, and extracellular matrix organization signatures. On Matrigel, VM-primed non-NE cells remodel extracellular matrix into hollow tubules in an integrin β1-dependent process. Conclusions: We identified VM as an exemplar of functional heterogeneity and plasticity in SCLC and these findings take considerable steps toward understanding the molecular events that enable VM. These results support therapeutic co-targeting of both NE and non-NE cells to curtail SCLC progression and to improve the outcomes of patients with SCLC in the future.
MeSH term(s)	Animals ; Mice ; Humans ; Lung Neoplasms/pathology ; Neovascularization, Pathologic/genetics ; Cell Transdifferentiation ; Cell Line, Tumor
Language	English
Publishing date	2023-07-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2432037-7
ISSN	1556-1380 ; 1556-0864
ISSN (online)	1556-1380
ISSN	1556-0864
DOI	10.1016/j.jtho.2023.07.012
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Zs.A 6664: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Inhibition of PI3K/BMX Cell Survival Pathway Sensitizes to BH3 Mimetics in SCLC.

Potter, Danielle S / Galvin, Melanie / Brown, Stewart / Lallo, Alice / Hodgkinson, Cassandra L / Blackhall, Fiona / Morrow, Christopher J / Dive, Caroline

Molecular cancer therapeutics

2016 Volume 15, Issue 6, Page(s) 1248–1260

Abstract: Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. ...

Abstract	Most small cell lung cancer (SCLC) patients are initially responsive to cytotoxic chemotherapy, but almost all undergo fatal relapse with progressive disease, highlighting an urgent need for improved therapies and better patient outcomes in this disease. The proapoptotic BH3 mimetic ABT-737 that targets BCL-2 family proteins demonstrated good single-agent efficacy in preclinical SCLC models. However, so far clinical trials of the BH3 mimetic Navitoclax have been disappointing. We previously demonstrated that inhibition of a PI3K/BMX cell survival signaling pathway sensitized colorectal cancer cells to ABT-737. Here, we show that SCLC cell lines, which express high levels of BMX, become sensitized to ABT-737 upon inhibition of PI3K in vitro, and this is dependent on inhibition of the PI3K-BMX-AKT/mTOR signaling pathway. Consistent with these cell line data, when combined with Navitoclax, PI3K inhibition suppressed tumor growth in both an established SCLC xenograft model and in a newly established circulating tumor cell-derived explant (CDX) model generated from a blood sample obtained at presentation from a chemorefractory SCLC patient. These data show for the first time that a PI3K/BMX signaling pathway plays a role in SCLC cell survival and that a BH3 mimetic plus PI3K inhibition causes prolonged tumor regression in a chemorefractory SCLC patient-derived model in vivo These data add to a body of evidence that this combination should move toward the clinic. Mol Cancer Ther; 15(6); 1248-60. ©2016 AACR.
MeSH term(s)	Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Biphenyl Compounds/administration & dosage ; Biphenyl Compounds/pharmacology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Synergism ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/metabolism ; Mice ; Nitrophenols/administration & dosage ; Nitrophenols/pharmacology ; Phosphatidylinositol 3-Kinases/metabolism ; Piperazines/administration & dosage ; Piperazines/pharmacology ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/pharmacology ; Protein-Tyrosine Kinases/metabolism ; Signal Transduction/drug effects ; Small Cell Lung Carcinoma/drug therapy ; Small Cell Lung Carcinoma/metabolism ; Sulfonamides/administration & dosage ; Sulfonamides/pharmacology ; Xenograft Model Antitumor Assays
Chemical Substances	ABT-737 ; Antineoplastic Agents ; Biphenyl Compounds ; Nitrophenols ; Piperazines ; Protein Kinase Inhibitors ; Sulfonamides ; BMX protein, human (EC 2.7.1.-) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2016-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-15-0885
Database	MEDical Literature Analysis and Retrieval System OnLINE

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