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C. Dive
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MS 12 - NSCLC Stems Cells: Are They a Real Target? (ID 30)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 4
- Moderators:C. Dive, K. Nakagawa
- Coordinates: 9/08/2015, 14:15 - 15:45, Mile High Ballroom 2c-3c
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MS12.01 - Biology of Cancer Stem Cells (ID 1900)
14:15 - 15:45 | Author(s): N. Watkins
- Abstract
- Presentation
Abstract:
There is general agreement amongst biomedical researchers that stem cells exist in multicellular organisms. The most well characterized model of adult somatic stem cells is the bone marrow, in which serial transplantation in both immunocompetent and immunodeficient mice have clearly identified the hematopoietic stem cell (HSC). Using the same models, it is now generally accepted, even amongst cancer stem cell (CSC) sceptics, that most forms of myeloid leukemia are maintained by a self-renewing, transplantable HSC-like cell, even though the initial transformation event may have occurred in a committed progenitor. Given that nature tends to conserve processes across evolution, it is logical to hypothesize that a similar functional hierarchy exists in solid tumors. Over two decades, numerous papers have reported the presence of a functionally distinct, rare population of cells within solid tumors with stem-like properties based on the same criteria used to define the HSC and leukemic CSC. However, the idea that CSCs exist solid tumors remains controversial at best. The difficulties in reproducing results in highly complex models systems, and questions over the validity of CSC surface markers in solid tumors, have clearly contributed to these, often heated, arguments. If we assume for a moment that CSCs do not exist in solid tumors, they would constitute the only multicellular entity in nature without a hierarchical organisation based on self-renewal and differentiation. If this were true, then solid tumors would behave like colonies of bacteria or yeast, in which all cells were identical, where the capacity to self-renew in the face of an environmental challenge would be entirely determined by random genetic variants. In the setting of acquired resistance to targeted therapies, there is convincing evidence for such a “rare clone” hypothesis. For example, the source of acquired resistance to tyrosine kinase inhibitor (TKI) therapy in EGRF-mutant adenocarcinoma seems to be pre-existing clones that already possess a point mutation that confers resistance. But, can this genetic model explain other stemness phenotypes in non-small cell lung cancer (NSCLC)? In clinical terms, a pressing question is whether random genetic events can explain the rapid regeneration of NSCLC tumors after a long period of dormancy following curative surgery. Equally, can the “rare clone” hypothesis explain innate the innate chemoresistance of quiescent CSC-like NSCLC cells that have a greatly enhanced capacity for self-renewal. If the answer to either of questions is “not always”, then targeting CSCs based on function rather than genome remains a potential avenue for improving outcomes in NSCLC patients. The characterization of NSCLC CSCs is made difficult by the phenotypic and genomic heterogeneity of the disease, problems identifying robust surface markers, and in defining what experimental endpoints constitute CSC function. In addition, there is no general agreement on which markers are associated with CSC in NSCLC, although several studies suggest that the surface markers CD44 and CD133 can prospectively identify such cells. In therapeutic terms, elimination of CSCs in NSCLC would require such markers be reproducible and robust, but can also be therapeutically targeted in humans. An alternative approach is to target embryonic signaling pathways known to regulate self-renewal in development. This idea is the driving force behind clinical trials of Notch and Hedgehog inhibitors in several cancer types. Unfortunately, most of these clinical trials add the experimental agent along side standard-of-care chemotherapy rather than delivering the experimental agent following treatment in order to determine whether stem-cell targeting can “burn out” quiescent, undifferentiated residual disease. One promising candidate marker in NSCLC is ALDH1. In most published studies, expression of ALDH1 or ALDH1A correlates with reduced overall survival, consistent with the presence of enhanced regenerative capacity and innate chemoresistance in NSCLC. Moreover, experimental evidence supports the notion that expression of the ALDH1 protein, and its enzymatic activity, is associated with enhanced CSC functions in vitro and in vivo. Since secondary prevention studies in advanced NSCLC are impractical, it may be possible strengthen the case for targeting NSCLC, using ALDH1 as an example, using more practical preclinical and clinical approaches. Such an approach might be: 1. Concentrate on one subgroup of NSCLC- for example KRAS mutant lung adenocarcinoma. 2. Show that rare, single ALDH1+ cells give rise to tumors with the same ratio of ALDH1+ to ALDH1- cells as was seen in the parent tumor. 3. Using single cell genomics, determine whether ALDH1+ and ALDH1- cells share the same genotype. 4. In lung cancer patients treated with neoadjuvant chemotherapy, show that the percentage of ALDH1+ cells increases in the residual tumor removed at surgery. 5. In lung cancer patients with recurrent disease following surgery, show that the recurrent tumor contains the same ratio of ALDH1+ to ALDH1- cells as was seen in the parent tumor. References: Jordan CT. Cancer stem cells: controversial or just misunderstood? Cell Stem Cell, 2009; 4:203-5. Alamgeer M, Peacock CD, Matsui W, Ganju V, Watkins DN. Cancer stem cells in lung cancer: Evidence and controversies. Respirology, 2013; 18:757-764 Sullivan JP, Spinola M, Dodge M, Raso MG, Behrens C, Gao B, Schuster K, Shao C, Larsen JE, Sullivan LA, Honorio S, Xie Y, Scaglioni PP, DiMaio JM, Gazdar AF, Shay J, Wistuba II, Minna JD. Aldehyde Dehydrogenase Activity Selects for Lung Adenocarcinoma Stem Cells Dependent on Notch Signaling. Cancer Res, 2010; 70:9937-48. Shao C, Sullivan JP, Girard L, Augustyn A, Yenerall P, Rodriguez-Canales J, Behrens C, Shay JW, Wistuba II, Minna JD. Essential Role of Aldehyde Dehydrogenase 1A3 for the Maintenance of Non–Small Cell Lung Cancer Stem Cells Is Associated with the STAT3 Pathway. Clin Cancer Res; 2014; 20:4154–66. Alamgeer M, Ganju V, Szczepny A, Russell PA, Prodanovic Z, Kumar B, Wainer Z, Brown T, Schneider-Kosky M, Conron M, Wright G, Watkins DN. The prognostic significance of ALDEHYDE DEHYDROGENASE 1A1 (ALDH1A1) and CD133 expression in early-stage non-small cell lung cancer. Thorax, 2013; 68(12):1095-104. Alamgeer M, Ganju V, Kumar B, Fox J, Hart S, White M, Harris M, Stuckey J, Prodanovic Z, Schneider M, Watkins DN. Changes in ALDEHYDE DEHYDROGENASE-1 (ALDH1) expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer. Breast Cancer Res, 2014; 16:R44.
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MS12.02 - Current Therapeutic Targets and Ongoing Trials (ID 1901)
14:15 - 15:45 | Author(s): M. Diehn
- Abstract
- Presentation
Abstract not provided
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MS12.03 - Where to Go from Here? (ID 1902)
14:15 - 15:45 | Author(s): R. Rosell, J. Codony, I. Chaib, C. Codony, S. Pilotto, A. Verlicchi, J.L. Ramírez-Serrano, N. Karachaliou, M.A. Molina-Vila, T. Bivona, P.C. Ma
- Abstract
Abstract:
Lung cancer is a dismal disease, however, anticipated selective responses are observed in a subgroup of non-small cell lung cancer (NSCLC) patients where the disease is driven by epidermal growth factor receptor (EGFR) mutations. EGFR mutations occur in 15 – 40% of lung adenocarcinomas, according to gender, smoking history and geographical region. Two types of EGFR mutations account for 90% of all lung adenocarcinoma-associated EGFR mutations and are related to sensitivity to treatment with oral tyrosine kinase inhibitors (TKIs), such as gefitinib, afatinib or AZD9291: (i) small in-frame deletions in exon 19 that lead to elimination of an LREA motif in the protein (DEL) and (ii) a point mutation in exon 21 that substitutes an arginine for a leucine at position 858 in the protein (L858R). Lung cancer patients bearing EGFR mutations show radiographic responses to TKIs in 60 – 70% of cases. Although the majority of patients achieve a significant therapeutic benefit, almost all invariably progress in less than 1 year. Therefore there is an unmet medical need for novel therapies in order to avoid resistance to treatment. We have employed a wide array of approaches (MTT, western blot analysis, PCR, Aldefluor assay and mouse models) to demonstrate that the combination of gefitinib, afatinib or AZD9291 with compounds targeting signal transducer and activator of transcription 3 (STAT3) can suppress the mechanisms of early adaptive resistance. STAT3 is a member of a family of proteins responsible for transmission of peptide hormone signals from the extracellular surface of the cells to the nucleus. STAT3 is a master regulator of several key hallmarks and enablers of cancer cells, including cell proliferation, resistance to apoptosis, metastasis, immune evasion, tumor angiogenesis, epithelial-mesenchymal transition, response to DNA damage and the Warburg effect. In addition STAT3 promotes an increase in the cell renewal of tumor-initiating cells or cancer stem cell subpopulation, mainly aldehyde dehydrogenase (ALDH). EGFR mutations cause receptor oligomerization and activation of intrinsic or receptor-associated tyrosine kinases, respectively. These activated kinases phosphorylate receptor tyrosine residues creating docking sites for recruitment of cytoplasmic STAT3. STAT3 docks to receptor phosphotyrosyl (pY) peptide sites through its Src-homology (SH2) domain which leads to its phosphorylation on Y705 followed by STAT3 tail-to-tail homodimerization (SH2 domain of each monomer binds to the pY peptide domain of each partner). STAT3 homodimers accommodate in the nucleus, where they bind to specific STAT3 response elements in the promotor of target genes and regulate their transcription. EGFR mutations and tyrosine kinase-associated receptor interleukin-6 (IL-6) lead to the activation of STAT3 that is not obliterated by EGFR TKIs. Even more, 2 hours after starting gefitinib treatment there is an increase in STAT3 activation in EGFR mutant cell lines (P. Ma, Cancer Research, 2011). Moreover, following erlotinib treatment there is an enrichment of ALDH+ stem-like cells through EGFR-dependent activation of Notch3. We have tested several small molecules that target STAT3. The combination inhibits cell viability in several human EGFR mutant cells and blocks STAT3 activation. However, neither the combination of EGFR TKIs with TPCA1 (repurposed as a STAT3 inhibitor), nor the combination of gefitinib with AZD0530 (a Src inhibitor) prevent the increment in the ALDH + cancer stem cell subpopulation. Therefore, we are exploring more in depth the crosstalk between EGFR and IL-6. As a whole, human EGFR mutant cell lines have increased levels of IL-6 which leads to STAT3 hyper-activation. Nevertheless, recent evidence indicates that IL-6-Src can induce YAP activation and NOTCH signaling. The downstream effectors of YAP and NOTCH ligands CTGF and HES1, respectively, are being examined in clinical tumor samples. We have examined the combination of Src, YAP and NOTCH inhibitors in addition to the use of STAT3 inhibitors. The triple combination of gefitinib plus TPCA1 plus AZD0530 had great synergism with a very low combination index and also eliminated the ALDH+ population (Figure). Furthermore, the overexpression of ALDH1A1 was decreased with the triple combination, however with only gefitinib plus TPCA1 or gefitinib plus AZD0530, ALDH1A1 mRNA was substantially increased in comparison with gefitinib alone (Figure). The western blot for the triple combination shows the inhibition of STAT3 Y705 phosphorylation as well as the phosphorylation of YAP (Ser397) and also from BMI1. We plan to confirm some of the data in clinical tumor samples to understand the contribution of IL6 and well established effectors-the SHP2-ERK, PI(3)K-Akt-mTORC1 and JAK-STAT3 modules and the interaction with YAP. Figure 1
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MS12.04 - Tumor-Propagating Cells in Non-Small Cell Lung Cancers (ID 1903)
14:15 - 15:45 | Author(s): C. Kim
- Abstract
- Presentation
Abstract:
Our long-term goal is to elucidate the role of stem cells in lung homeostasis as a prerequisite to the development of therapeutic strategies that can be used to prevent or attenuate lung disease and lung cancer. Our previous experience isolating the first stem cell population from the adult murine lung, termedbronchioalveolar stem cells (BASCs), and our demonstration of a role for these cells in lung cancer serves as a platform to address these questions. We have recently developed three-dimensional co-culture and subcutaneous co-injection assays that allow us to quantitatively assess the identity and the differentiation potential of lung stem cells. This approach led us to uncover a cross-talk between lung endothelial cells and lung stem cells via a novel signaling axis involving Bmp4, NFATc1 and Tsp1;this pathway drives BASCs to differentiate into the alveolar epithelial cell lineage. Our work in the intersection of stem cell biology and lung disease has expanded into new insights for understanding metastasis and non-small cell lung cancer (NSCLC). We previously showed the adenocarcinoma Kras/p53 mutant mouse model contains Sca1+ tumor-propagating cells (TPCs), the cells that recapitulate the tumor by transplantation. We recently showed multiple lung tumor sub-populations can give rise to metastatic disease, and that the Sca1+ CD24+ TPCs have the highest metastatic potential. We also showed the Hippo pathway mediators Yap/Taz are necessary andsufficient for lung cancer progression. Finally, in a new mouse model of lung squamous cancer, the second most common type of NSCLC, we identified a TPC population defined by the markers Sca1 and NGFR. These studies illustrate the utility of stem cell biology approaches to provide new avenues for lung cancer therapeutic targeting.
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Author of
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MINI 22 - New Technology (ID 134)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
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MINI22.12 - Molecular Characterisation of SCLC Using Both Circulating Tumour DNA and Circulating Tumour Cells Isolated from the Same Whole Blood Sample (ID 251)
16:45 - 18:15 | Author(s): C. Dive
- Abstract
- Presentation
Background:
Small Cell Lung Cancer (SCLC) is an aggressive, highly metastatic disease with dismal prognosis. Response rates to first line chemotherapy are generally high, but progression free survival is short due to development of chemotherapy resistance via mechanisms not well understood. Due to the difficulty in collecting tissue biopsies in SCLC, blood, which can be sampled simply and routinely, provides a means of inferring the current genetic status of a patients tumour via analysis of circulating tumour cells (CTCs) or circulating tumour DNA (ctDNA). These offer a minimally invasive opportunity to study drug resistance mechanisms, evaluate tumour heterogeneity and potentially reveal new drug targets in this disease. However, accurate assessment of both CTCs and ctDNA requires all blood cells be maintained intact until samples are processed, particularly when analytes present are at very low concentrations. Here we describe and validate a blood collection protocol that does not require on-site processing, and which is amenable for analysis of both CTCs and ctDNA following storage at ambient temperature in CellSave vacutainers for up to 96 hours after blood collection.
Methods:
To evaluate the suitability of using CellSave preserved samples for circulating free DNA (cfDNA) analysis, we undertook a 20 healthy normal volunteers (HNV) study and 45 patient sample study, with parallel EDTA and CellSave bloods collected. For each sample cfDNA was isolated between 4 hours and 96 hours post-draw and cfDNA yields determined. A potential issue with using CellSave blood was that the CellSave preservative could act as a DNA damaging agent and effectively increase background sequencing errors. To test this, the EDTA and CellSave cfDNA samples were subjected to next generation sequencing (NGS) to estimate the overall mutation burden. In addition, the utility of CellSave ctDNA for targeted NGS was also determined. Finally, SCLC-specific copy number aberrations (CNA) were analysed in ctDNA and CTCs isolated from the same CellSave blood sample from individual SCLC patients.
Results:
We demonstrate that yields of cfDNA obtained from 96-hour whole blood CellSave samples are equivalent to those obtained from conventional EDTA plasma processed within 4 hours of blood draw. Targeted and genome-wide NGS revealed comparable DNA quality and resultant sequence information from cfDNA within CellSave and EDTA samples, thereby validating CellSave blood as a viable source of ctDNA. We also demonstrate that CTCs and ctDNA can be isolated from the same patient blood sample, and give the same patterns of CNA allowing direct comparison of the genetic status of patients’ tumours.
Conclusion:
In summary, we have demonstrated the suitability of whole blood CellSave samples for both CTC and ctDNA molecular analysis in SCLC. The ability to generate informative molecular profiles of both CTCs and ctDNA from a simple whole blood sample, up to 4 days post-draw represents a significant methodological improvement for clinical benefit. We posit that as minimally invasive, liquid biopsies become increasingly employed for cancer patient management, the ability to routinely and simply draw blood and ship samples to accredited biomarker assessment laboratories will greatly facilitate the delivery of personalised cancer medicines.
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MS 07 - SCLC Biology & Models (ID 25)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:D. Carney, C.M. Rudin
- Coordinates: 9/07/2015, 14:15 - 15:45, Mile High Ballroom 4a-4f
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MS07.05 - Circulating Tumour Cells (ID 1876)
14:15 - 15:45 | Author(s): C. Dive
- Abstract
- Presentation
Abstract:
Circulating Tumour Cells Dr Fiona Blackhall and Professor Caroline Dive Progress in understanding the molecular biology of small cell lung cancer has undoubtedly been hampered by lack of tissue resources suitable for comprehensive systems biology analysis. Tissue quantities sufficient for molecular analysis are more commonly from surgical resections and open biopsies from patients with very limited stage disease and therefore not representative of the majority of SCLC patients. Serial biopsies are even rarer to obtain. As an alternative to tumour tissue, circulating tumour cells (CTCs) are highly prevalent and abundant in patients with SCLC. These surrogate biomarkers, increasingly referred to as ‘virtual’ or ‘liquid’ biopsies, may be more relevant to understanding the biology of this disease that is hallmarked by early and widespread haematogenous dissemination. In our own series (Hou et al. JCO 2012) blood samples from 97 treatment naive patients, 31 with limited stage (LS) and 66 with extensive stage (ES), were assessed for CTCs using the EpCam-based immunomagnetic detection method, CellSearch. CTCs were detectable in the majority (85%) of patients and abundant. The mean ± standard deviation for CTC number(#) in a 7.5ml blood sample was 1,589 ± 5,565 and median CTC# was 24 (range 0 – 44, 896). CTC# was significantly associated (higher) with ES, lactate dehydrogenase, presence of liver metastases and number of sites of metastases. In multivariate analysis, adjusting for these clinical associations, pretreatment CTC# and change in CTC# after one cycle of chemotherapy were independent prognostic factors. A statistically derived cut off of 50 CTCs demonstrated most significant discrimination in survival estimation. The overall survival was 5.4 months for patients with ≥ 50 CTCs/7.5 mL of blood compared with 11.5 months (P < .0001) for patients with less than 50 CTCs/7.5 mL of blood before chemotherapy (hazard ratio = 2.45; 95% CI, 1.39 to 4.30; P =0 .002). In addition to prognostic information CTCs are pharmacodynamic and amenable to biomarker assay development (protein expression, omic profiling, FISH etc). CTCs ex vivo are also tumourigenic. We have established a series of CTC derived xenografts (CDX) in immune compromised (IC) mice (Hodgkinson et al. Nat Med 2014). Of 6 initial patients whose CTCs were implanted in IC mice, 4 gave rise to tumours in less than 5 months. Implantation and CDX tumour formation was associated with higher CTC# (>400 CTCs / 7.5mls of blood). The immunohistochemical characteristics of the CDX tumours were consistent with SCLC morphology and neuroendocrine marker expression. Whole genome sequencing demonstrated that the tumours had mutations (e.g. TP53 and RB1) and copy number variation (e.g. loss of 3p and 13q) commonly observed in SCLC. Furthermore, the same genetic abnormalities as the CDX were present in single cells CTCs isolated from the corresponding patient. On exposure of the CDX to platinum and etoposide chemotherapy a remarkable correlation was observed for the tumour responses compared to the patients’ tumour responses and survival. For example the most chemoresistant CDX was established from CTCs of a patient who survived for only 0.9 months and who had chemorefractory disease, whereas the most chemosensitive CDX was obtained from a patient who responded to platinum/etoposide chemotherapy and who survived for 9.7 months. A CDX of intermediate chemosensitivity was derived from a patient who survived for 3.5 months. Once the CDX tumours are established they can be harvested for passage, frozen and resurrected. Ongoing work aims to establish serial CDX models from patients who have progressed after initial treatment for study of biology, particularly that of acquired chemoresistance, and for preclinical testing of novel therapeutics in treatment naïve and previously treated SCLC. There is also possibility to incorporate serial CTC analysis and CDX model generation into clinical trials as ‘co-clinical trials’ with interrogation of pharmacodynamic and putative predictive biomarkers in addition to discovering mechanisms of resistance to novel therapeutics. CTC analysis and CDX model generation are technically challenging and resource intensive, but essential tools to further develop if we are to end the impasse on a targeted therapy breakthrough for this disease. References Hou JM, Krebs MG, Lancashire L, Sloane R, Backen A, Swain RK, Priest LJ, Greystoke A, Zhou C, Morris K, Ward T, Blackhall FH, Dive C. Clinical significance and molecular characteristics of circulating tumor cells and circulating tumor microemboli in patients with small-cell lung cancer. J Clin Oncol. 2012 Feb 10;30(5):525-32. Hodgkinson CL, Morrow CJ, Li Y, Metcalf RL, Rothwell DG, Trapani F, Polanski R, Burt DJ, Simpson KL, Morris K, Pepper SD, Nonaka D, Greystoke A, Kelly P, Bola B, Krebs MG, Antonello J, Ayub M, Faulkner S, Priest L, Carter L, Tate C, Miller CJ, Blackhall F, Brady G, Dive C. Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer. Nat Med. 2014 Aug;20(8):897-903.
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ORAL 25 - Biology and Other Issues in SCLC (ID 125)
- Event: WCLC 2015
- Type: Oral Session
- Track: Small Cell Lung Cancer
- Presentations: 2
- Moderators:J. Sage, L. Montuenga
- Coordinates: 9/08/2015, 10:45 - 12:15, 605+607
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ORAL25.02 - Vasculogenic Mimicry in Small Cell Lung Cancer (ID 2654)
10:45 - 12:15 | Author(s): C. Dive
- Abstract
Background:
Small cell lung cancer (SCLC) accounts for 15-20% of lung cancer cases worldwide and is characterised by early dissemination. Despite initial responses to chemotherapy, most patients relapse with drug resistant disease and long term survival is rare. Targeting tumour vasculature in SCLC with anti-angiogenic drugs produced disappointing results. However, angiogenesis-independent tumour vascularisation including vasculogenic mimicry (VM), warrant further investigation. VM describes the ability of aggressive tumour cells with ‘stem-like’ plasticity to adopt endothelial characteristics and form fluid conducting channel-like structures independent of host vasculature. We sought to determine the prevalence of VM in SCLC and explore associations of VM with chemotherapy sensitivity and patient outcomes. We investigated the role of a VM-associated protein, VE-Cadherin in vitro and in vivo and in SCLC CTCs. We are testing the hypothesis that VM may contribute to the high prevalence of CTCs in SCLC and components of the VM pathway may be targets for SCLC therapeutics.
Methods:
VM was evaluated using CD31/periodic acid-Schiff (PAS) staining in a tissue micro-array (TMA) from 41 limited stage SCLC chemo-naive patients and in tumours from 11 Circulating Tumour Cell (CTC) Derived Explant (CDX) models (Hodgkinson et al Nature Medicine, 2014). The relative abundance of VM channels (CD31-ve/PAS+ve) compared to host derived blood vessels (CD31+ve/PAS+ve), (VM/total vessels) in the TMA was compared to patient overall survival (OS). VM was evaluated in vitro by network formation in Matrigel (Hendrix et al., PNAS 2001) in a panel of SCLC cells lines and in H446 cells where VE-Cadherin was knocked down with shRNA. H446 cells +/- VE-Cadherin were grown in vivo as xenografts and evaluated for VM. ISET filtered, DAPI stained CTCs were immune-stained for CD45, cytokeratin and VE-cadherin and a VM score was generated.
Results:
In the TMA, a VM/Total Vessels score >10% was a poor prognostic factor for OS by univariate (p=0.011) and multivariate (p=0.014) analyses. VM was present in all CDX models provide surrogate tissues in which to study VM. Of 12 SCLC cell lines studied, H446 showed significant VE-Cadherin expression and formed networks in Matrigel; VE-Cadherin shRNA abrogated this network formation. Similarly, a pilot in vivo study demonstrated that there were fewer VM vessels when VE-Cadherin was reduced. In CTC samples 37/38 chemonaive SCLC patients contained a sub-population of VE-Cadherin expressing CTCs where the VM score ranged from 0 – 100% (median 11%, mean 21%).
Conclusion:
We present the first evidence of VM in SCLC which correlates with poor OS consistent with findings in other cancer types. VE-Cadherin is required in SCLC for VM network formation in vitro and preliminary data indicate that VE-Cadherin influences VM in vivo. Furthermore, VE-Cadherin and pan-cytokeratin co-expression was found in SCLC CTC sub-populations. We are investigating the role of VE-Cadherin in VM in SCLC and are exploring the hypotheses that VE-cadherin and VM may play a role in drug delivery and/or sensitivity and may represent an aggressive, ‘stem-like’ population that may contribute to dissemination and relapse in this highly aggressive disease.
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ORAL25.08 - Discussant for ORAL25.05, ORAL25.06, ORAL25.07 (ID 3361)
10:45 - 12:15 | Author(s): C. Dive
- Abstract
Abstract not provided
