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Julie George
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OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)
- Event: WCLC 2019
- Type: Oral Session
- Track: Biology
- Presentations: 9
- Now Available
- Moderators:Luis M Montuenga, Julie George
- Coordinates: 9/09/2019, 11:00 - 12:30, Interlaken (1988)
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OA08.01 - Organoid Cultures as Novel Preclinical Models of Non-Small Cell Lung Cancer (Now Available) (ID 2115)
11:00 - 12:30 | Presenting Author(s): Ming Sound Tsao | Author(s): Roushi Shi, Nikolina Radulovich, Christine Ng, Hirotsugu Notsuda, Michael Cabanero, Sebastiao N Martins-Filho, Vibha Raghavan, Quan Li, Arvind Singh Mer, Ni Liu, Nhu-An Pham, Benjamin Haibe-Kains, Geoffrey Liu, Nadeem Moghal
- Abstract
- Presentation
Background
There is an unmet need to develop novel clinically relevant models of NSCLC to accelerate identification of drug targets and our understanding of the disease. Organoids, which are cells grown in three-dimensional environments in Matrigel, have emerged as novel preclinical models of cancer. Recently protocols for generating NSCLC organoids have been reported, but the growth, and molecular features of organoids as compared to their matching primary patient tumor or patient-derived xenografts (PDX) remain vague.
Method
Thirty surgically resected NSCLC patient tumor and 35 PDX tissue of lung adenocarcinoma and squamous cell carcinoma subtypes were processed for organoid establishment. Organoids and matching tumor tissues were characterized by histology and immunohistochemistry, and molecularly profiled by whole exome and RNA-sequencing. Subcutaneous injection of organoids in vivo was performed to confirm tumorgenicity. Organoids were subjected to drug testing and drug response was verified in the matched PDX.
Result
Using a novel culture condition that our laboratory developed, we have collected tumor samples from 16 primary and 13 PDX samples of adenocarcinoma (n=29) and 14 primary and 22 PDX samples of squamous cell carcinoma (n=36). Over 85% (57/65) of our patient and PDX tumor tissues formed organoids that exhibited a wide range of short-term (<3 months) and long-term (>3 months) growth. Specifically, the success rate of establishing short-term and long-term models are 74% (48/65) and 14% (9/65), respectively. The long-term propagable organoids recapitulated the histology of the patient and PDX tumor. They also retained the ability to form xenograft in NOD-SCID mice. The organoids preserved mutation, copy number aberrations and global gene expression profile of the parental tumors. We additionally showed the utility of short-term and long-term organoids for identifying biomarkers of sensitivity to drugs and combinational targeted therapies.
Conclusion
NSCLC organoids are novel patient-derived ex-vivo tumor models for anti-cancer drug screening and biomarker discovery, thus could be incorporated into novel drug discovery pipelines. Further efforts are ongoing to increase the success rate of establishing long-term organoid lines.
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OA08.02 - A Multidisciplinary Multi-Omics Study of Spatial and Temporal Tumor Evolution in Thoracic Cancers with Clinical Implications (Now Available) (ID 2365)
11:00 - 12:30 | Presenting Author(s): Matthieu Foll | Author(s): Nicolas Alcala, Lise Mangiante, Arnaud Poret, Aurélie Gabriel, Jules L Derks, Laura Moonen, Sandrine Boyault, Nolwenn Le Stang, Akram Ghantous, Séverine Tabone-Eglinger, Francesca Damiola, Jean-Yves Blay, James McKay, Anne Marie Clasina Dingemans, Ernst-Jan M Speel, Christophe Caux, Nicolas Girard, Sylvie Lantuejoul, Talya Dayton, Francoise Galateau Sallé, Lynnette Fernandez-Cuesta
- Abstract
- Presentation
Background
In the context of the MESOMICS and lungNENomics projects1, we generated comprehensive molecular profiles of Malignant Pleural Mesothelioma (MPM)2 and pulmonary carcinoids (PCa)3. We showed that a continuous molecular model can better explain the prognosis of MPM than the three histologies, with strong differences in the expression of immune checkpoints and pro-angiogenic genes across samples. We also identified a new entity of PCa (supra-carcinoids) with carcinoid-like morphology yet the molecular and clinical features of LCNEC, which challenges the general believe that PCa have no relationship or genetic, epidemiologic, and clinical traits in common with LCNEC and SCLC. These two studies suggest an important role of heterogeneity in the biology of these tumors.
Method
Much progress has been made in revealing the evolutionary history of individual cancers, in particular using multi-region sequencing. However, most studies focused on a single ‘omic technique, and lacked temporal samples. Here we present the results of an innovative approach to study spatial and temporal tumor evolution based on (i) integration of whole-genome and transcriptome sequencing and EPIC 850K methylation arrays on multiple regions from 12 MPM, and (ii) a novel tumor-derived organoid-based strategy for studying the evolution of PCa.
Figure 1. Multi-omic multi-regional profiling of a MPM patient. A) Somatic Copy Number Variants (CNV), somatic Structural Variants (SV), kernel density plots of (top) somatic single nucleotide variants (SNVs) allelic fractions, (middle) expression normalized read counts, and (bottom) methylation array M-values. B) Projection of the transcriptomic profile of two tumoral regions into the Principal Component Analysis (PCA) space computed from 284 malignant pleural mesotheliomas2C) Expression (z-score of normalized read counts) for two clinically relevant genes with substantial inter-regional differences.
Biorepositories: French MESOBANK; LungNEN Network
Result
In the data analyses of the 12 MPM we detected significant intra-tumor heterogeneity (ITH) in the expression of immune checkpoints and pro-angiogenic genes (see example in Fig. 1). This might explain the modest and variable response to treatment in clinical trials assessing immunotherapies and antiangiogenic drugs. In the case of PCa, we are currently analysing the organoids genomic data and we will present the preliminary data for the temporal evolution of these diseases.
Conclusion
We found that our approach can detect clinically and biologically meaningful ITH. All the computational methods we developed for these evolutionary studies are available to the scientific community4.
1RareCancersGenomics.com
2Alcala et al., under review in Cancer Res
3Alcala et al., under review in Nat Commun
4https://github.com/IARCbioinfoLFC and MF co-supervised this work
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OA08.03 - A Single-Cell Resolution Map of EMT and Drug Resistance States for Evaluating NSCLC Clinical Specimens (Now Available) (ID 2771)
11:00 - 12:30 | Presenting Author(s): Loukia Georgiou Karacosta | Author(s): Benedict Anchang, Nikolaos Ignatiadis, Samuel C Kimmey, Jalen A Benson, Joseph B Shrager, Arthur Wai Sung, Joel W Neal, Heather A Wakelee, Robert Tibshirani, Sean C Bendall, Sylvia K Plevritis
- Abstract
- Presentation
Background
The role of epithelial-mesenchymal transition (EMT) in NSCLC is well reported and has been shown to prime cells for metastasis. EMT can be adopted or reversed (i.e. mesenchymal-epithelial transition, MET) by cells, revealing plasticity that can also lead to drug resistance. Although it is appreciated that EMT is not a binary process of two extremes but instead a spectrum of intermediate states of EMT phenotypes, these are poorly defined at the single-cell proteomic level in NSCLC clinical specimens. Our overall goal was to dynamically capture and characterize EMT-related drug resistance states in lung cancer cells to construct a single-cell resolution state map of clinical applicability.
Method
We used mass cytometry (CyTOF) time-course experimentation and novel computational tools to analyze TGFβ and drug treated NSCLC cell lines, as well as NSCLC clinical samples to identify clinically relevant drug resistant EMT and MET states and construct a single-cell resolution proteomic map of phenotypic states.
Result
Through TGFβ treatment and withdrawal we resolved previously unrealized EMT and MET states in NSCLC cell lines by analyzing the expression of up to 30 surface and intracellular markers. Using a novel computational tool (TRACER) we also provide evidence that EMT and MET trajectories differ and exert differential drug sensitivity profiles. We used the identified EMT and MET states to construct a NSCLC reference EMT-MET state map, on which we projected NSCLC clinical samples to characterize their phenotypic profile in terms of our in vitro EMT-MET analysis. Finally, we extended our mass cytometry time-course analysis to NSCLC cells that underwent various drug treatments (e.g. Erlotinib, Docetaxel) and subsequent withdrawal to augment our EMT-MET state map with drug resistance phenotypic traits. We found that NSCLC resistant cells displayed through time overlapping morphological and cell signaling features with EMT and MET and were able to rebound from short-term drug-induced effects. These data are currently being used to evaluate EMT-related drug resistant cell states detected in pleural effusions during and after the course of treatment in different NSCLC patient therapy time-points.
Conclusion
In summary, we provide a framework that can be extended to phenotypically characterize clinical samples with single-cell resolution in the context of in vitro studies showing differential EMT-MET traits related to drug sensitivity. This sets the foundation for developing tools towards evaluating - at a personalized level – disease status and response to treatment in NSCLC patients.
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OA08.04 - Discussant - OA08.01, OA08.02, OA08.03 (Now Available) (ID 3760)
11:00 - 12:30 | Presenting Author(s): Luca Roz
- Abstract
- Presentation
Abstract not provided
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OA08.05 - Notch Inhibition Overcomes Resistance to Tyrosine Kinase Inhibitors Promoted by Gate-Keeper Mutations in EGFR-Driven Lung Adenocarcinoma (Now Available) (ID 639)
11:00 - 12:30 | Presenting Author(s): Antonio Maraver | Author(s): Emilie Bousquet, Xavier Quantin, Jean Louis Pujol, Kwok-Kin Wong, Jean-Charles Soria, Julien Mazieres, Luis Paz-Ares
- Abstract
- Presentation
Background
EGFR mutated lung adenocarcinoma patients treated with gefitinib and osimertinib showed a therapeutic benefit limited by the appearance of secondary mutations, such as EGFRT790M and EGFRC797S. It has been generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, indicating that the use of single drug to treat efficiently EGFR-driven lung adenocarcinoma might have limited value while a strategy based on combinational drug therapy could be more effective at mitigating the effects of gatekeeper mutations.
Method
We have combined the use of EGFR-driven genetic engineered mouse models and patient-derived xenografts, adenocarcinoma cell lines and primary samples from EGFR mutated patients.
Result
We uncover here that gefitinib and osimertinib increase STAT3 phosphorylation (pSTAT3) in EGFRT790M and EGFRC797S tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induces a pSTAT3-dependent strong reduction in the levels of the transcriptional repressor HES1. Importantly, we show that tyrosine kinase inhibitor resistant tumors, with EGFRT790M and EGFRC797S mutations, are highly responsive to the combined treatment of Notch inhibitors with gefitinib and osimertinib respectively. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increase during relapse and correlate with shorter progression-free survival.
Conclusion
Our results show that the Notch pathway plays a major role in the relapse of lung adenocarcinoma patients treated with EGFR TKIs, providing a rationale to treat patients that become resistant to EGFR TKI with a combination of the same TKI and Notch inhibitors.
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OA08.06 - Reciprocal Change in Glucose Metabolism of Cancer and Immune Cells Mediated by Different GLUT Predicts Immunotherapy Response (Now Available) (ID 642)
11:00 - 12:30 | Presenting Author(s): Hongyoon Choi | Author(s): Kwon Joong Na, Young Tae Kim
- Abstract
- Presentation
Background
Tumor metabolism represented by aerobic glycolysis is dynamically changed in tumor microenvironment (TME) to achieve immune escape. However, in vivo properties of glucose metabolism in cancer and immune cells are poorly understood and their clinical implications are still lacking. We scrutinized the association of tumor metabolism and immune properties of TME by comprehensive analyses using tissue RNA-seq, positron emission tomography (PET), and single cell RNA-seq data.
Method
Lung squamous cell carcinoma (LUSC) samples with both RNA-seq and 18F-deoxyglucose (FDG) PET (n = 63) were collected to examine the association of in vivo glucose metabolism, gene expression levels related to glucose metabolism, and immune cell enrichment. An overall enrichment score of TME (ImmuneScore) was estimated from tissue RNA-seq data. The gene expression levels of each cell component of TME were analyzed by single cell RNA-seq from lung cancer patients. The expression patterns of glucose transporters (GLUTs) were evaluated in patients who underwent immunotherapy to investigate whether it can predict immunotherapy response.
Result
Single cell RNA-seq showed that GLUT1 was mostly expressed in cancer cells while GLUT3 was mostly found in myeloid cells in TME. ImmuneScore showed a negative correlation with GLUT1 (r=-0.70, p<0.01) and a positive correlation with GLUT3 (r=0.39, p<0.01) in LUSC samples, and it was validated in TCGA cohort (r=-0.44, p<0.01 for GLUT1; r=0.26, p<0.01 for GLUT3). LUSC samples were divided into two distinct groups (immure-rich and immune-poor) by ImmuneScore. In immune-poor cluster, FDG uptake was positively correlated with GLUT1 (r=0.27, p=0.04), while not correlated with GLUT3. In immune-rich cluster, FDG uptake was positively correlated with GLUT3 (r=0.78, p=0.01), while not correlated with GLUT1. ImmuneScore was negatively correlated with FDG uptake in immune-poor cluster, while there was positive correlation in immune-rich cluster. We defined GLUT3-GLUT1 ratio (GLUTratio) as a metabolic biomarker representing immune status in TME. High GLUTratio indicates increased metabolic activity in immune cells and decreased metabolic activity in cancer cells in TME. For melanoma patients who underwent anti-PD-1 therapy, GLUTratio was significantly higher in responders than nonresponders (p=0.03).
Conclusion
Our findings support a reciprocal change of glucose metabolism between cancer and immune cells within TME mediated by different GLUTs. A new glucose metabolism-based biomarker, GLUTratio, can reflect reciprocal metabolic activity of immune and cancer cells in TME, and be a feasible predictive biomarker for immunotherapy.
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OA08.07 - Aberrant Epigenetic SMAD3 Signaling in Tumor-Associated Fibroblasts Modulates Fibrosis and Response to Nintedanib in NSCLC (Now Available) (ID 1972)
11:00 - 12:30 | Presenting Author(s): Rafael Yamashita Ikemori | Author(s): Marta Gabasa, Miguel Vizoso, Paula Duch, Sebastian Moran, Sabrina Gea-Sorli, Paloma Bragado, Toni Jauset, Manel Esteller, Laura Soucek, Eduard Monsó, Victor Peinado, Cristina Fillat, Frank Hilberg, Noemi Reguart, Jordi Alcaraz
- Abstract
- Presentation
Background
Tumor-associated fibroblasts (TAFs) exhibit a fibrotic phenotype in non-small cell lung cancer (NSCLC) that has beeen associated with critical steps of cancer progression. Paradoxically, we reported that the profibrotic TGF-β transcription factor SMAD3 was epigenetically downregulated through promoter hypermethylation in TAFs from NSCLC patients compared to patient-matched control fibroblasts. In addition, we reported that the antifibrotic drug nintedanib elicited a stronger inhibition of the fibrotic phenotype and its tumor-promoting effects in TAFs from adenocarcinoma (ADC) patients compared to squamous cell carcinoma (SCC) patients upon TGF-β1 stimulation in vitro, which was consistent with the selective therapeutic response to nintedanib observed in a clinical trial in ADC (but not SCC) patients. These previous results support the hypothesis that TGF-β1 signaling may be altered in lung TAFs according to their histologic subtype.
Method
In this study we tested our working hypothesis by determining the expression and activity of SMAD3 and its closely related homologue SMAD2 in patient-derived TAFs and paired control fibroblasts, and by dissecting their potential contribution to the differential therapeutic responses to nintedanib observed in ADC and SCC using in vitro and in vivo preclinical models.
Result
In vitro studies revealed a marked SMAD3 epigenetic repression through promoter hypermethylation, a low pSMAD3/pSMAD2 ratio and a limited fibrotic phenotype selectively in SCC-TAFs. In contrast, ADC-TAFs overexpressed a panel of fibrotic markers upon TGF-β1 stimulation concomitantly with a high pSMAD3/pSMAD2 ratio and a limited SMAD3 promoter methylation. Histologic analysis of a large patient cohort (112 ADC, 96 SCC) confirmed that the extent of fibrosis is larger in ADC than SCC patients. In addition, knocking-down SMAD3 in ADC-TAFs was sufficient to reduce the antifibrotic and antigrowth effects of nintedanib in vitro and in tumor xenografts in vivo. On the other hand, long-term exposure of pulmonary fibroblasts to cigarette smoke condensate was sufficient to hypermethylate the SMAD3 promoter. Since SCC and ADC tumors typically arise in the upper airways and distal pulmonary sites, respectively, it is conceivable that fibroblasts might be more exposed to the smoking epigenetic effects on SMAD3 in SCC.
Conclusion
We report for the first time that tumor fibrosis is higher in ADC than SCC patients, in association with a selective therapeutic response to the antifibrotic drug nintedanib in the former, and identify the subtype-specific extent of SMAD3 epigenetic repression in TAFs and the subsequent aberrant SMAD3/SMAD2 imbalance as major regulatory mechanisms of tumor fibrosis and response to nintedanib in NSCLC.
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OA08.08 - Discussant - OA08.05, OA08.06, OA08.07 (Now Available) (ID 3761)
11:00 - 12:30 | Presenting Author(s): Luis M Montuenga
- Abstract
- Presentation
Abstract not provided
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OA08.09 - Adi F. Gazdar Lectureship Award for Translational Science (Now Available) (ID 3898)
11:00 - 12:30 | Presenting Author(s): Roman Thomas
- Abstract
- Presentation
Abstract not provided
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Author of
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MS12 - Genome Screenings (ID 75)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Wan Lam, Julian Carretero
- Coordinates: 9/10/2019, 11:30 - 13:00, Vancouver (2003)
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MS12.05 - Genomic Studies on Small Cell Lung Cancer (Now Available) (ID 3510)
11:30 - 13:00 | Presenting Author(s): Julie George
- Abstract
- Presentation
Abstract
Section not applicable
Information from this presentation has been removed upon request of the author.
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OA15 - Targeted Agents and Immunotherapy for Small Cell Lung Cancer (ID 152)
- Event: WCLC 2019
- Type: Oral Session
- Track: Small Cell Lung Cancer/NET
- Presentations: 1
- Now Available
- Moderators:Raffaele Califano, Charles M Rudin
- Coordinates: 9/10/2019, 14:30 - 16:00, Hilton Head (1978)
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OA15.05 - BIOLUMA: A Phase II Trial of Nivolumab and Ipilimumab in Lung Cancer – Prospective Evaluation of TMB in SCLC Patients (Now Available) (ID 592)
14:30 - 16:00 | Presenting Author(s): Julie George
- Abstract
- Presentation
As requested by the author, the abstract for this presentation will not be published
Information from this presentation has been removed upon request of the author.
