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Marisol Arroyo-Hernandez
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MS05 - Novel Biological Pathways and Druggable Targets (ID 68)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Biology
- Presentations: 5
- Now Available
- Moderators:Jin Jen, Marisol Arroyo-Hernandez
- Coordinates: 9/09/2019, 11:00 - 12:30, Vancouver (2003)
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MS05.01 - Epigenetic Therapeutics in Lung Cancer (Now Available) (ID 3461)
11:00 - 12:30 | Presenting Author(s): Kwok-kin Wong
- Abstract
- Presentation
Abstract
Epigenetic Targets and Drugs to enhance immune response in Lung Cancer
Kwok-Kin Wong
Effective therapies for non–small cell lung cancer (NSCLC) remain challenging despite an increasingly comprehensive understanding of somatically altered oncogenic pathways. It is now clear that therapeutic agents with ability to impact the tumor immune microenvironment potentiate immune-orchestrated therapeutic benefit. We have previously demonstrated the immunoregulatory properties of histone deacetylase (HDAC) and bromodomain inhibitors, two classes of drugs that modulate the epigenome, with a focus on key cell subsets that are engaged in an immune response. By evaluating human peripheral blood and NSCLC tumors, we have shown that the selective HDAC6 inhibitor ricolinostat promotes phenotypic changes that support enhanced T-cell activation and improved function of antigen-presenting cells. The pan-bromodomain inhibitor JQ1 attenuated CD4+FOXP3+ T regulatory cell suppressive function and synergized with ricolinostat to facilitate immune-mediated tumor growth arrest, leading to prolonged survival of mice with lung adenocarcinomas. Finally, we have recently performed in vivo CRISPR screens to identify additional novel epigenetic targets that would synergize with PD1 blockade in KRAS driven NSCLC.
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MS05.02 - Genetics Abnormalities in Chromatin Modifiers: Connection with MYC Pathway and Exploration for Therapeutics (Now Available) (ID 3462)
11:00 - 12:30 | Presenting Author(s): Montse Sanchez-Cespedes
- Abstract
- Presentation
Abstract
The understanding about the complexity of the molecular networks that regulate the epigenetic control of gene expression is boosting. Moreover, it is accepted that an abnormal function of these networks, due to genetic alterations of its components, play an essential role during tumorigenesis. Among the networks involved in this epigenetic control, there is the SWI/SNF-chromatin remodeling complex, a regulator of the accessibility of the chromatin to DNA-binding proteins (1-2). Inactivating mutations at different members of the complex have been found to be inherent to most human cancers. Our team had pioneered these investigations, being the first to report inactivating mutations at BRG1 (also SMARCA4) which codes for the ATPase of the SWI/SNF complex (3-4). In lung cancer (LC), alterations at any member of this complex affect about half of the tumors and occur in a background of wild type MYC (either C, L or N) (3). In the lasts years, inactivating mutations at other members of the complex (e.g. SNF5, PRBM, ARID1A, ARID2) have been shown to evolve in most human cancers (2,5). More recently, our laboratory also pioneered the identification of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in small cell lung cancers, where it is present in tumors that are wild type for MYC and BRG1 (6). Altogether, the genetic observations indicate the existence of an important network, involving SWI/SNF and MAX/MYC, which is critical to LC development. Using LC as a model, we have scrutinized genomic data, whole exome sequencing (WES) and RNA-sequencing, collected from patient-derived xenografts (PDXs), from patient-derived cells (PDCs) and from public databases (Sanger-COSMIC and CCLE), to delineate the gene alteration profile at epigenetic controllers (including already known drivers and novel candidates) in LC. Combined, all the alterations at epigenetic controllers include different members of the SWI/SNF complex (SMARCA4/BRG1, ARID1A, PBRM1) as well as interesting candidates such as the MAX-binding protein, MGA, or the histone-modifying enzymes (KMT2D/MLL2, KMT2G/SETD1B), among others. Some of these alterations appeared in a mutually exclusive pattern, suggesting a functional connection
We have also integrated this information to search for cancer vulnerabilities.Components of the SWI/SNF complex are known to bind to various nuclear receptors, such as those of estrogens, progesterone, androgens, glucocorticoids (GCs) and retinoic acid (RA), thereby adapting the gene expression programs to the demands of the cell environmental requirements (7-9). We found that the restitution of BRG1 in LC cells restores the gene expression signature of normal lung and that cells lacking BRG1 did not respond to RA or GCs, while restoration of BRG1 restored sensitivity (10). The co-administration of the epigenetic compounds azacitidine (demethylating agent) and SAHA (inhibitor of histone deacetylases) enhanced all these effects, both in cell cultures and in vivo, accompanied by sustained reductions in genome-wide DNA methylation. Together, these data support the notion that an inactive BRG1 confers resistance to RA and GCs, which prevents cancer cell differentiation. In contrast, the observations also indicate that RA/GC-based treatments could be designed to treat LC patients with MYC-amplified tumours. On the other hand, recent investigations have searched for vulnerabilities of BRG1-mutant cells that may be therapeutically approachable and have found that the inhibition of cyclin-dependent kinase 4/6 (CDK4/6) appear to be synthetic lethal in BRG1-deficient tumours (10). In my presentation I will be showing our last and novel observations of epigenetic-related compounds that promote cell growth inhibition specifically in BRG1-mutant lung cancers.
In parallel, gene alterations at other epigenetic-related components have also been reported in cancer. Some of these include the methyltransferase EZH2, a transcriptional repressor, the transcriptional co-activator protein p300, a histone acetyltransferase that regulates transcription via chromatin remodelling or the histone acetyltransferase CREBBP, which also acts as a scaffold to stabilize additional protein interactions with the transcription complex. In LC these alterations are more common in small cell lung cancer (SCLC). In SCLC, there is also recurrent inactivation of MAX and of MGA, proteins directly linked to the MYC trans-activation activities. Here, we found that the gene expression profile of MAX-mutant SCLC cells cluster to that of the ASCL1-transcription factor dependent group of SCLCs, which also includes NMYC- and LMYC-activated but not with MYC or BRG1-mutant SCLC cells. MGA, is an extraordinary large protein that is also recurrently inactivated in NSCLC. The MYC-MAX and MADs/MGA-MAX complexes have opposed functions in transcription, being MAX a central player in this network. MAX and MGA have shown to also act as part of the Polycomb Repression Complex 1 (PRC1), specifically the non-canonical PRC1 complex designated as ncPRC1. I will also present our data on the functional characterization of the role of MYC and of MGA in the MAX-deficient SCLC cells.
References:
1.Peterson CL et al. Five SWI/SNF gene products are components of a large multisubunit complex required for transcriptional enhancement. Proc Natl Acad Sci USA. 1994; 91: 2905-8.
2.Wilson GB, Roberts CWM. SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer 2011; 11: 481-92.
3.Medina PP et al. Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines. Hum Mut. 2008; 29: 617-22a.
4.Rodriguez-Nieto S et al. Massive parallel DNA pyrosequencing analysis of the tumor suppressor BRG1/SMARCA4 in lung primary tumors. Hum Mut. 2011; 32: E1999-2017.
5.Romero OA, Sanchez-Cespedes M. The SWI/SNF genetic blockade: effects in cell differentiation, cancer and developmental diseases. Oncogene 2014; 33: 2681-9.
6. Romero OA et al. MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1. Cancer Discov. 2014; 4: 292-303.
7. Chiba H, et al. Two human homologues of Saccharomyces cerevisiae SWI2/SNF2 and Drosophila brahma are transcriptional coactivators cooperating with the estrogen receptor and the retinoic acid receptor. Nucleic Acids Res. 1994; 22: 1815-182015.
8.Romero OA et al. The tumour suppressor and chromatin-remodelling factor BRG1 antagonizes Myc activity and promotes cell differentiation in human cancer. EMBO Mol Med. 2012; 4: 603-16.
9. Romero OA et al. Sensitization of retinoids and corticoids to epigenetic drugs in MYC-activated lung cancers by antitumor reprogramming. Oncogene 2017;36:1287-96.
10. Xue Y, et al.SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer. Nat Commun. 2019;10:557.
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MS05.03 - Notch Signalling (Now Available) (ID 3463)
11:00 - 12:30 | Presenting Author(s): Shirish Gadgeel
- Abstract
- Presentation
Abstract
Notch Signaling
The Notch signaling pathway is a highly conserved pathway that has a vital role in embryonic development and post-embryonic functions such as hematopoiesis, neural cell development and angiogenesis (1). The signaling pathway is activated by the interaction of 4 Notch receptors and their interactions with 5 different ligands. Signaling is characterized by juxtacrine interaction between ligands and receptors on neighboring cells or within the same cell. Alterations in this pathway have been detected in several tumors both as tumor promoter and tumor suppressor.
Notch signaling does appear to have relevance in non-small cell lung cancers (NSCLC) (2). In approximately 30% of NSCLCs loss of Numb, a negative regulator of Notch1, leads to increased Notch activity and about 10% of NSCLCs have gain of function mutations in Notch1. A meta-analysis demonstrated that higher expression of Notch1 was correlated with more advanced tumors (3). In addition, higher expressions of both Notch1 and Notch3 were associated with poor prognosis (4,5). In pre-clinical studies inhibition of Notch3 signaling has reduced growth of lung cancers. In addition, it has been demonstrated that there is cross talk between Notch3 and EGFR pathways and inhibition of both pathways can induce expression of anti-apoptotic protein BIM. Finally, Notch signaling may have a role in induction of the epithelial to mesenchymal phenotype (EMT) in cancers (6). EMT is known to be associated with resistance to both cytotoxic agents and targeted agents and inhibition of Notch signaling can not only reverse EMT but also can enhance the anti-tumor activity of cytotoxic agents such as cisplatin and targeted agents such as erlotinib. The EMT phenotype is frequently observed in a sub-population of cancer cells with self-renewal capacity or cancer stem cells. Notch signaling may be crucial to survival of cancer stem cells and persistence of this population may contribute to resistance to therapeutic agents.
In squamous cell lung cancers Notch signaling may have tumor suppressive properties (7). Loss of function mutations in Notch family of genes, predominantly in Notch receptors, are frequently identified in several squamous cell cancers including squamous cell cancer of the lung. Similarly, loss of function mutations in Notch genes, particularly Notch1 have been identified in small cell lung cancer (SCLC). Expression of Notch receptor in a mouse model of SCLC reduced tumor burden, suggesting its tumor suppressive properties. The expression of DLL3, one of the Notch ligands is induced in SCLC by a key transcription factor ASCL1.DLL3 is shown to downregulate Notch signaling in SCLCs and enhance the carcinogenic phenotype.
All the above data suggest that Notch signaling is highly contextual. In some tumors this pathway may have tumor suppressive properties but in others tumor promoting properties. Defining the role of this pathway in tumor types may guide development of therapeutic strategies targeting the Notch signaling pathway.
References
Bigas A, Espinosa L. The multiple usages of Notch signaling in development, cell differentiation and cancer. Curr Opin Cell Biol 2018;55:1-7.
Westhoff B, Colaluca IN, D’Ario G, et al. Alterations of the Notch pathway in lung cancer. Proc Natl Acad Sci 2009;106:22293-8.
Yuan X, Wu H, Xu H, et al. Meta-analysis reveals the correlation of Notch signaling with non-small cell lung cancer progression and prognosis. Sci Rep 2015;5:10338.
Donnem T, Andersen S, Al-shibili K, et al. Prognostic impact of Notch ligands and receptors in nonsmall cell lung cancer: coexpression of Notch-1 and vascular endothelial growth factor-A predicts poor survival. Cancer 2010:116:5674-85.
Hassan WA, Yoshida R, Kudoh S, et al. Evaluation of role of Notch3 signaling pathway in human lung cancer cells. J Cancer Res Clin Oncol 2016;142:981-93.
Yuan X, Wu H, Han N, et al. Notch signaling and EMT in non-small cell lung cancer: biological significance and therapeutic application. J Hematol Oncol 2014;7:87.
Nowell CS, Radtke F. Notch as a tumor suppressor. Nat Rev Cancer 2017;17:145-159.
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MS05.04 - Innate Immune Mediators in Lung Cancer (Now Available) (ID 3464)
11:00 - 12:30 | Presenting Author(s): Antonio Calles Blanco
- Abstract
- Presentation
Abstract
Non-small-cell lung cancer (NSCLC) accounts for about 85% of total lung cancer cases. The major types of NSCLC—squamous cell carcinoma and adenocarcinoma—harbor distinct histopathologies, biomarker expression, genomic alterations, and response to therapy [1,2]. Recent studies have shown that there are also differences in their tumor immune microenvironments [3–6]. Specifically, adenocarcinomas have increased infiltration of tumor-associated macrophages, while squamous lung tumors exhibit an enrichment in tumor-associated neutrophils (TANs) in both mouse and human lung tumors. The two major subtypes of NSCLC are also associated with distinct lineage-specific master regulators: SOX2 is commonly amplified and up-regulated in the vast majority of squamous tumors anddrives the squamous fate, whereas NKX2-1 is highly expressed in adenocarcinoma and governs adenocarcinoma fate [2]. We developed novel genetically engineered mouse models (GEMMs) of squamous lung cancer on the basis of overexpression of the transcription factor Sox2 and loss of the tumor suppressor Lkb1 (SL mice) (Mukhopadhyay et al, Cell Rep, 2014 [7]). SL tumors recapitulated gene expression and immune infiltrate features of human squamous NSCLC, including an enrichment of TANs and a decrease in expression of NKX2-1. Deletion of Nkx2-1in SL mice (SNL) revealed that NKX2-1 suppresses SOX2-driven squamous tumorigenesis by repressing adeno-to-squamous transdifferentiation. We further employed multiple GEMMs to elucidate the role of SOX2 and NKX2-1 in tumor cell fate and TAN recruitment. In Kras-driven adenocarcinomas,mis-expression of Sox2 or loss of Nkx2-1 led to TANrecruitment. SOX2 recruits, whereas NKX2-1 suppresses, TANs at least partly through inverse regulation of the chemokineCxcl5. Tumor-derived CXCL5 is sufficient to recruit TANs. Single cell RNA sequencing (scRNA-seq) revealed that TANs exhibit tumor-promoting features, including production of reactive oxygen species (ROS), and distinct gene expression profiles compared to blood neutrophils (Mollaoglu et al, Immunity, 2018 [8]). Depletion of TANs through LY6G blocking antibodies or CXCR2 inhibitors in SNL mice reduced squamous tumors, suggesting that TANs foster squamous cell fate. Furthermore, TAN depletion coupled with scRNA-seq suggests that TANs regulate distinct aspects of tumor cell fate. Together, these data suggest that lineage-defining transcription factors determine the tumor immune microenvironment, which in turn can impact the nature of the tumor.
References
1 Langer, C.J. et al. (2016) Incremental Innovation and Progress in Advanced Squamous Cell Lung Cancer: Current Status and Future Impact of Treatment. J. Thorac. Oncol.11, 2066–2081.
2 Campbell, J.D.et al. (2016) Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas. Nat. Genet.48, 607–616.
3 Kargl, J. et al. (2017) Neutrophils dominate the immune cell composition in non-small cell lung cancer. Nat. Commun.8, 14381
4 Nagaraj, A.S. et al. (2017) Cell of Origin Links Histotype Spectrum to Immune Microenvironment Diversity in Non-small-Cell Lung Cancer Driven by Mutant Kras and Loss of Lkb1. Cell Reports 18, 673–684.
5 Xu, C. et al. (2014) Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated PD-L1 Expression. Cancer Cell 25, 590–604.
6 Ferone G., et al. SOX2 Is the Determining Oncogenic Switch in Promoting Lung Squamous Cell Carcinoma from Different Cells of Origin. Cancer Cell. 2016;30(4):519-532. doi:10.1016/J.CCELL.2016.09.001.
7 Mukhopadhyay, A. et al. (2014) Sox2 Cooperates with Lkb1 Loss in a Mouse Model of Squamous Cell Lung Cancer. Cell Reports 8, 40–49.
8 Mollaoglu, G. et al. (2018) The Lineage-Defining Transcription Factors SOX2 and NKX2-1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment. Immunity 49, 764-779.e9.
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MS05.05 - Harnessing Oncogene Dependencies in Lung Cancer (Now Available) (ID 3465)
11:00 - 12:30 | Presenting Author(s): Martin L Sos
- Abstract
- Presentation
Abstract
The introduction of precision medicine had a dramatic impact on the overall survival of genomically selected lung cancer patients. This is primarily true for lung adenocarcinomas in which druggable targets like mutant EGFR or rearranged ALK are frequently oncogenically activated. The major challenge in these patients is the inevitable emergence of drug resistant clones that abrogate the effects of selected tyrosine kinase inhibitors. Through a detailed characterization of patients that relapse under osimertinib treatment we identified novel routes to overcome individual resistance mutations in EGFR. At the same time, the majority of lung lacks directly druggbale targets and thus remains largely unaffected by this therapeutic revolution. The induction of programmed cell death by perturbing the pro- and anti-apoptotic members of the BCL-2 family may represent an attractive strategy to circumvent this medical need. We sought to explore dependencies on individual BCL-2 family members with different therapeutic strategies to identify therapeutically relevant pathways in lung cancer models.
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Author of
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P1.01 - Advanced NSCLC (ID 158)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.01-117 - Pulmonary Function Monitoring in Patients with Oligometastatic NSCLC Who Receive Stereotactic Body Radiation Therapy (ID 2044)
09:45 - 18:00 | Presenting Author(s): Marisol Arroyo-Hernandez
- Abstract
Background
Patients with early and oligometastatic stage Non-small cell lung cancer (NSCLC) who are non-surgical candidates benefit from new radiation treatment modalities, such as stereotactic body radiotherapy (SBRT). Previously we reported the correlation of lung function decline and the presence of lung toxicity related to concomitant chemo-radiotherapy. This work aims to evaluate lung function performance after SBRT in patients with oligometastatic NSCLC.
Method
A one-year prospective multicentric study was conducted at the Instituto Nacional de Cancerología in Mexico. Twenty-six patients with stage IV NSCLC with a single metastasis considered non-operable were treated with SBRT. Lung function was assessed at the baseline and at one, six, twelve, twenty-four and fifty-two weeks after SBRT, using forced spirometry with a bronchodilator, a carbon monoxide diffusing capacity (DLCO) test and oxygen saturation (SpO2) measurement. The study was registered in clinicaltrials.gov (NCT01580579).
Result
Fourteen patients were evaluated with lung function tests, the results were adjusted for the Mexican population. At baseline, the mean for post-bronchodilator (post-BD) FVC (l) was 2.16 (±1.09), for FEV1 2.25 (±1.06), DLCO (ml/min/mmHg) 20.22 (±8.44) and SpO2 of 94% (±2.81). A reduction of <10% of relative change (max. 294 ml) was observed in lung volume in FEV1 and FVC (l) post-BD follow-up with non-significant results. A statistically significant reduction in DLCO 18% (p=0.03) at week 12 was observed, Fig.1. All patients maintained an oxygen saturation level over 90% during the study. Quality of life reduces significantly at week six after SBRT (p=0.03), while respiratory symptoms were non-considerable in the first 12 weeks after receiving SBRT.
Conclusion
Although lung function tests showed a reduction trend, no statistically significant differences were found. The magnitude of lung volume reduction had no significant impact on respiratory symptoms, these findings could suggest that there is less damage in the surrounding tissue after SBRT. This research is an ongoing prospective study of one-year follow-up where several patients continue the be monitored; therefore, we expect to strength our findings by the end of the study.
