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Emerging evidence demonstrates that long non-coding RNAs (lncRNAs) are deeply involved in the development of various cancers. This study identified that SBF2-AS1, an early-stage-specific lncRNA, is critical for the tumorigenesis of lung adenocarcinoma (LUAD). We first analyzed LUAD transcriptome data from The Cancer Genome Atlas and the GEO database by weighted gene co-expression network analysis (WGCNA). Five early LUAD-specific lncRNAs were filtered out, and only SBF2-AS1 was upregulated in LUAD. High expression of SBF2-AS1 indicates poor survival of LUAD, especially the early-stage LUAD, but not lung squamous cell carcinoma. SBF2-AS1 promotes LUAD cells proliferation in vitro, and RNA-sequencing data shows that many cell-cycle-related genes were downregulated after SBF2-AS1 knockdown. Mechanically, SBF2-AS1 could competitively bind with miR-338-3p and miR-362-3p to increase E2F1 expression. Finally, we show that the SBF2-AS1-miR-338-3p/362-3p-E2F1 axis could promote LUAD tumorigenesis in vitro and in vivo. Our study demonstrates that SBF2-AS1, an early-stage-specific lncRNA, promotes LUAD tumorigenesis by sponging miR-338-3p and miR-362-3p and increasing E2F1 expression. The SBF2-AS1-miR-338-3p/362-3p-E2F1 regulatory axis may serve as a prognostic marker and potential therapeutic target for LUAD. Keywords: WGCNA, lung adenocarcinoma, tumorigenesis, ceRNA, SBF2-AS1, lncRNA

COVID-19 presents a unique threat to patients with lung cancer, with mortality rates as high as ~32%. Given the convergence of these two deadly diseases, the lung cancer research and advocacy communities rapidly mobilized in early 2020 to create the COVID Lung Cancer Consortium (CLCC), a global assembly of leading experts in thoracic oncology, immunology, virology, vaccines and patient advocacy. With ongoing robust exchange of data and shared learning and rational planning for clinical and laboratory investigations, the CLCC is bringing its collective expertise to bear on beginning to address the question of why patients with lung cancer are at such elevated risk of worse outcomes from COVID-19. These efforts led to a recently funded U54 CA260560 grant as part of the National Cancer Institute’s SeroNet initiative to study the magnitude, quality and duration of antibody responses to SARS-CoV-2 infection in patients with lung cancer compared to healthy controls. In the first project, our Mt. Sinai U54 Serological Center of Excellence will follow a prospective lung cancer cohort (750 patients) and a matched non-lung cancer control group (750 individuals) to determine if there are differences in antibody responses related to age, gender, tobacco history, and race/ethnicity. Given that effective SARS-CoV-2 vaccines are now being deployed, the study will also analyze antibody responses to vaccination across these two patient cohorts. The second project will examine biological determinants correlating with susceptibility to infection, including analysis of both ACE2 and TMPRSS2 levels, and antibody-mediated neutralization in pre-clinical models of established lung cancer and normal lung epithelial cell lines. In order to capture a diverse and inclusive patient population, this effort will be supported by GO2 Foundation for Lung Cancer through its national network of Centers of Excellence. This rapid global mobilization of the lung cancer community through the CLCC and the resulting Serological Center of Excellence is positioned to answer fundamental questions regarding the susceptibility of patients with lung cancer to SARS-CoV-2 infection and severe COVID-19 disease and provide information to allow assessment of the value of vaccination and the utility of specifically designed vaccine programs for this high-risk patient population. Citation Format: Amy C. Moore, Paul A Bunn Jr., Beatriz Fontoura, Adolfo García-Sastre, Jorge Gomez, Florian Krammer, Phillip Mack, John D. Minna, Christian Rolfo, Yu Shyr, Peter Ujhazy, Fred R. Hirsch. Assessing vulnerability of patients with lung cancer to SARS-CoV-2 infection based on serological antibody analyses [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2021 Feb 3-5. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(6_Suppl):Abstract nr S01-02.

The intramural the National Cancer Institute (NCI) and more recently the University of Texas Southwestern Medical Center with many different collaborators comprised a complex, multi‐disciplinary team that collaborated to generated large, comprehensively annotated, cell‐line related research resources which includes associated clinical, and molecular characterization data. This material has been shared in an anonymized fashion to accelerate progress in overcoming lung cancer, the leading cause of cancer death across the world. However, this cell line collection also includes a range of other cancers derived from patient‐donated specimens that have been remarkably valuable for other types of cancer and disease research. A comprehensive analysis conducted by the NCI Center for Research Strategy of the 278 cell lines reported in the original Journal of Cellular Biochemistry Supplement, documents that these cell lines and related products have since been used in more than 14 000 grants, and 33 207 published scientific reports. This has resulted in over 1.2 million citations using at least one cell line. Many publications involve the use of more than one cell line, to understand the value of the resource collectively rather than individually; this method has resulted in 2.9 million citations. In addition, these cell lines have been linked to 422 clinical trials and cited by 4700 patents through publications. For lung cancer alone, the cell lines have been used in the research cited in the development of over 70 National Comprehensive Cancer Network clinical guidelines. Finally, it must be underscored again, that patient altruism enabled the availability of this invaluable research resource., Infographic showing the results of a comprehensive analysis conducted by the NCI Center for Research Strategy of the downstream use of the 278 human cancer cell lines reported in the original cell line supplement issue (1). These cell lines and related meta data were available to the research community across the world at the cost of only shipping and cell line curation. The research and care impact of this access over the ensuing twenty five years was determined for publications, citations, supporting grants, patents and linked clinical trials.

Despite the paucity of therapeutic advances in SCLC, considerable progress in understanding the biology, molecular biology, model systems and potential therapeutic targets has been made. Studies of early lung and neuroendrocrine cell development models have provided insights into the cell of origin for SCLC. New GEMMs have illustrated the universal importance of TP53 and RB1 gene mutations in the pathogenesis and the potential role of additional genetic changes as well as changes in transcription factor expression. PDXs and CDXs provide new means for preclinical testing of new therapies. Molecular studies have identified the high mutation burden found in SCLC and have identified differences between SCLC, carcinoids and large cell neuroendocrine tumors. Potential therapeutic targets including EZH2, PARP, CDK1, MCL1, BCL2, BIM, SHH (Sonic Hedgehog), WNT, NOTCH1, Aurora Kinase, FGFR, PIK3CA, RET, THZ1, JAK-STAT, FAK, CXCR4, PD-L1, Fuc-GM1, CD56 and CD47. Ongoing and future clinical trials have to show which of these candidates can be translated into an effective targeted therapy. Thus, the future of improving outcomes for SCLC patients appears promising but there are still a number of unanswered questions which need to be addressed in the future and these are outlined below. Small Cell Lung Cancer Major Questions of Translational Relevance What are the mechanisms underlying the universal development of chemoresistance? SCLC is in nearly every case very sensitive to platinum-etoposide chemotherapy with dramatic clinically beneficial responses. However, in nearly every case the tumors become resistant to this chemotherapy. What is the mechanism of this resistance, are there ways to avoid it, and what are additional therapies that could kill such resistant tumor cells? What are the mechanisms of highly metastatic behavior in SCLC? SCLC is in nearly every case highly metastatic from the time of clinical diagnosis. What are the most important mechanisms responsible for the metastatic behavior and can these be therapeutically targeted? A subset of this question, is that SCLC appear to be much enriched in cancer stem cells (“tumor initiating cells”, TICs) and does targeting stem cell signaling pathways provide effective therapy for primary and metastatic sites of SCLC? Are there therapeutic targets of “acquired vulnerability” associated with RB1 or TP53 mutations in SCLC? Tumor suppressor genes RB1 and TP53 abnormalities are essentially universal in SCLCs. Are there acquired vulnerabilities associated with changes in these two genes that can be therapeutically targeted? Do the many other mutations occurring in human SCLC (but not in GEMMs) provide therapeutic targets – “acquired vulnerabilities for human SCLC?” Current evidence indicates that human SCLCs have many other genetic (mutations) and epigenetic changes besides those involving the key oncogenic drivers (such as TP53, RB1, LMYC, NFIB). By contrast, mouse GEMM SCLC have very few additional changes. Presumable the differences in mutation rates result from exposure to cigarette carcinogens in humans but not in mice. Do the other mutations in human SCLC provide acquired vulnerabilities of therapeutic vulnerabilities, do any these represent “synthetic lethalities” with the main driver oncogene changes, and are there several vulnerabilities common across multiple SCLCs or are these vulnerabilities “private” and found in only individual tumors? Can we develop therapeutic strategies targeting important SCLC driver transcription factors? Several transcription factors appear to be very important in the growth and survival of SCLC including ASCL1, NeuroD1, myc family members, and SOX2). Are there therapeutic strategies that can be directed against these key transcription factors and do they provide quantitatively multiple logs of tumor cell kill to allow development of curative strategies? What are the important differences in human preclinical models of SCLC that influence discovery and validation of new therapies? Currently there are several types of human preclinical models of SCLC including SCLC lines, SCLC cell line xenografts (CDXs), patient derived SCLC xenografts (PDXs), and circulating SCLC tumor cells isolated from peripheral blood of SCLC patients. While these all share common genetic abnormalities found in SCLC (such as TP53, RB1, myc family members), we need to know what are the molecular differences between these different models and SCLC tumor samples and whether preclinical therapeutic responses are similar or different between these models. Can we continue to use all of the models for development of new therapies or do we need to only use one type of preclinical model? Are the differences between human SCLC and GEMM of SCLC that influence the discovery and validation of new therapies? Genetically engineered mouse models of lung cancer (GEMMs) appear to be very similar to human SCLC. However, it appears that mouse GEMM SCLC do not appear to be sensitive to platin-etoposide chemotherapy. What are the differences between human and the GEMM models of SCLC that explain this discrepancy? Are there important differences between human and GEMM preclinical models that could influence the discovery and validation of new SCLC therapies? What are the biologic reasons for SCLCs expressing ASCL1 vs NeuroD1 as a lineage oncogene? The majority of human SCLCs have ASCL1 as the major neuroendocrine lineage driver gene. However, a subset of human SCLCs express high levels of NeuroD1 and not ASCL1. Currently, there is no evidence that mouse lung neuroendocrine cells can express Neuro D1. This raises the question of whether small cell cancers predominantly expressing NeuroD1 arise in the human lung or in some other primary site. Do genetic abnormalities in histologically normal epithelium of SCLC patients provide diagnostic and chemopreventative targets? There appear to be a much greater frequency of genetic abnormalities in the histologically normal epithelium of patients with SCLC compared to those with NSCLC. Does this information provide ways for early diagnosis or implementation of chemoprevention strategies for SCLC using these genetic alterations as molecular biomarkers? Most recently the US National Cancer Institute released a Request for Application (RFA) (PAR-16-049, PAR-16-050, PAR-16-051) for grants specifically focusing on SCLC, and hopefully through these grants many of the above questions will be addressed.

The standard of care for both limited stage and extensive stage SCLC has seen little change since the introduction of platinum/etoposide doublet therapy in the mid-1980s (1,2). There have been advances in the clinic since then, including the approval of topotecan for recurrent SCLC and the application of new radiation therapy strategies, but despite these advances the outlook for patients afflicted with SCLC remains dismal (3-8). The frequent and rapid incidence of acquired resistance to these therapies (6) and the inability to detect early-stage disease by radiographic approaches (9-11) has bedeviled progress in this deadly disease.