Faculty Bibliography

Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis and limited therapeutic options. The extracellular matrix protein fibulin-3/EFEMP1 accumulates in the pleural effusions of MPM patients and has been proposed as a prognostic biomarker of these tumors. However, it is entirely unknown whether fibulin-3 plays a functional role on MPM growth and progression. Here, we demonstrate that fibulin-3 is upregulated in MPM tissue, promotes the malignant behavior of MPM cells, and can be targeted to reduce tumor progression. Overexpression of fibulin-3 increased the viability, clonogenic capacity and invasion of mesothelial cells, whereas fibulin-3 knockdown decreased these phenotypic traits as well as chemoresistance in MPM cells. At the molecular level, fibulin-3 activated PI3K/Akt signaling and increased the expression of a PI3K-dependent gene signature associated with cell adhesion, motility, and invasion. These pro-tumoral effects of fibulin-3 on MPM cells were disrupted by PI3K inhibition as well as by a novel, function-blocking, anti-fibulin-3 chimeric antibody. Anti-fibulin-3 antibody therapy tested in two orthotopic models of MPM inhibited fibulin-3 signaling, resulting in decreased tumor cell proliferation, reduced tumor growth, and extended animal survival. Taken together, these results demonstrate for the first time that fibulin-3 is not only a prognostic factor of MPM but also a relevant molecular target in these tumors. Further development of anti-fibulin-3 approaches are proposed to increase early detection and therapeutic impact against MPM.

Background: Detection of residual disease post-NA treatment (tx) using ctDNA may indicate response and post-surg relapse risk. We profiled ctDNA and describe ctDNA dynamics in pts with NSCLC pre- and post-NA tx with atezo (anti-PD-L1) and post-surg in the LCMC3 study.
Method(s): Pts (N=181) with stage IB to select IIIB NSCLC received 2 cycles of NA atezo before surg. Tumour tissue-informed, germline-corrected ctDNA was measured pre- and post-atezo and post-surg using the AVENIO Oncology Surveillance Test (ctDNA+ defined as ctDNA detection index <=0.05). We correlated quantitative ctDNA levels and ctDNA presence with major pathologic response (MPR; primary endpoint), pathologic response, change in tumour size and disease-free survival (DFS).
Result(s): 126 pts had sufficient tissue to test, of which 106 (84%) had tumour variants suitable for monitoring. Of these, ctDNA was detected in 72% of pre-atezo (n=101), 56% of post-atezo (n=102) and 10% of post-surg samples (n=49). Median ctDNA levels (range) dropped from 3 (0-4448) mean tumour molecules/mL plasma (mtm/mL) pre-atezo to 0.5 (0-406) mtm/mL post-atezo and 0 (0-35) mtm/mL post-surg (all paired comparisons P<0.01). Greater ctDNA reduction post-atezo was seen in pts with MPR vs non-MPR (median log2 fold change -4.8 vs 0.3, P<0.001). Reduced ctDNA levels post-atezo were also associated with pathologic response (P<0.001, r=0.38) and reduction in radiographic tumour size (P<0.001, r=0.42). 2-yr DFS rate for pts who were ctDNA- vs ctDNA+ post-surg was 75% vs 40% (HR, 3.6; 95% CI: 1.0, 13.1; P=0.054). In 64 pts with non-squamous tumours, higher disease stage was associated with higher rates of pre-atezo ctDNA+ status and ctDNA levels (all P<0.05).
Conclusion(s): >60% of pts with resectable lung cancers had sufficient tissue, trackable tumour variants, and were ctDNA+ pre-atezo. ctDNA reductions post-atezo correlated with pathologic response and reduced radiographic tumour size. 2-yr DFS was better in pts who were ctDNA- post-surg. Combining changes in ctDNA with pathologic and radiographic assessment may provide a thorough measurement of response to NA therapy, and may inform management of early NSCLC pts. Clinical trial identification: NCT02927301. Editorial acknowledgement: Medical writing assistance for this abstract was provided by Derrick Afful, PhD and Christopher Lum, PhD of Health Interactions Inc, and funded by Genentech, Inc. Legal entity responsible for the study: Genentech, Inc.
Funding(s): Genentech, Inc. Disclosure: M.G. Kris: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, Editorial Support: Genentech; Financial Interests, Personal, Other, Consultant: Novartis; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Janssen. J.M. Grindheim: Financial Interests, Personal, Full or part-time Employment: Genentech, Inc; Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech. J.E. Chaft: Financial Interests, Personal, Other, editorial/ medical writing assistance: Genentech; Financial Interests, Personal, Other, Consultant: AstraZeneca; Financial Interests, Personal, Other, Consultant: Bristol Myers Squibb; Financial Interests, Personal, Other, Consultant: Genentech; Financial Interests, Personal, Other, Consultant: Merck. J.M. Lee: Financial Interests, Personal, Other, Editorial/ medical writing Support: Novartis; Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech; Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Genentech; Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Other, Consulting Fees: AstraZeneca; Financial Interests, Personal, Other, Consulting fees: Bristol Myers Squibb; Financial Interests, Personal, Other, Consulting Fees: Genentech; Financial Interests, Personal, Other, Consulting Fees: Novartis; Financial Interests, Personal, Speaker's Bureau: AstraZeneca; Financial Interests, Personal, Speaker's Bureau: Bristol Myers Squibb; Financial Interests, Personal, Speaker's Bureau: Genentech; Financial Interests, Personal, Speaker's Bureau: Novartis; Financial Interests, Personal, Speaker's Bureau: eCancer; Financial Interests, Personal, Speaker's Bureau: Medscape; Financial Interests, Personal, Other, meeting attendance support: AstraZeneca; Financial Interests, Personal, Other, meeting attendance support: Genentech; Financial Interests, Personal, Leadership Role, Steering or Executive Committee for Clinical Trials: AstraZeneca; Financial Interests, Personal, Leadership Role, Steering or Executive Committee for Clinical Trials: Genentech; Financial Interests, Personal, Leadership Role, Steering or Executive Committee for Clinical Trials: Novartis. B.E. Johnson: Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Research Grant: Cannon Medical Systems; Financial Interests, Personal, Advisory Board: Hengrui Therapeutics; Financial Interests, Personal, Advisory Board: Checkpoint Therapeutics; Financial Interests, Personal, Advisory Board: Boston Pharmaceuticals; Financial Interests, Personal, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: G1 Therapeutics; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Jazz Pharmaceuticals; Financial Interests, Personal, Advisory Board: Janssen Scientific; Financial Interests, Personal, Other, Consultant: Novartis; Financial Interests, Personal, Other, Dana-Farber Cancer Institute: Dana-Farber Cancer Institute. V.W. Rusch: Financial Interests, Institutional, Other, Institutional Clinical Trial: Genelux, Inc.; Financial Interests, Institutional, Other, Institutional clinical trial: Genentech; Financial Interests, Personal, Other, Travel reimbursement for robotic mentoring: Intuitive Surgical; Financial Interests, Personal, Other, Travel and meeting prep reimbursement for Co-Chair of Thoracic Malignancy Staging Committee: NIH/Coordinating Center for Clinical Trials. P.A. Bunn: Financial Interests, Personal, Other, editorial/ medical writing support: Genentech; Financial Interests, Personal, Other, Consulting fees: AstraZeneca; Financial Interests, Personal, Other, Consulting fees: Ascentage; Financial Interests, Personal, Other, Consulting fees: CStone; Financial Interests, Personal, Other, Consulting fees: Imidex; Financial Interests, Personal, Other, Consulting fees: Viecure; Financial Interests, Personal, Other, Consulting fees: Lilly; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Ascentage; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: CStone; Financial Interests, Personal, Advisory Board: Imidex; Financial Interests, Personal, Advisory Board: Viecure; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Leadership Role: Verastem,.H. Pass: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech; Financial Interests, Personal, Research Grant: Delfi; Financial Interests, Personal, Research Grant: Micronoma; Financial Interests, Personal, Royalties: NCI (cell lines); Financial Interests, Personal, Speaker's Bureau: PER; Financial Interests, Personal, Speaker's Bureau: RTP; Financial Interests, Personal, Other, Patent: IL8 for Lung Cancer; Financial Interests, Personal, Leadership Role, Steering committee for Skyscaper: Genentech; Financial Interests, Personal, Leadership Role, Steering committee for IMpower: Genentech. E. Schum: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Genentech. J. Carlisle, M. Weyant: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech. A. Nicholas, A. Johnson, D. Shames: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech; Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Genentech. I. I Wistuba: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech; Financial Interests, Personal, Research Grant: Genentech; Financial Interests, Personal, Research Grant: HTG Molecular; Financial Interests, Personal, Research Grant: DepArray; Financial Interests, Personal, Research Grant: Merck; Financial Interests, Personal, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Research Grant: Medimmune; Financial Interests, Personal, Research Grant: Adaptive; Financial Interests, Personal, Research Grant: Adaptimmune; Financial Interests, Personal, Research Grant: EMD Serono; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Research Grant: Takeda; Financial Interests, Personal, Research Grant: Amgen; Financial Interests, Personal, Research Grant: Karus; Financial Interests, Personal, Research Grant: Johnson & Johnson; Financial Interests, Personal, Research Grant: Bayer; Financial Interests, Personal, Research Grant: Iovance; Financial Interests, Personal, Research Grant: 4D; Financial Interests, Personal, Research Grant: Novartis; Financial Interests, Personal, Research Grant: Akoya; Financial Interests, Personal, Other, Consulting Fees: Genentech/Roche; Financial Interests, Personal, Other, Consulting fees: Bayer; Financial Interests, Personal, Other, Consulting Fees: Bristol Myers Squibb; Financial Interests, Personal, Other, Consulting Fees: AstraZeneca; Financial Interests, Personal, Other, Consulting Fees: Pfizer; Financial Interests, Personal, Other, Consulting fees: HTG Molecular; Financial Interests, Personal, Other, Consulting fees: Asuragen; Financial Interests, Personal, Other, Consulting Fees: Merck; Financial Interests, Personal, Other, Consulting fees: GlaxoSmithKline; Financial Interests, Personal, Other, Consultant Fees: Guardant Health; Financial Interests, Personal, Other, Consultant fees: Flame; Financial Interests, Personal, Other, Consultant Fees: Novartis; Financial Interests, Personal, Other, Consutant fees: Sanofi; Financial Interests, Personal, Other, Consultant Fees: Daiichi Sankyo; Financial Interests, Personal, Other, Consultant Fees: Amgen; Financial Interests, Personal, Other, Consultant fees: Oncocyte; Financial Interests, Personal, Other, Consultant fees: MSD; Financial Interests, Personal, Speaker's Bureau: Medscape; Financial Interests, Personal, Speaker's Bureau: MSD; Financial Interests, Personal, Speaker's Bureau: Genentech/Roche; Financial Interests, Personal, Speaker's Bureau: Platform Health; Financial Interests, Personal, Speaker's Bureau: Pfizer; Financial Interests, Personal, Speaker's Bureau: AstraZeneca; Financial Interests, Personal, Speaker's Bureau: Merck. D.P. Carbone: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Other, Consultant: Bristol Myers Squibb; Financial Interests, Personal, Other, Consultant: Bristol Myers Squibb KK (Japan); Financial Interests, Personal, Other, Consultant: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Daiichi Sankyo Inc.; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: EMD Serono/Merck; Financial Interests, Personal, Advisory Board: Flame Biosciences; Financial Interests, Personal, Other, Consultant: FENIX; Financial Interests, Personal, Other, Consultant: Genentech/Roche; Financial Interests, Personal, Other, Consultant: GI Therapeutics/ Intellisphere; Financial Interests, Personal, Advisory Board: Glaxo-Smith Kline; Financial Interests, Personal, Other, Consultant: Glaxo-Smith Kline; Financial Interests, Personal, Advisory Board: Gritstone; Financial Interests, Personal, Other, Consultant: Janssen; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Other, Consultant: Mirati; Financial Interests, Personal, Other, Consultant: Novocure; Financial Interests, Personal, Other, Consultant: OncoCyte; Financial Interests, Personal, Other, Consultant: OncoHost; Financial Interests, Personal, Other, Consultant: Piper Sandler; Financial Interests, Personal, Other, Consultant: Roche China; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Other, Consultant: Seattle Genetics; Financial Interests, Personal, Other, editorial/ medical writng support: Genentech. K. Schulze: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech; Financial Interests, Personal, Full or part-time Employment: Genentech; Financial Interests, Personal, Stocks/Shares: Genentech. D.J. Kwiatkowski: Financial Interests, Personal, Other, Editorial/ medical writing Support: Genentech.
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PURPOSE:Approximately 10%-40% of patients with lung cancer report no history of tobacco smoking (never-smokers). We analyzed whole-exome and RNA-sequencing data of 160 tumor and normal lung adenocarcinoma (LUAD) samples from never-smokers to identify clinically actionable alterations and gain insight into the environmental and hereditary risk factors for LUAD among never-smokers. METHODS:We performed whole-exome and RNA-sequencing of 88 and 69 never-smoker LUADs. We analyzed these data in conjunction with data from 76 never-smoker and 299 smoker LUAD samples sequenced by The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium. RESULTS:= .82). A subset of never-smoker samples (5.9%) showed mutation signatures that were suggestive of passive exposure to cigarette smoke. Finally, analysis of RNA-sequencing data showed distinct immune transcriptional subtypes of never-smoker LUADs that varied in their expression of clinically relevant immune checkpoint molecules and immune cell composition. CONCLUSION:In this comprehensive genomic and transcriptome analysis of never-smoker LUADs, we observed a potential role for germline variants in DNA repair genes and passive exposure to cigarette smoke in the pathogenesis of a subset of never-smoker LUADs. Our findings also show that clinically actionable driver alterations are highly prevalent in never-smoker LUADs, highlighting the need for obtaining biopsies with adequate cellularity for clinical genomic testing in these patients.

Chemoresistance is a hallmark of malignant pleural mesothelioma (MPM) management and the expression of ALDH1A3 is responsible for the survival and activity of MPM chemoresistant cell subpopulations (ALDH^bright cells). We enriched mesothelioma ALDH^bright cells to near homogeneity by FACS sorting and an Aldefluor assay and performed unbiased Affymetrix gene expression profiling. Viability and ELISA assays were used to rule out significant apoptosis in the sorted cell subpopulations and to assess target engagement by butein. Statistical analysis of the results, pathway enrichment and promoter enrichment were employed for the generation of the data. Q-RTPCR was used to validate a subset of the identified, modulated mRNAs In this work, we started from the observation that the mRNA levels of the ALDH1A3 isoform could prognostically stratify MPM patients. Thus, we purified MPM ALDH^bright cells from NCI-H2595 cells and interrogated their gene expression (GES) profile. We analyzed the GES of the purified cells at both a steady state and upon treatment with butein (a multifunctional tetrahydroxy-chalcone), which abates the ALDH^bright cell number, thereby exerting chemo-sensitizing effects in vitro and in vivo. We identified 924 genes modulated in a statistically significant manner as a function of ALDH status and of the response to the inhibitor. Pathway and promoter enrichment identified the molecular determinant of high ALDH status and how butein treatment altered the molecular portrait of those chemoresistant cell subpopulations. Further, we unraveled an eighteen-gene signature with high prognostic significance for MPM patients, and showed that most of the identified prognostic contributors escaped the analysis of unfractionated samples. This work proves that digging into the unexplored field of intra-tumor heterogeneity (ITH) by working at the cell subpopulation level may provide findings of prognostic relevance, in addition to mechanistic insights into tumor resistance to therapy.

Background High resistance to therapy and poor prognosis characterizes malignant pleural mesothelioma (MPM). In fact, the current lines of treatment, based on platinum and pemetrexed, have limited impact on the survival of MPM patients. Adaptive response to therapy-induced stress involves complex rearrangements of the MPM secretome, mediated by the acquisition of a senescence-associated-secretory-phenotype (SASP). This fuels the emergence of chemoresistant cell subpopulations, with specific gene expression traits and protumorigenic features. The SASP-driven rearrangement of MPM secretome takes days to weeks to occur. Thus, we have searched for early mediators of such adaptive process and focused on metabolites differentially released in mesothelioma vs mesothelial cell culture media, after treatment with pemetrexed.

BACKGROUND AND AIM/OBJECTIVE:Patients with severe coronavirus disease 2019 (COVID-19) develop a profound cytokine-mediated pro-inflammatory response. This study reports outcomes in 10 patients with COVID-19 supported on veno-venous extracorporeal membrane oxygenation (VV-ECMO) who were selected for the emergency use of a hemoadsorption column integrated in the ECMO circuit. MATERIALS AND METHODS/METHODS:Pre and posttreatment, clinical data, and inflammatory markers were assessed to determine the safety and feasibility of using this system and to evaluate the clinical effect. RESULTS:During hemoadsorption, median levels of interleukin (IL)-2R, IL-6, and IL-10 decreased by 54%, 86%, and 64%, respectively. Reductions in other markers were observed for lactate dehydrogenase (-49%), ferritin (-46%), d-dimer (-7%), C-reactive protein (-55%), procalcitonin (-76%), and lactate (-44%). Vasoactive-inotrope scores decreased significantly over the treatment interval (-80%). The median hospital length of stay was 53 days (36-85) and at 90-days post cannulation, survival was 90% which was similar to a group of patients without the use of hemoadsorption. CONCLUSIONS:Addition of hemoadsorption to VV-ECMO in patients with severe COVID-19 is feasible and reduces measured cytokine levels. However, in this small series, the precise impact on the overall clinical course and survival benefit still remains unknown.

Objective/UNASSIGNED:The aim of this review is addressing the mechanisms of asbestos carcinogenesis, including chronic inflammation and autophagy-mediated cell survival, and propose potential innovative therapeutic targets to prevent mesothelioma development or improve drug efficacy by reducing inflammation and autophagy. Background/UNASSIGNED:) gene and other genes are predisposed to developing cancers, prevalently mesothelioma. Their risk of developing mesothelioma further increases upon exposure to asbestos. Recent studies have revealed the mechanisms and the role of inflammation in asbestos carcinogenesis. Biomarkers for asbestos exposure and malignant mesothelioma have also been identified. These findings are leading to the development of novel therapeutic approaches to prevent or delay the growth of mesothelioma. Methods/UNASSIGNED:Review of full length manuscripts published in English from January 1980 to February 2021 gathered from PubMed.gov from the National Center of Biotechnology Information and the National Library of Medicine were used to inform this review. Conclusion/UNASSIGNED:Key regulators of chronic inflammation mediate asbestos-driven mesothelial cell transformation and survival through autophagic pathways. Recent studies have elucidated some of the key mechanisms involved in asbestos-induced chronic inflammation, which are largely driven by extracellular high mobility group box 1 (HMGB1). Upon asbestos exposure, mesothelial cells release HMGB1 from the nucleus to the cytoplasm and extracellular space, where HMGB1 initiates an inflammatory response. HMGB1 translocation and release also activates autophagy and other pro-survival mechanisms, which promotes mesothelioma development. HMGB1 is currently being investigated as a biomarker to detect asbestos exposure and to detect mesothelioma development in its early stage when therapy is more effective. In parallel, several approaches inhibiting HMGB1 activities have been studied and have shown promising results. Moreover, additional cytokines, such as IL-1β and TNF-α are being targeted to interfere with the inflammatory process that drives mesothelioma growth. Developing early detection methods and novel therapeutic strategies is crucial to prolong overall survival of patients with mesothelioma. Novel therapies targeting regulators of asbestos-induced inflammation to reduce mesothelioma growth may lead to clinical advancements to benefit patients with mesothelioma.

The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC.