bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B24: Differential sensitivity to Aurora kinase inhibition in RIT1- and KRAS-mutant lung adenocarcinoma
Authors: Holmes Kristin D. , Mundt Filip , Mertins Phillip , Carr Steve , Berger Alice 
Published: February 2019

Abstract
Mutations in Ras-family genes Kirsten rat sarcoma viral oncogene (KRAS) and Ras-like in all tissues (RIT1) occur in 30% and 2% of lung adenocarcinomas, respectively. Targeted therapies have shown promise in lung adenocarcinomas and other cancers; however, there are currently no FDA-approved drugs that directly target RIT1 or KRAS. To identify critical effector pathways and/or genetic dependencies that might be targeted for clinical benefit in these cancers, we undertook complementary proteomic and small-molecule screens in multiple human lung cancer models.
To better understand the signaling networks modulated by RIT1 and KRAS, we performed deep characterization of total protein and phosphoproteins in non-transformed human lung epithelial cells engineered to express mutant or wild-type RIT1 or KRAS. 10,131 proteins were detected across all samples, 9,001 of which were detected in every sample. 29,172 phosphorylated sites were detected with 14,769 of these identified in every sample. Gene set enrichment analysis (GSEA) identified pathways significantly modulated by RIT1 M90I, KRAS G12V, or KRAS Q61H mutations. Whereas some pathways, such as MYC, were commonly activated by both mutant RIT1 and KRAS, others, such as Aurora kinase signaling, were specifically perturbed by RIT1.
Previously, we found that mutant RIT1 and KRAS can transform human lung epithelial cells and confer resistance to EGFR blockade in EGFR-dependent lung adenocarcinoma. To identify opportunities for therapeutic intervention of RIT1- and KRAS-mutant tumors, we screened a collection of 160 small molecules for their ability to block RIT1/KRAS-induced drug resistance in PC9 cells, an EGFR-mutant lung adenocarcinoma cell line. Interestingly, RIT1 M90I-expressing cells were selectively killed as a result of treatment with the Aurora kinase inhibitors, alisertib and barasertib, while KRAS G12V cells were resistant to these inhibitors. The specific effect of Aurora kinase inhibition on RIT1 mutant cells was also confirmed in a fibroblast transformation assay and could not be attributed to proliferation rate, which was similar between RIT1- and KRAS-expressing cells. Moreover, Aurora kinase B (AURKB) was among the most differentially expressed transcripts when comparing RIT1- or KRAS-expressing cells, suggesting differential effects of RIT1 and KRAS on Aurora kinase activity.
These findings nominate Aurora kinase inhibition as a potential therapeutic strategy in RIT1- , but not KRAS-mutant, lung cancer.
Citation Format: Kristin D. Holmes, Filip Mundt, Phillip Mertins, Steve Carr, Alice Berger. Differential sensitivity to Aurora kinase inhibition in RIT1- and KRAS-mutant lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B24.
Abstract B28: Targeted inhibition of EGFR and glutaminase induces metabolic crisis in EGFR-mutant lung cancer
Authors: Momcilovic Milica , Bailey Sean T. , Lee Jason T. , Magyar Clara , Braas Daniel , Graeber Thomas , Parlati Francesco , Demo Susan , Krysan Konstyantyn , Walser Tonya C. , Dubinett Steven M. , Sadeghi Saman , Christofk Heather R. , Shackelford David B. 
Published: February 2019

Abstract
Cancer cells exhibit increased use of nutrients, including glucose and glutamine, to support the bioenergetic and biosynthetic demands of proliferation. We tested the small-molecule inhibitor of glutaminase CB-839 in combination with erlotinib on epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) as a therapeutic strategy to simultaneously impair cancer glucose and glutamine utilization and thereby suppress tumor growth. Here, we show that CB-839 cooperates with erlotinib to drive energetic stress and activate the AMP-activated protein kinase (AMPK) pathway in EGFR (del19) lung tumors. Tumor cells undergo metabolic crisis and cell death, resulting in rapid tumor regression in vivo in mouse NSCLC xenografts. Consistently, positron emission tomography (PET) imaging with 18F-fluoro-2-deoxyglucose (18F-FDG) and 11C-glutamine (11C-Gln) of xenografts indicated reduced glucose and glutamine uptake in tumors following treatment with CB-839 + erlotinib. Therefore, PET imaging with 18F-FDG and 11C-Gln tracers can be used to noninvasively measure metabolic response to CB-839 and erlotinib combination therapy.
Citation Format: Milica Momcilovic, Sean T. Bailey, Jason T. Lee, Clara Magyar, Daniel Braas, Thomas Graeber, Francesco Parlati, Susan Demo, Konstyantyn Krysan, Tonya C. Walser, Steven M. Dubinett, Saman Sadeghi, Heather R. Christofk, David B. Shackelford. Targeted inhibition of EGFR and glutaminase induces metabolic crisis in EGFR-mutant lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B28.
Abstract B30: Three-dimensional organoid model for acquired drug resistance in non-small cell lung cancer
Authors: Shukla Navika D. , Salahudeen Ameen A. , Padda Sukhmani K. , Neal Joel W. , Wakelee Heather A. , Kuo Calvin J. 
Published: February 2019

Abstract
Background: Targeted therapies against specific driver mutations of cancer progression have been used to improve survival of lung adenocarcinoma patients. In KRAS mutant NSCLC specifically, however, after some initial improvement in lung cancer patients, targeted therapies often fail due to acquired drug resistance. To uncover mechanisms of resistance and to discover new drivers, genome-scale sequencing of lung cancers has identified candidate genes, but these data have not rapidly translated in preclinical validation. A major obstacle in lung cancer research has been the deficiencies of standard in vitro models.
Methods: To address the deficiencies within standard models we have developed an in vitro 3-dimensional, KRAS-mutated “organoid” model of lung adenocarcinoma that surpasses both in vitro and in vivo models by possessing the tractability of cell lines and the 3-dimensional architecture and morphology of animal models. We have engineered a p53 knockout and KRAS mutation on top of normal wild-type lung epithelium to achieve oncogenicity.
Result: Through an optimized growth period in the presence of drug, an organoid model of resistance has been developed through which de novo genetic events underlying acquired resistance can be studied.
Conclusion: The highly defined genetic background of the KRAS-mutated 3-D organoid model serves as a tabula rasa upon which stochastic secondary genetic and epigenetic changes can be identified and mechanistically studied by forward and reverse genetics approaches in order to rapidly identify mechanisms of acquired drug resistance and validate therapeutic options.
Citation Format: Navika D. Shukla, Ameen A. Salahudeen, Sukhmani K. Padda, Joel W. Neal, Heather A. Wakelee, Calvin J. Kuo. Three-dimensional organoid model for acquired drug resistance in non-small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B30.
Abstract B34: Safety and activity of the IL-15/sIL-15Rα complex ALT-803 in combination with the anti-PD1 mAb nivolumab in metastatic non-small cell lung cancer
Authors: Wrangle John , Velchetti Vamshidar , Patel Manish , Suriano Samantha , Swiderska-syn Marzena , Anderton Kate , Ravenel James , Hill Elisabeth , Rock Amy , Wong Hing , Rubinstein Mark 
Published: February 2019

Abstract
This abstract is being presented as a short talk in the scientific program. A full abstract is printed in the Proffered Abstracts section (PR05) of the Conference Proceedings.
Citation Format: John Wrangle, Vamshidar Velchetti, Manish Patel, Samantha Suriano, Marzena Swiderska-syn, Kate Anderton, James Ravenel, Elisabeth Hill, Amy Rock, Hing Wong, Mark Rubinstein. Safety and activity of the IL-15/sIL-15Rα complex ALT-803 in combination with the anti-PD1 mAb nivolumab in metastatic non-small cell lung cancer [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B34.
Abstract IA09: Inflammation and immunity in pulmonary premalignancy
Authors: Krysan Kostyantyn , Tran Linh M. , Grimes Brandon S. , Dubinett Steven M. 
Published: February 2019

Abstract
Unleashing the immune response against pulmonary premalignancy could transform therapy and outcomes. We are evaluating the mutational landscape of pulmonary premalignancy and the associated premalignant microenvironment by whole-exome DNA sequencing and immunohistochemistry. Remarkably, we find putative neoepitopes and frequent immune-effector cell infiltration as well as evidence of immune suppression in pulmonary premalignancy. These findings suggest that premalignant-associated antigens are recognized and elicit immune responses at the earliest points of lung adenocarcinoma development. Identification of neoepitopes that can be targeted before the development of invasive lung cancer could eventually shift the approach to disease interception through immunoprevention and treatment of the very earliest phase of the disease.
Citation Format: Kostyantyn Krysan, Linh M. Tran, Brandon S. Grimes, Steven M. Dubinett. Inflammation and immunity in pulmonary premalignancy [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA09.
Abstract IA11: Gene networks, airway smoke injury, and cancer risk
Authors: Ponder Bruce A.J. 
Published: February 2019

Abstract
Background: Fifteen percent of smokers and former smokers develop lung cancer. This might be chance; an alternative is that some are at greater risk because of different individual responses to airway smoke injury. Several groups have investigated gene expression in normal airway epithelium as a readout of smoke injury and as a stratifier for risk. Questions include, but are not limited to: i) Can nasal epithelium provide a useful and accessible surrogate for bronchial? ii) Is there an inherited component to the injury-related risk? iii) What components of the injury response contribute most to increased risk in current and in former smokers? iv) What is the distribution of injury response in the healthy current and former smoker populations, rather than symptomatic patients, and how does this relate to risk?
Results and Work in Progress: We, like others, have based our analysis on gene expression in normal bronchial and nasal epithelium. We use transcription factor-centered gene regulatory networks, derived from normal bronchial and nasal epithelium, to identify the overlying cellular regulatory mechanisms that differ between injury responses. We identify transcriptional “master regulators” (MRs), the activity of which differs between cancer and benign, and confirm the overlap of MRs between nasal and bronchial epithelium. A preliminary pathway analysis suggests the involvement of these MRs in oxidative stress response, DNA repair, immune responses, and developmental processes. Using data from the TRICL consortium, we show that the regulons of a subset of these MRs are enriched in genes located at lung GWAS loci. This suggests that the observed gene expression differences between cancer and benign are in part causal, related to inherited variation rather than secondary to the cancer.
Using samples from the Cambridge Bioresource volunteers, we are analyzing data from nasal samples to compare healthy current and former smokers with healthy never-smokers, and so obtain a “smoke injury response.” We will use this to describe the distribution of injury response in the healthy smoker/former smoker populations. Our aim is to test what component of risk-related gene response may be apparent in this healthy asymptomatic smoker population rather than at the “later” symptomatic stages of hospital investigation, and to find which genes or regulatory processes contribute most to this. The results may have implications both for risk prediction and possible interventions in these populations.
My talk will be a “work in progress” aimed at stimulating discussion about questions and approaches, rather than a presentation of finished results.
Citation Format: Bruce A.J. Ponder. Gene networks, airway smoke injury, and cancer risk [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA11.
Abstract IA14: Circulating tumor DNA in early-stage NSCLC: A lung TRACERx study
Authors: Abbosh Christopher 
Published: February 2019

Abstract
The Cancer Research UK-funded study TRACERx (TRAcking Cancer Evolution through therapy [Rx]) aims to recruit patients undergoing surgery for early-stage non-small cell lung cancer (NSCLC). Patients donate blood pre- and postoperatively alongside multi-region sampled primary tumor tissue. Up to 40% of patients undergoing surgery for NSCLC experience relapse of their disease. At this point patients are approached for relapse tissue sampling. TRACERx therefore provides a strong platform for evaluating circulating tumor DNA (ctDNA) in early-stage NSCLC and a minimal residual disease (MRD) setting.
In this presentation we will describe data arising from a phylogenetic, patient-specific approach to ctDNA evaluation in the first 100 patients analyzed as part of TRACERx. We will discuss clinicopathologic factors associated with ctDNA detection in early-stage NSCLC and suggest the existence of distinct tumor phenotypic characteristics that predict the presence of ctDNA at measurable quantities in plasma. Additionally, we will discuss tumor volume limit of detection analyses and highlight potential implications of our findings within the context of early cancer detection. We will then examine data arising from the ctDNA profiling of postoperative plasma samples taken in the adjuvant setting. These data demonstrate that ctDNA detection is specific for NSCLC relapse and that ctDNA detection precedes clinical diagnosis of NSCLC relapse (median lead-time of 77 days, range 10 to 346 days). We will provide examples of using phylogenetic ctDNA profiling to characterize the subclonal nature of relapsing NSCLC as a potential method to personalize relapse therapeutic intervention. Finally, we will highlight potential advantages of patient-specific ctDNA profiling in an adjuvant MRD setting and suggest ways that this technology can be used to fuel adjuvant drug development in NSCLC by driving novel study designs.
Citation Format: Christopher Abbosh. Circulating tumor DNA in early-stage NSCLC: A lung TRACERx study [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA14.
Abstract IA36: Regulatory T cells, polymorphisms, and response to checkpoint blockade: From mechanisms to potential biomarkers
Authors: Quezada Sergio 
Published: February 2019

Abstract
In mice, anti-CTLA-4 monoclonal antibodies (mAbs) require Fc-gamma receptor (FcγR)-mediated depletion of intratumoral regulatory T (Treg) cells to promote tumor rejection. However, the relevance of this mechanism in the human setting remains controversial. Using a mouse model expressing human FcγRs, and analysis of clinical samples from ipilimumab-treated melanoma patients, we investigate the potential role of Treg depletion in the activity of antibodies targeting human CTLA-4.
Citation Format: Sergio Quezada. Regulatory T cells, polymorphisms, and response to checkpoint blockade: From mechanisms to potential biomarkers [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA36.
Abstract A013: Haploidentical stem cell transplantation and subsequent immunotherapy with antiGD2 antibody for patients with relapsed metastatic neuroblastoma
Authors: Lang Peter , Flaadt Tim , Ebinger Martin , Schlegel Patrick , Lode Holger , Ladenstein Ruth , Lang Anne-Marie , Ambross Peter , Schaefer Juergen , Fuchs Joerg , Loibner Hans , Schwinger Wolfgang , Handgretinger Rupert 
Published: February 2019

Abstract
Background: Pediatric patients with relapsed metastatic neuroblastomas have a poor prognosis and additional strategies are needed. We present results of a phase I/II-trial with subsequent immunotherapy with an anti-GD2mAb (CH14.18/CHO) after HLA-mismatched, haploidentical stem cell transplantation (SCT). Methods: T- and B-cell depleted stem cells from parental donors were used in combination with melphalan 140mg/m², thiotepa 10mg/kg, fludarabin 160mg/m² and ATG-F. CH14.18/CHOmAb was started on day 60-180 post-transplant: 6 cycles with 20mg/m²/day x 5; in cycles 4-6, 1x106 U/m² Interleukin 2 was given additionally. Disease status was evaluated with whole body MRI, MIBG scan and MRD detection in bone marrow aspirates. Primary endpoint was success of treatment, defined as a patient receiving the full protocol treatment, still alive 180 days after end of treatment without progression/unacceptable toxicity or severe GvHD. Results: 56 patients with 1st or ≥2nd metastatic relapse were enrolled. Disease status prior to antibody infusions was: CR (n=19), PR (n=31), mixed (n=6). 41% of patients with measurable tumor burden responded and reached CR after treatment. 90% of patients with initial CR could maintain this status. In total, success of treatment was observed in 60%. 3-year OS and EFS was 58% and 45%, respectively. Causes of death were: progression/relapse (25%) or TRM (7%). Factors of influence on EFS were (1) remission status prior to SCT (with CR, PR or mixed response resulting in 70%, 45% and 11% 3yEFS) and (2) bone marrow involvement prior to CH14.18 treatment (no MRD detectable: 60% 3yEFS vs. any MRD detectable: 20% 3yEFS). Frequent side effects were pain, fever, CRP elevation; rare side effects comprised SIRS/capillary leak syndrome, seizures, accommodation disturbances. Transient acute severe GvHD occurred in 1 patient. Conclusions: CH14.18/CHO infusions after haploidentical SCT are feasible with acceptable toxicity. Our results suggest an antitumor effect of the new, donor-derived immune system in combination with CH14.18 treatment.
Citation Format: Peter Lang, Tim Flaadt, Martin Ebinger, Patrick Schlegel, Holger Lode, Ruth Ladenstein, Anne-Marie Lang, Peter Ambross, Juergen Schaefer, Joerg Fuchs, Hans Loibner, Wolfgang Schwinger, Rupert Handgretinger. Haploidentical stem cell transplantation and subsequent immunotherapy with antiGD2 antibody for patients with relapsed metastatic neuroblastoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A013.
Abstract A029: Unexpected antagonism between oncolytic virus derived type I interferon and EGFRvIII CAR T-cells
Authors: Evgin Laura , Huff Amanda L. , Wongthida Phonphimon , Thompson Jill , Kottke Timothy , Sampson John , Perez Luis Sanchez , Vile Richard 
Published: February 2019

Abstract
Although the chimeric antigen receptor (CAR) T-cell platform has experienced clinical success in patients with hematologic malignancies, CAR T-cells specific to solid tumor targets have met with more limited efficacy. The highly inflammatory nature of oncolytic viruses and their ability to remodel the tumor microenvironment suggested to us that they would provide a complementary mechanism of action to both recruit and potentiate the functionality of CAR T-cells. VSVmIFNβ injection into B16EGFRvIII tumors increased the expression of chemokines such as CXCL10 and CCL5, which we would expect to recruit CXCR3+and CCR5+ EGFRvIII specific murine CAR T-cells. However, we did not observe an increase in overall survival or tumor control using the combination strategy compared to monotherapy with CAR T-cells. We recovered fewer viable CD8+ CAR T-cells from tumors injected with VSVmIFNβ early after adoptive transfer, and observed a similar reduction in the number of CD8+ CAR T-cells which persisted long term in the blood. We have shown that type I interferon increases the expression of the CAR from the retroviral LTR and in turn sensitizes these cells to tonic signaling mediated exhaustion and apoptosis. Correspondingly, CAR T-cells prepared from IFNAR KO T-cells were protected from the deleterious effect of type I IFN in vivo. We are currently investigating strategies to overcome the interference between these two modalities and to uncouple the regulation of the expression of the CAR from type I IFN signaling.
Citation Format: Laura Evgin, Amanda L. Huff, Phonphimon Wongthida, Jill Thompson, Timothy Kottke, John Sampson, Luis Sanchez Perez, Richard Vile. Unexpected antagonism between oncolytic virus derived type I interferon and EGFRvIII CAR T-cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A029.