bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fatty-acid-binding proteins as a novel target for the treatment of anti-PD-1-resistant tumors.
Authors: Welsh James William , Niknam Sharareh , Schoenhals Jonathan E. , Barsoumian Hampartsoum B. , Younes Ahmed I. A. , Li Ailin , Cortez Maria Angelica 
Published: September 2018

11562 Background: The mechanisms underlying immunosuppression and resistance to PD1 inhibitors in cancer are not well understood. We attempted to fill this gap with an integrated transcriptome analysis in an anti-PD1-resistant lung adenocarcinoma mouse model. The model was created by in vivo passage of 344SQ murine lung cancer cells (p53R172HΔg/+K-rasLA1/+) in a syngeneic host repeatedly dosed with anti-mouse PD1 antibodies. Anti-PD1-resistant 344SQ (344SQ_R) and 344SQ parental (344SQ_P) cells were then inoculated into syngeneic 129Sv/ev mice, which were then dosed twice with anti-PD1 or control IgG antibodies. Methods: Tumor tissues were collected and analyzed as follows: transcriptome with Affymetrix; protein levels by reverse phase protein array analysis; signature enrichment by gene set enrichment analysis; metabolome by mass spectrometry; and lipid content with fluorescent probes Oil O and BODIPY. We also isolated tumor-infiltrating immune cells for flow cytometry and gene expression analyses. Results: We identified lipid-related metabolic pathways as being the most highly enriched in anti-PD1-resistant tumors (344SQ_R) vs. their 344SQ_P counterparts; the resistant cells also had more lipid droplets than the 344SQ_P cells. The anti-PD1-resistant tumors overexpressed several genes involved in lipogenesis and fatty acid pathways, including fatty acid binding proteins (FABPs). Specifically, FABP overexpression promoted fatty acid uptake and lipid-droplet accumulation in resistant tumors. 344SQ_R tumors promoted immune suppressive cells by upregulating FABPs expression in M2-like macrophages, marked by increased fatty acid intake and fatty acid oxidation. Conversely, percentages of CD4+ and CD8+ tumor-infiltrating lymphocytes were reduced in the resistant tumors. Conclusions: These results suggest that lipid metabolic rewiring drives resistance PD1 inhibitors supporting the accumulation of immunosuppressive cells, including M2-like macrophages, preventing type I immune responses elicited by T cells. Collectively, these findings reveal new potential lipid-related targets for drug development or new treatments combining inhibitors of these targets with anti-PD1 therapy.
FDG PET/CT and N0 mediastinal nodal status in early stage non-small cell lung cancer: A single institution retrospective experience.
Authors: Cingam Shashank Reddy , Connor Sean , Patel Abhishek Harshad , Master Samip R. , Takalkar Amol 
Published: September 2018

11570 Background: The increasing use of CT and now low-dose screening CT scans for at-risk patients have led to increasing detection of lung cancer at early stages. FDG PET/CT is used as an adjunct to conventional imaging to assess loco-regional lymph node spread. However, there is a potential for false-negative results, especially in smaller lesions or early nodal involvement. The main objective of this study was to study the value of PET/CT scan to evaluate for true negative mediastinal nodes in patients with early stage NSCLC. Accurate determination of N0 status can have a significant impact on the cost-effectiveness and timely management of early stage NSCLC. Methods: Of a total of 404 patients with NSCLC managed at our facility between 2008 to 2015, 29 adult patients whose PET scan showed no or equivocal mediastinal nodal involvement and subsequently underwent surgical exploration of mediastinal lymph nodes were included in the study. Data variables that were collected included the cancer site, date of PET, node status on PET, type and date of surgery, cancer histology, and the tissue diagnosis of the sampled nodes. SAS software was used for the analysis of the data. Results: Of the 29 patients with N0 or equivocal nodes on FDG PET/CT, 7 (24.13%) had evidence of malignancy on biopsy of the surgically resected lymph nodes. No statistically significant differences were noted between the site of the neoplastic lesion, cancer histology, duration between the date of PET and the date of surgery in the true negative (TN) and false negative (FN) groups. The recurrence rate was higher in the FN group 60 % (3/5) compared to 21 % (4/19) in the TN group who had follow up for atleast 2 years. Conclusions: Our findings suggest incidence of false negative results of FDG PET/CT for evaluation of N0 nodes in early stage NSCLC is 24.13%. This is comparatively higher than false negatives rates with mediastinoscopy (5-10%) reported in other studies. Although our sample size is small, if confirmed, such a relatively high incidence of false negative results on FDG PET/CT for N0 disease supports the current recommendations for exploratory mediastinoscopy and/or surgery for definitive staging in early stage NSCLC.
Clinical utility of molecular testing to select therapy in relapsed/refractory non-Hodgkin lymphoma: Mayo Clinic Center for Individualized Medicine experience.
Authors: Bennani Nabila Nora , Ansell Stephen Maxted , Witzig Thomas E. , Feldman Andew L. , McAllister Tammy M , Lazaridis Konstantinos N , Egan Jan B. , Stewart A. Keith , Nowakowski Grzegorz S. 
Published: September 2018

11571 Background: Relapsed/refractory (R/R) non-Hodgkin lymphomas (NHL) have a poor prognosis with limited treatment options. Our expanding knowledge of molecular alterations seen in R/R NHL allows identification of patients that potentially may benefit from a precision medicine approach. However, experience in routine clinical implementation of precision medicine has been limited. Here, we summarize our clinical experience in molecular characterization of RR NHL targeted therapy (TT) using next-generation sequencing (NGS), and selection of targeted therapy (TT) based on molecular profile. Methods: We conducted a prospective study in RR NHL through the Center for Individualized Medicine at Mayo Clinic. Consenting patients underwent NGS using FoundationOne Heme panel from biopsies done at time of relapse. Results of NGS were discussed at the Genomic Tumor Board and recommendations for TT were given based on matching specific molecular alteration(s) with potential agent(s) predicted to be active based on NGS. The agents could include FDA-approved, off-label use and clinical trial therapies. Results: 28 cases were enrolled: 18 aggressive NHL, 10 follicular lymphoma (FL). Molecular alterations were present in all cases. In aggressive B-cell NHL, CDKN2A/B gene cluster alterations were seen in 73% (8/11), while seen in only 1/7 T-cell lymphomas (TCL), and 1/10 FL. TP53 deletions were second most common genomic alterations in DLBCL (57%) and seen in 40% FL. JAK-STAT and ERBB pathways were altered in TCL (2/7 each). IGH-BCl-2 gene rearrangement were common in FL (70%), followed by MLL gene alterations (50%). Targetable mutations were present in 86% (24/28) of cases. A TT was recommended in all 24 cases, but received by 2 patients only. Remaining patients did not due to benefit from current therapy (10/24), ineligibility or lack of clinical trial (7/24) or interim clinical deterioration (5/24). Conclusions: Targetable mutations were identified in most cases of RR NHL with TT recommended for all cases. However, access to TT limits potential clinical benefit of molecular-based matching strategy. More studies are needed to assess impact on clinical outcomes.
Antitumor activity of indenoisoquinoline inhibitors of topoisomerase 1 (TOP1) via apoptosis and autophagocytosis pathways in animal models.
Authors: Kinders Robert J. , Dull Angie B , Wilsker Deborah , LeBlanc Amy , Mazcko Christina , Hollingshead Melinda G. , Parchment Ralph E. , Doroshow James H. 
Published: September 2018

11588 Background: We performed pharmacodynamic biomarker analysis for response to a panel of three indenoisoquinolines (LMP776, LMP400 and NSC706744, J. Med. Chem. 49:7740, 2006) that have demonstrated anti-tumor activity in dogs. In preclinical xenograft models treated with indenoisoquinolines, we observed that gH2AX was not a useful biomarker for the biological activity of compound 706744, but was a reasonable biomarker of drug activity (Clin. Canc. Res. 16:5447, 2010) for the other two compounds, even though in vitro data indicated that all 3 compounds inhibited TOP1 and killed tumor cells. It has been reported that irinotecan activates autophagy (Pharm. Rev. 65:1162, 2013) which correlated with its metabolism to SN-38; we therefore developed, validated and tested an immunofluorescence microscopy assay for LC3 as a marker of autophagy. Methods: Assays were developed to evaluate apoptosis by co-localization of cleaved caspase 3 and gH2Ax, and autophagy by LC3 immunofluorescence on formalin fixed, paraffin-embedded tissue sections of xenografts models or lymphomas from outbred dogs. Percent positive cells containing LC3 puncta were quantitated using a spot morphology algorithm. Analysis of gH2AX and cleaved caspase 3 cellular co-localization was developed using a blebbing morphology algorithm (Definiens). Results: LC3 reported that indenoisoquinoline 706744 activates autophagy in vitro with the absence of cleaved caspase 3-dependent apoptosis while the -776 and -400 compounds do not activate autophagy, but instead demonstrate apoptosis in response to drug treatment. Results in animal models confirmed that both autophagy and apoptosis were active. Clinical readiness of the assays was confirmed on canine biopsy FFPE slides. Conclusions: 1,Structurally-related TOP1 inhibitors may trigger alternative pathways of cell destruction; 2,Autophagy may report drug anti-tumor activity or tumor drug resistance according to current literature. This assay may be useful for determination of pharmacodynamic pathways associated with anti-tumor activity to elucidate mechanism of action of investigational agents used in clinical trials.
Validation of an expanded neoantigen identification platform for therapeutic and diagnostic use in immuno-oncology.
Authors: Boyle Sean Michael , Harris Jason , Bartha Gabor , Alla Ravi , Jongeneel Patrick , Karbelashvili Mirian , Kirk Scott , Chervitz Steve , Levy Eric , Rowell Craig , Thomas Daryl , McCord Robert , Luo Shujun , West John , Chen Richard 
Published: September 2018

11589 Background: Neoantigen identification is increasingly critical for clinical immuno-oncology applications including predicting immunotherapy response and neoantigen-based personalized cancer vaccines. Although standard research pipelines have been developed to aid neoantigen identification, building a robust, validated neoantigen identification platform suitable for clinical applications has been challenging due to the complex processes involved. Methods: To improve neoantigen identification, we extended standard sequencing and informatics methods. We developed an augmented and content enhanced (ACE) exome sequenced at 200X to increase sensitivity to SNPs and indels used for neoantigen identification as well as HLA performance. To accurately identify fusions and variants from RNA, we optimized our ACE transcriptome for FFPE tissue. To improve neoantigen pipelines based on MHC binding algorithms, we developed peptide phasing, high accuracy HLA typing, TCR interaction predictors, and transcript isoform estimation tools to detect neoantigens from indel and fusion events. We performed comprehensive analytical validation of the platform including the ACE Exome, somatic SNV/indel calls, RNA based variant and fusion calls, and HLA typing. This was followed by an overall in silico validation of neoantigen identification using 23 experimentally validated immunogenic neoepitopes spiked into exome data. Results: Analytical validation of our ACE exome platform showed > 97% sensitivity for small variants with a specificity of > 98% at minor allele frequency > 10%. From the ACE transcriptome we achieved a fusion sensitivity of > 99% and RNA based variant calls sensitivity of > 97%. Our ACE exome based HLA typing was 98% and 95% concordant with Class I and II HLA results (respectively) from clinical testing. Our in silico validation of neoantigen predictions resulted in identification of 22 out of 23 immunogenic neoepitopes. Conclusions: We developed sequencing and informatics improvements to standard approaches that can enhance neoantigen identification and demonstrated a comprehensive validation approach that may support neoantigen use in future clinical settings.
Co-amplification of MET and PIK3CA in NSCLC and data on a PDX mouse model.
Authors: Kang Jin , Zhang Xu-Chao , Su Jian , Xie Zhi , Li Wen-Feng , Wu Yi-Long , Yang Jin-Ji 
Published: September 2018

11591 Background: Amplification of the mesenchymal-epithelial transition ( MET) proto-oncogene or phosphatidylinositol3-kinase ( PI3K) is common in non-small-cell lung cancer (NSCLC) and represents a potential therapeutic target. NSCLC with coexisting driver mutations or amplifications is a cause of great concern. Methods: From 2013 until now, fluorescence in situ hybridization was used to screen for MET amplified NSCLC patients.The amplification of the MET was defined as centromere 7 ratio ≥ 2.0 and the criterion of Cappuzzi. The amplification of the PIK3CA was copy numbers ≥ 4.0. We established the patient-derived exnograft (PDX) mouse model from a dual MET/PIK3CA-amplified patient. Preclinical efficacy of single versus dual inhibition was evaluated in vivo. Six groups were allocated to receive the treatment of vehicle control, bozitinib,crizotinib, taselisib (PI3K inhibitor), bozitinib+taselisib, or crizotinib+taselisib, respectively. Results: Totally, 568 (568/2321, 24.47%) patients harbored positive MET amplification and 6 (6/568,1%) were comfirmed with dual MET/PI3K amplification. The two stageⅣ patients received MET inhibitor treatment.One trial (NCT02896231) patient was treated with bozitinib and achieved confirmed PR, but with 3 months PFS and 5 months OS. The best response was PR and PFS was 5.6 months for the other one receiving the study drug capmatinib (NCT02276027). In the PDX mouse model experiment, we found three single-anget inhibitors monotherapy to be active but only transiently effective in controlling the growth of PDX. The PDX models showed more sensitivity to taselisib among the three single-anget groups. In contrast, the combination of the two inhibitors caused a stronger and long-lasting growth inhibition in PDX models. The addition of taselisib to bozitinib or crizotinib monotherapy provided obvious enhanced activity. Regretfully, two mice died because of the toxicities in the crizotinib+taselisib group. Conclusions: Patients with dual MET/PIK3CA amplification represent a rare molecular subtype of NSCLC and have a relatively short duration of response to MET inhibitors.The combination of MET/PI3K inhibitors is synergistic preclinically.
ABCG2 and TOP-1 mRNA expression as predictive biomarkers for adjuvant FOLFIRI treatment in stage III colon cancer patients: Results from the PETAAC-3 prospective randomized clinical trial.
Authors: Brunner Nils , Stenvang Jan , Budinska Eva , Nygaard Sune Boris 
Published: September 2018

11594 Background: FOLFIRI as adjuvant treatment in primary colon cancer was previously tested in two pivotal prospective randomized clinical trials (PETACC-3 and CALGB 89803), both of which failed to demonstrate significant beneficial effects when adding irinotecan to 5FU. As a consequence, FOLFIRI is presently not used as adjuvant treatment for colon cancer. Methods: The study included 580 patients with mRNA expression data performed on tumor samples (FFPE) from stage III colon cancer patients enrolled in the PETACC-3 study, which randomized the patients to 5FU plus Leucovorin +/- irinotecan. Primary end-points were recurrence-free survival (RFS) and overall survival (OS). Median ABCG2 and the 75 percentile TOP-1 mRNA expression data were used to allocate the patients into one of two groups: One with high ABCG2 expression (above median) and low TOP-1 expression (below 75 percentile) (n = 167) and another group including all other combinations of these two genes. Kaplan Meier curves and Cox proportional hazards model were used to visualize differences between groups and calculate p-values (log-rank test). Results: The survival statistics showed a significant difference for both RFS (HR: 0.63 (0.44-0.92); p = 0.017) and OS (HR: 0.6 (0.39-0.93); p = 0.021) between the two groups when the patients received FOLFIRI. In contrast, no significant differences were observed between the groups when patients received 5FU and Leucovorin alone (p-values: RFS: 0.58; OS: 0.75). Conclusions: We here show that the combination of two independent gene expression abundance with a strong association to irinotecan treatment (high ABCG2 drug efflux pump and low TOP-1, the latter being the target for irinotecan) identified a group of stage III colon cancer patients who will not benefit from FOLFIRI adjuvant treatment while patients with other combinations of expression of these two genes appear to significantly benefit from adjuvant FOLFIRI treatment. The lack of a similar effect in patients receiving treatment with 5FU and Leucovorin only, points to a predictive value of ABCG2 and TOP-1 measurements.
Biomarker-driven indication selection in JTX-2011 ICONIC clinical trial.
Authors: Hirsch Heather Anne , Reeves Jason , Zi Tong , Deshpande Amit , Yang Guang , Needham Alexander , Shu Jenny , Khattri Arun , Brisson Ryan J. , Tan Carol , Harvey Christopher , Law Deborah , Michaelson Jennifer , Trehu Elizabeth G. , Sathyanarayanan Sriram , Seiwert Tanguy Y. 
Published: September 2018

11602 Background: ICOS (Inducible T cell CO-Stimulator) is a co-stimulatory molecule expressed primarily on T lymphocytes. Clinical and preclinical data suggest that ICOS mediates anti-CTLA-4 driven anti-tumor responses. JTX-2011 is an ICOS agonist antibody in clinical development in advanced solid tumors (ICONIC trial). JTX-2011 is designed to generate an anti-tumor immune response via stimulation of T effector cells and preferential reduction of intra-tumoral T regulatory cells. Single agent preclinical efficacy correlates with the percentage of ICOS-expressing T cells within the tumor. We report indication selection and patient enrichment strategy for ICONIC using in silico and IHC analysis and assessment of potential predictive biomarkers for JTX-2011 using ex vivo tumor histoculture. Methods: Integrated analysis was performed from the TCGA for ICOS expression in histologic and molecularly defined tumors and immune cell signatures. ICOS expression was analyzed by IHC in a subset of indications based on in silico analysis. ICOS expression on intra-tumoral Tregs and PD-L1 were analyzed in a cohort of 126 head and neck squamous cell carcinomas (HNSCC). Ex vivo histoculture assays of human HNSCC was treated with JTX-2011 and assessed for IFNg gene signature induction. Results: ICOS mRNA expression was analyzed in ~10,000 solid tumors samples across ~30 indications. ICOS expression in key indications was confirmed using IHC. Based on frequency of high ICOS expression, non-small cell lung cancer, HNSCC, triple negative breast carcinoma, gastric cancer, and melanoma were selected as indications for ICONIC. Results were confirmed in clinical samples using multiplex immunofluorescence and ICOS IHC. A wide range of ICOS expression was observed suggesting that identification of an ICOS “high” group may enrich for patients likely to benefit from ICOS agonist therapy. In ex vivo histoculture assays of human HNSCC tumors treated with JTX-2011, ICOS IHC and ICOS RNA gene signatures correlated to response endpoints. Comparison of ICOS and PDL1 expression identified subsets of tumors in multiple indications with high ICOS but low PDL1 expression. Conclusions: These data support prioritization of specific tumor types the ICONIC trial.
A technical feasibility report on correlative studies from the investigator-initiated phase II study of pembrolizumab (Pembro) immunological response evaluation (INSPIRE).
Authors: Clouthier Derek L. , Yang Cindy , Lien Scott , Gray Diana , Colombo Ilaria , Lheureux Stephanie , Lewin Jeremy Howard , Abdul Razak Albiruni Ryan , Spreafico Anna , Bedard Philippe L. , Butler Marcus O. , Day Daphne , Hansen Aaron Richard , Pugh Trevor John , Chow Helen , Kobori Sawako , Giesler Amanda , Ohashi Pamela S , Siu Lillian L. 
Published: September 2018

11607 Background: Validated biomarkers of response to immune checkpoint inhibitors are needed. Methods: INSPIRE (NCT02644369) is a biomarker-driven study to comprehensively evaluate changes in genomic and immune landscapes in tumors and blood of patients (pts) treated with pembro at 200 mg IV Q3W. It consists of 5 histological cohorts of 20 evaluable pts each: head and neck squamous cell cancer (SCCHN), triple negative breast cancer (TNBC), high grade serous ovarian cancer (HGSOC), melanoma (MM) and mixed solid tumors (MST). All pts undergo pre- and on-treatment (week 6-9) fresh tumor biopsies (bx), and at progression for responders. The first core bx is for immunohistochemistry and subsequent cores are pooled to create single cell suspension for 5 prioritized biomarker assay groups: (1) whole exome/RNA-/TCR-sequencing; (2) T/B/NK, APCs, and/or Treg phenotyping; (3) patient-derived xenografts; (4) RNA-seq on viably sorted immune populations; (5) TIL expansion and characterization. Serial blood samples for immunophenotyping, chemokines/cytokines and ctDNA are collected. Results: 53 pts were enrolled from March 21, 2016-January 16, 2017 (5 SCCHN, 8 TNBC, 17 HGSOC, 7 MM, 16 MST). 84 tumor bx (53 pre-, 30 on-treatment, 1 progression) and 244 blood-based biomarker samples have been collected. The most common sites of tumor bx were: lymph nodes (27%), liver (22%) and skin (14%) (see table). For the 5 cohorts, the % of tumor bx with sufficient cellularity for biomarker assay groups 1 and 2 are: SCCHN (33%), TNBC (9%), HGSOC (52%), MM (55%), MST (55%). Conclusions: This report provides robust technical feasibility data to plan immune and molecular characterization of tumor and blood-based biomarkers in pts receiving ICI. Clinical trial information: NCT02644369. [Table: see text]