bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1263: Comprehensive genomic profiling to identify biomarkers predictive of response to immunotherapy
Authors: Noel Pawan , Hall David W. , Udhane Sameer S. , Wang Min , Alyaqoub Fadel S. , Szelinger Szabolcs , Ozols Audrey A. , LoBello Janine R. , Baehner Frederick L. , Basu Gargi D. 
Published: June 2022

Abstract
Background: Immune-oncology (I-O) drugs show promise across multiple tumor types, and several biomarkers (BM) predict responsiveness to I-O therapy. In this descriptive study of clinical lab experience (2018-2021), we investigated the prevalence of genomic BMs associated with sensitivity and resistance to I-O drugs across solid tumors.
Methods: The GEM ExTra® assay was used to exome-sequence 2,359 paired samples at 180X and 400X coverage for germline and tumor DNA respectively. Reportable alterations were single base substitutions, indels, copy number alterations, fusions, alternate transcripts, as well as tumor mutational burden (TMB) and microsatellite instability (MSI) status. For I-O sensitive BMs we recorded MSI-High status, TMB-High (&gt; 10 mut/Mb) status, and mutations in POLE/POLD1, MLH1, MSH2/3/6, PMS1/2, PD-L1/-L2, CTLA4, CD28, ARID2, and PBRM1. For I-O resistance BMs, IDO1 amplification and mutations in B2M, JAK1/2, IDO1, KRAS and STK11 were tallied. Results: I-O sensitive BMs varied from 0% to 58% (results in Table 1 for selected tumor types). Overall, TMB-High was in 6% of samples and MSI-High in 3%; all MSI-High were also TMB-High. In the 46% of renal cell carcinoma samples with I-O-sensitive BMs, PBRM1 mutation was common (94%). In 3 TMB-High endometrial samples, POLE/POLD1 was mutated, indicative of an ultra-mutated phenotype. Of note, 35% of colorectal cancer and 8% of melanoma samples with I-O sensitive mutations also had loss-of-function mutations in JAK1/2 and B2M, suggestive of I-O resistance. In non-small cell lung cancer, co-mutation of STK11 and KRAS, suggesting inferior response to I-O therapy, was present in 4% of samples with I-O BMs. IDO1 amplification was present in less than 1% of entire cohort.
Conclusions: Our study found I-O sensitive BMs in common and in rare aggressive cancers. The GEM ExTra assay can stratify cancer patients for likely responsiveness to immunotherapy.
Table 1. Immune-oncology sensitive biomarkers observed across select tumors Solid tumor type % of samples with signature All (n = 2,360) 13% Melanoma (n = 50) 54% Other skin cancers (n = 13) 62% Renal cell carcinoma (n = 200) 46% Urothelial (n = 86) 22% Endometrial (n = 88) 20% Gastro-intestinal (n = 360) 12% Sarcoma (n = 90) 11% Prostate (n = 151) 6% Lung (n = 100) 4% Breast (n = 297) 2% Central nervous system (n = 60) 0%
Citation Format: Pawan Noel, David W. Hall, Sameer S. Udhane, Min Wang, Fadel S. Alyaqoub, Szabolcs Szelinger, Audrey A. Ozols, Janine R. LoBello, Frederick L. Baehner, Gargi D. Basu. Comprehensive genomic profiling to identify biomarkers predictive of response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1263.
Abstract 1271: Detection of ALK, ROS1 and RET fusion transcripts in FFPE samples of non-small cell lung cancer patients using a novel RT-PCR based assay
Authors: Denis Marc G. , Vallée Audrey , Sagan Christine , Herbreteau Guillaume , Charpentier Sandrine , Rajamani Jaya , Lee Michael , Ordinario Ellen 
Published: June 2022

Abstract
Background and objective: Detection of genomic rearrangements like ALK fusions are mandatory in non-small cell lung cancer (NSCLC) as those alterations can be targeted by an increasing number of drugs. Fluorescence in-situ hybridization (FISH) is the gold standard but multiplexed technologies allow the analysis of several targets simultaneously. We have evaluated a novel RT-PCR based assay for the detection of ALK, ROS1 and RET rearrangement in NSCLC patients in this research study.
Materials and Methods: FFPE tissue sections from 309 patients with late stage NSCLC were screened for ALK and ROS1 status using immunohistochemistry (IHC) and confirmed with FISH. Total nucleic acids were extracted from tissue sections using the Maxwell RSC RNA FFPE kit (Promega). Fusions were detected by RT-PCR using a prototype ALK/RET/ROS1 Fusion Panel assay (Roche). A subset of discordant cases were further analyzed by RNA sequencing using the QIAseq Targeted RNAscan Lung Cancer Panel (Qiagen).
Results: All 309 samples were tested by RT-PCR with a 0% invalid rate. ALK fusions were detected in 39 samples: 29 were ALK FISH+, 5 were ALK FISH not contributive, 3 were ALK FISH- (less than 15% tumor cells presenting a gene fusion), and 2 were ALK IHC- and not tested by FISH. ROS1 fusions were detected in 12 samples: 9 were ROS1 FISH+, 1 was ROS1 FISH-, and 2 were ROS1 IHC- and not tested by FISH. RET fusions were detected in 3 samples. The remaining 255 samples were RT-PCR-: 5 were ALK FISH+ containing fusions not covered by the RT-PCR assay, 1 was ALK FISH+ containing ALK polysomy, 1 was ROS1 FISH+ containing a fusion not covered by the RT-PCR assay, 1 was ROS1 FISH+ containing ROS1 amplification, 1 was ROS1 FISH+ but ROS1 RNAseq-, and 246 samples were IHC- or IHC+/FISH-. The overall concordance rate between RT-PCR and FISH for ALK and ROS1 gene rearrangements was 91.9%. Although the RT-PCR assay did not detect 5 ALK and 1 ROS1 fusions due to design limitations, it did identify the presence of fusions in 9 tumors that were undetected by FISH (8 ALK and 1 ROS1).
Conclusion: Using limited amount of biological material, RT-PCR was able to detect a substantial majority of ALK and ROS1 fusions identified by FISH, as well as fusions that were missed by the initial IHC/FISH screening. This study demonstrates RT-PCR as a feasible approach to detecting fusions in NSCLC.
Citation Format: Marc G. Denis, Audrey Vallée, Christine Sagan, Guillaume Herbreteau, Sandrine Charpentier, Jaya Rajamani, Michael Lee, Ellen Ordinario. Detection of ALK, ROS1 and RET fusion transcripts in FFPE samples of non-small cell lung cancer patients using a novel RT-PCR based assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1271.
Abstract 1276: Nucleolin has prognostic value in neuroblastoma patients
Authors: Cangelosi Davide , Brignole Chiara , Bensa Veronica , Tamma Roberto , Malaguti Fabiana , Carlini Barbara , Calarco Enzo , Perri Patrizia , Ribatti Domenico , Fonseca Nuno A. , Moreira Joao N. , Eva Alessandra , Amoroso Loredana , Conte Massimo , Garaventa Alberto , Sementa Angela R. , Corrias Maria V. , Ponzoni Mirco , Pastorino Fabio 
Published: June 2022

Abstract
Background: Neuroblastoma (NB) represents the most frequent form of extracranial solid tumor of infants, responsible for 15% of childhood cancer deaths. Nucleolin (NCL) prognostic value in NB was here investigated.
Methods: NCL protein expression was evaluated in NB patients at diagnosis and after induction chemotherapy. NCL mRNA prognostic value was first assessed in a cohort of 20 stage M NB patients and confirmed in the MultiPlatform786 including 786 NB patients of all stages. Overall and event-free survival curves were plotted by Kaplan-Meier method and compared by log-rank test.
Findings: NCL protein resulted significantly overexpressed in NB tumors compared to the non tumoral counterpart, and higher in stage M compared to stage L patients. In the stage M cohort and in MultiPlatform786 dataset, patients with high NCL mRNA expression revealed a significant lower survival probability than those with low NCL expression. In MultiPlatform786 dataset, NCL mRNA expression was significantly higher in patients with age &gt;18 months, in stage M and in MYCN amplified tumors than in patients with age ˂18 months and in stage L or MS and with MYCN non amplified tumors, respectively. Multivariate analysis suggested NCL has a significant prognostic value even in the model adjusted for established prognostic markers. NCL significantly stratified patients with age &lt;18 and age &gt;18, stage M, &gt;18 months and stage M tumor, stages L or MS, and with MYCN not amplified. A significant correlation between NCL and MYCN, MYC, and TERT was found in two independent datasets. Gene set enrichment analysis revealed a significant positive enrichment of MYC target genes and genes involved in telomerase maintenance. NCL protein resulted down-modulated after chemotherapy, in association with morphological features of neuroblastic differentiation.
Interpretation: NCL is a novel and independent prognostic marker for NB.
Funding: IMH-EuroNanoMed II-2015 (ER-2015-2360441-Eranet) and AIRC IG n. 24397 to PF.
Citation Format: Davide Cangelosi, Chiara Brignole, Veronica Bensa, Roberto Tamma, Fabiana Malaguti, Barbara Carlini, Enzo Calarco, Patrizia Perri, Domenico Ribatti, Nuno A. Fonseca, Joao N. Moreira, Alessandra Eva, Loredana Amoroso, Massimo Conte, Alberto Garaventa, Angela R. Sementa, Maria V. Corrias, Mirco Ponzoni, Fabio Pastorino. Nucleolin has prognostic value in neuroblastoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1276.
Abstract 1296: MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells
Authors: Limagne Emeric , Nuttin Lisa , Thibaudin Marion , Jacquin Elise , Aucagne Romain , Bon Marjorie , Ballot Elise , Revy Solène , Barnestein Robby , Truntzer Caroline , Derangère Valentin , Fumet Jean-David , Cédric Rébé , Bellaye Pierre-Simon , Kaderbhai Coureche-Guillaume , Spill Aodrenn , Collin Bertrand , Callanan Mary , Lagrange Aurélie , Favier Laure , Coudert Bruno , Arnould Laurent , Ladoire Sylvain , Routy Bertrand , Joubert Philippe , Ghiringhelli François 
Published: June 2022

Abstract
Chemotherapy with anti PD-1/PD-L1 mAb has become the standard of care for patients with metastatic non-small cell lung cancer (NSCLC). Using lung tumor models, where pemetrexed-platinum chemotherapy (PEM/CDDP) remains unable to synergize with immune checkpoint inhibitors (ICI), we linked failure of this treatment with its inability to induce CXCL10 expression and CD8+ T cell recruitment. Using drug screening, we showed that combining a MEK inhibitor (MEKi) with PEM/CDDP triggers CXCL10 secretion by cancer cells and CD8+ T cell recruitment, and restores ICI efficacy. PEM/CDDP plus MEKi promotes optineurin (OPTN)-dependent mitophagy, resulting in CXCL10 production in a mitochondrial DNA and TLR9-dependent manner. TLR9 or autophagy/mitophagy processes genetic inactivation of abort the antitumor efficacy of PEM/CDDP plus MEKi/anti PD-L1 therapy. In human NSCLC, high OPTN, TLR9 and CXCL10 expression is associated with better response to ICI. Our results underline the role of TLR9 and OPTN-dependent mitophagy in enhancing chemoimmunotherapy efficacy.
Citation Format: Emeric Limagne, Lisa Nuttin, Marion Thibaudin, Elise Jacquin, Romain Aucagne, Marjorie Bon, Elise Ballot, Solène Revy, Robby Barnestein, Caroline Truntzer, Valentin Derangère, Jean-David Fumet, Rébé Cédric, Pierre-Simon Bellaye, Coureche-Guillaume Kaderbhai, Aodrenn Spill, Bertrand Collin, Mary Callanan, Aurélie Lagrange, Laure Favier, Bruno Coudert, Laurent Arnould, Sylvain Ladoire, Bertrand Routy, Philippe Joubert, François Ghiringhelli. MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1296.
Abstract 1303: FAP-targeted molecular radiotherapy attenuates tumor growth and synergizes with immunotherapy for the treatment of malignant melanoma
Authors: Capaccione Kathleen M. , Doubrovin Mikhail , Braumuller Brian , Leibowiz Dvora , Bhatt Nikunj , Molotkov Andrei , Kissner Michael , Momen-Heravi Fatemeh , Mintz Akiva 
Published: June 2022

Abstract
Immunotherapy has drastically improved outcomes in many patients with melanoma, however the majority do not attain a durable response to treatment and therefore additional agents are desperately needed. Here, we tested the efficacy of 177Lu-FAPI-04, a novel FAP-targeted radiotherapy, alone and in combination with anti-PD-1 and anti-CTLA-4 immunotherapy in a mouse model of melanoma to attenuate tumor growth. Using B16F10 murine melanoma cells, we implanted tumors in C57BL/6 mice. Animals were divided into four groups: untreated control, molecular targeted 177Lu-FAPI-04 radiotherapy treatment, immunotherapy treatment, and combined radio- and immunotherapy treatment. We assessed tumor growth over time and animals were sacrificed at 21 days. After sacrifice, tumors were dissected out and preserved for immunohistochemistry and flow cytometry. Growth curves demonstrated that immunotherapy and radiotherapy each individually attenuated tumor growth, but together they resulted in tumor regression in the majority of animals. Immunohistochemistry demonstrated increased caspase-3 staining in tumors treated with combined 177Lu-FAPI-04 radiotherapy and immunotherapy compared to untreated tumors or tumors treated with either therapy alone indicating an increase in apoptotic cell death. Ki67 expression exhibited inverse staining with moderate expression in untreated samples, low expression in immunotherapy and radiotherapy treated samples, and no staining in tumors treated with combined therapy. Flow cytometric analysis demonstrated that tumors treated with either therapy exhibited an increase in M2 macrophages, however this population was obliterated in dual-treated tumors. Together, these data support that targeting FAP with targeted radiotherapy is an effective treatment which synergizes with immunotherapy to modulate cells of the myeloid lineage as an effective anticancer therapy for melanoma. Future translational studies are needed to further study the synergies between FAP-targeted radiotherapies and immunotherapy.
Citation Format: Kathleen M. Capaccione, Mikhail Doubrovin, Brian Braumuller, Dvora Leibowiz, Nikunj Bhatt, Andrei Molotkov, Michael Kissner, Fatemeh Momen-Heravi, Akiva Mintz. FAP-targeted molecular radiotherapy attenuates tumor growth and synergizes with immunotherapy for the treatment of malignant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1303.
Abstract 1312: Pro-survival lipid metabolism activates intracellular complement signaling to induce inflammasome-mediated tumor metastasis
Authors: Janneh Alhaji H. , Ogretmen Besim 
Published: June 2022

Abstract
Tumor metastasis remains one of the major causes of cancer-related deaths in patients with solid tumors. Mechanisms by which metabolic alterations regarding pro-survival lipid signaling activation in inducing cancer cell migration and metastasis are largely unknown. Here, we demonstrate that sphingosine 1-phosphate (S1P) metabolism activates endogenous complement signaling for inducing tumor metastasis via inducing inflammasome-mediated pro-inflammation. Our studies using molecular, pharmacologic, and genetic tools showed that activation of S1P and S1P receptor 1 (S1P/S1PR1) induces tumor metastasis via enhanced intracellular complement signaling by the regulation of the C3-PPIL1 complex and subsequent inflammasome activation in cancer cells and in vivo xenograft-derived tumors.
Citation Format: Alhaji H. Janneh, Besim Ogretmen. Pro-survival lipid metabolism activates intracellular complement signaling to induce inflammasome-mediated tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1312.
Abstract 1350: The role of phosphatidylserine scramblases in tumor progression
Authors: Gadiyar Varsha , Davra Viralkumar , Calianese David , Lahey Kevin , Birge Raymond B. 
Published: June 2022

Abstract
Introduction: Phosphatidylserine (PS), an anionic phospholipid, is asymmetrically distributed in the inner leaflet of the phospholipid bilayer in normal cells under homeostasis. However, PS is constitutively externalized in the tumor microenvironment (TME); on viable cells that undergo stress, such as hypoxic tumor cells, stressed tumor vascular endothelial cells, as well as on cells undergoing apoptosis. This high PS harbors a pro-tumorigenic micro-environment, as myeloid cells expressing PS receptors (Mertk, Tyro3 and Axl) engage with externalized PS and secrete immunosuppressive cytokines. PS is externalized on viable cells by a calcium activated scramblase TMEM16F and on apoptotic cells by a caspase activated scramblase called Xkr8. Here, to study the mechanisms by which PS is externalized in the TME, we hypothesize that TMEM16F and Xkr8 are the major scramblases responsible for creating an immune suppressive milieu in the tumor microenvironment.
Methods: To study the mechanisms of PS dysregulation in the tumor microenvironment, TMEM16F and Xkr8 were knocked out in E0771 murine breast cancer cell line using CRISPR/Cas9. The knockouts were validated by western blotting, q-RT-PCR and surveyor assays.
Results: TMEM16F KO E0771 cells express lower basal levels of PS compared to WT E0771 cells when detected by Annexin V staining by flow cytometry. TMEM16F KO cells are also less responsive to activation by calcium ionophore. TMEM16F KO, Xkr8 KO and WT E0771 cells have similar viability and migration patterns in response to Gas6, indicating that the cells themselves do not have altered oncogenic potential. TMEM16F KO E0771 cells injected into the inguinal mammary gland fat pad of C57BL6 syngeneic mice showed modest but significantly reduced tumor growth compared to the E0771 WT tumors, suggesting that TMEM16F mediated PS externalization could play a role in exacerbating tumor progression.
Conclusion: TMEM16F driven PS externalization contributes to tumor growth. The effect of TMEM16F KO on immune regulation of the tumor milieu will be discussed. These data corroborate previous studies targeting PS in tumors therapeutically using anti-PS antibodies and suggests a role for scramblases in pleiotropic immune-suppression in the tumor.
Citation Format: Varsha Gadiyar, Viralkumar Davra, David Calianese, Kevin Lahey, Raymond B. Birge. The role of phosphatidylserine scramblases in tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1350.
Abstract 1388: Mutations in transcriptional activators of MHC I antigen presentation, NLRC5 and CIITA, are mutually exclusive and have different effects on melanoma gene transcripts
Authors: Galvez Mildred , Campbell Katie M. , Medina Egmidio , Ribas Antoni 
Published: June 2022

Abstract
Response to many immunotherapies depends on effective recognition and eradication of tumor cells by the immune system. This is mediated by the successful presentation of tumor-specific antigens on major histocompatibility complex class I (MHC I) molecules on the surface of tumor cells. Studies have focused on alterations in MHC I complex proteins (e.g. HLA, B2M) and gene regulatory elements (e.g. NLRC5). However, the impact on tumor response of individual defects in components regulating and composing the MHC I antigen processing and presentation machinery (APM) have not been extensively studied. Using a harmonized dataset of six clinical trials of patients with melanoma treated with ICB, whole-exome sequencing (WES, n= 244) and RNA sequencing (RNAseq, n= 426) data from untreated tumor samples were assessed to identify mutations in genes associated with MHC I APM and their regulation. Somatic alterations were correlated with clinical response to ICB and with gene expression profiles in tumor-matched RNAseq data. Mutations in MHC I and MHC I-related genes were found in 63% of patients (n= 154/244). The most recurrently mutated genes were NCAM1 (11%, n=28), TRIM48 (7%, n=17), and CAMK2B (6.6%, n=16), and the transcriptional regulators NLRC5 (9.4%, n=23) and CIITA (9.4%, n=23). Mutations in NLRC5 and CIITA trended toward being mutually exclusive from one another (Fisher’s exact test, p= 0.157) and mutations were overrepresented in tumors with stable or progressive disease following ICB therapy. In addition, lower expression of NLRC5 and CIITA were associated with stable or progressive disease status. NLRC5-mutant tumors that progressed following ICB therapy trended towards lower expression of transcriptional target HLA-A (Kruskal-Wallis, p=0.27); however, there was no difference in HLA-A expression across NLRC5-wildtype tumors. For class II transactivating factor, CIITA, which can induce MHC I expression, mutational status was not associated with HLA-A expression across all clinical response groups. There are genetic alterations spanning MHC I and MHCI-associated genes that may be responsible for inactivating class I antigen presentation by melanoma cells. The impact of these alterations may result in varied clinical responses to ICB therapies. The landscape of these alterations needs to be further delineated to understand how tumors are directly evading class I-mediated recognition and elimination.
Citation Format: Mildred Galvez, Katie M. Campbell, Egmidio Medina, Antoni Ribas. Mutations in transcriptional activators of MHC I antigen presentation, NLRC5 and CIITA, are mutually exclusive and have different effects on melanoma gene transcripts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1388.