bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lyc-55716: A novel small-molecule RORγ agonist immuno-oncology agent: Rationale for tumor selection and clinical evaluation of gastric and esophageal carcinoma in phase 2a expansion.
Authors: Weems Garry Alan , Hu Xiao , Liu Xikui , Li Hongxiu , Bogdan Madhumita , Gao Yilin , Fox Brian , Wilkins H. Jeffrey , Carter Laura 
Published: January 2019

67 Background: Type 17 effector T cell differentiation and function are regulated by the master transcription factor retinoic acid receptor–related orphan receptor γt (RORγ). Synthetic RORγ agonists, which modulate immune cell gene expression to enhance effector functions and decrease Treg and checkpoint pathways, have shown promise as mono- and combination therapy in syngeneic tumor models. Translational and bioinformatics assessments were performed during Phase 1 testing of the investigational RORγ agonist LYC-55716 to support inclusion of patients with gastric carcinoma (GC) and esophageal carcinoma (EC) in a Phase 2a expansion of clinical trial LYC-55716-1001 (NCT02929862). Methods: Transcriptional profiling of murine and human T cells treated ± RORγ agonists identified a gene signature. Using The Cancer Genome Atlas (TCGA), and other public datasets, data on GC and EC patients were evaluated to determine: (a) RORγ and RORγ-inducing cytokine expression; (b) signature genes associated with RORγ biology, surrogate biomarkers for endogenous RORγ ligands, and correlations with prognosis; (c) tumor microenvironment (TME) immune profiles. Results: Expression: In TCGA RNA sequencing data analysis, 50%-70% of GC and EC samples expressed moderate to high levels of RORγ, indicating infiltration of Type 17 T cells into the tumors. Furthermore, genes that support expression of RORγ were highly expressed in ~75% of GC and EC tumors. Biology: TCGA data showed that GC and EC tumors express low levels of sterol efflux genes, suggesting low levels of endogenous agonists in the TME. In analysis of public datasets, expression of the RORγ target gene IL17A correlated with a favorable prognosis for EC. In addition, some of the other RORγ signature genes also correlated with good prognosis in GC and EC. Immune profile: TCGA showed infiltration of T cells and a high mutational burden in GC and EC, which are positively associated with efficacy of immunotherapy. Conclusions: Bioinformatics assessments of RORγ expression, biology, and tumor immune profiles support the inclusion of GC and EC patients in an ongoing Phase 2 clinical trial of LYC-55716.
Circulating angiogenesis-related markers as predictors of benefit from regorafenib in metastatic colorectal cancer (mCRC) patients (pts).
Authors: Antoniotti Carlotta , Marmorino Federica , Pennati Marzia , Zaffaroni Nadia , Rossini Daniele , Borelli Beatrice , Zucchelli Gemma , Moretto Roberto , Pietrantonio Filippo , Masi Gianluca , Vannini Francesca , Colombo Camilla , Gini Serenella , Saettini Alessandra , Delliponti Laura , Brunetti Isa Maura , Pfanner Elisabetta , Falcone Alfredo , Cremolini Chiara 
Published: January 2019

675 Background: Regorafenib is a treatment option for refractory mCRC pts. Considering its limited clinical benefit and the palliative setting, patients’ selection is essential to optimize the cost-effectiveness ratio. We aimed to describe the modulation of selected circulating angiogenic factors by regorafenib and to investigate their correlation with clinical outcome. Methods: IL-8, Ang-2, PDGF, bFGF, Tie-2, sVEGFR2, sVEGFR3, PlGF, VEGF-A, VEGF-B were assessed by ELISA on plasma samples collected at baseline (d1), after 15 days of treatment (d15), at the best RECIST response, at disease progression (PD) in mCRC pts treated with regorafenib, as per indication. Comparisons among concentrations of each marker at different timepoints were performed by Wilcoxon test. Markers showing significant changes were analyzed for correlation with outcome. Results: 105 pts were included. Median PFS and OS were 2.1 and 7.0 months (mos), respectively. As compared to d1, IL-8 and Ang-2 levels increased at PD. An early decrease at d15 was observed for PDGF, Tie-2, sVEGFR2 and sVEGFR3 levels, followed by an increase at PD. Conversely, PlGF levels increased at d15 and then decreased at PD. Baseline levels of Ang-2 and Tie-2 below the median value were associated with longer PFS (HR:0.61 [0.37-0.83] p = 0.006; HR:0.69 [0.43-0.95] p = 0.04, respectively) and OS (HR:0.45 [0.26-0.60] p < 0.0001; HR:0.68 [0.44-0.98] p = 0.04, respectively). With regard to Ang-2, 40 (45%) out of 89 pts with available plasma samples at d15 showed increased levels at d15 as compared to d1. Among them, 21 (53%) achieved disease control, as compared to 14 out of 49 (29%) pts with Ang-2 decreased levels (p = 0.03). Median PFS of pts with increased and decreased Ang-2 levels were 3.1 and 1.8 mos, respectively (HR:0.57 [0.33-0.78] p = 0.004). Conclusions: A dynamic modulation of plasma angiogenic factors occurs during the treatment with regorafenib. Low baseline Ang-2 and Tie-2 levels seem to be associated with good prognosis. The early modulation of Ang-2 levels may predict benefit from regorafenib. These results need validation in independent series.
ALK alteration association with prognosis in metastatic colorectal cancer: A single institution retrospective cohort study.
Authors: Kasi Anup , Chidharla Anusha , Schmitt Sarah , Pessetto Ziyan Y. , Gupta Nikhil , Paluri Ravi Kumar , Saeed Anwaar Mohammed , Godwin Andrew K. 
Published: January 2019

676 Background: The Anaplastic Lymphoma Kinas (ALK) gene is altered in various malignancies which can be targeted with several inhibitors. However, the incidence of mutations in ALK are not well defined in colorectal cancers (CRC). We aim to study the prevalence of ALK mutations in metastatic CRC (mCRC) patients and correlate with clinical outcomes. Methods: We retrospectively evaluated 54 mCRC patients treated with chemotherapy at Kansas University Cancer Center between June 2010 and September 2017 who underwent our inhouse targeted 17 gene next-generation sequencing test using an illumina MiSeq technology. The panel included AKT1, ALK, BRAF, EGFR, FLT3, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, NPM1, NRAS, PDGFRA, PIK3CA, PTEN, and TP53 genes. We compared baseline characteristics, tumor location (left vs right) and clinical outcomes between patients with ALK mutations versus ALK wild type. Results: We retrospectively evaluated 54 mCRC patients treated with chemotherapy at Kansas University Cancer Center between June 2010 and September 2017 who underwent our inhouse targeted 17 gene next-generation sequencing test using an illumina MiSeq technology. We compared baseline characteristics, tumor location (left vs right) and clinical outcomes between patients with ALK mutations versus ALK wild type. Results: We found 10 pts (18.5%) with ALK mutations and compared with 44 patients that were ALK wild type. Demographic and baseline characteristics (ALK mutation/wild type) were as follows: Median age 61 vs 61 years, Gender (male): 80% vs 50%, Left sided tumor 70% vs 60%. Of 41 evaluable patients (ALK mutation vs wild type), Objective response rate (stable + partial response) was 50% vs 91% [p = 0.03], 6-month PFS 33% vs 77%, Median PFS 12 months vs 17.7 months [p = 0.2], Median OS was 14.5 months vs not reached [HR 28.98, p = 0.025]. Conclusions: Patients harboring ALK mutations had a statistically significant poorer objective response rate and OS compared to ALK wild type patients. Findings of our study highlight the importance of assessing ALK gene alteration as a prognostic biomarker for mCRC. Therefore ALK mutation appears to be poor prognostic factor and needs to be validated in larger cohorts.
Therapeutic relevance of homologous recombination repair (HRR) pathway variants in metastatic colorectal cancer (mCRC).
Authors: Narra Ravi Kishore , Singavi Arun K. , Ritch Paul S. , Thomas James P. , Alqwasmi Abdel , Szabo Aniko , George Ben 
Published: January 2019

677 Background: Intact HRR pathway genes play a critical role in repairing double-stranded DNA breaks. Genomic alterations (GA) in several HRR pathway genes have been well characterized, demonstrating prognostic and predictive significance. However, there are many variants of unknown significance (VUS) in the HRR pathway genes that need better characterization. Methods: Patients (pts) with mCRC that harbored VUSs in HRR pathway genes (HRR- VUS; BRCA1/2, ATM, ATR, RAD50, RAD51, PALB2, CHEK1, CHEK2) and treated with front line platinum therapy were identified by review of our institutional molecular data base (MDB) and EMR. Time to 2nd line therapy (TT2L) and Overall Survival (OS) were calculated. DNA was extracted from formalin fixed paraffin embedded clinical specimens and Next Generation Sequencing (NGS) was performed on hybrid-capture, adaptor ligation based libraries to a mean coverage depth of > 600 unique reads utilizing the Foundation Medicine NGS platform. Results: Among the 873 pts in our institutional MDB, 96 (11%) had mCRC, 20 (21%) harbored HRR pathway GAs, 15 (16%) were categorized as VUSs. HRR-VUS pts had a median age of 57 at diagnosis, 5 (33%) were male, 3 (20%) were right-sided. Distribution of HRR-VUSs in this cohort is summarized in table 1. All pts with HRR-VUSs were micro-satellite stable (MSS), median TMB was 4.5 (range 0 – 8.1). Median TT2L and OS in mCRC pts with HRR-VUSs were 8.0 and 43 months (m) respectively. Two pts with HRR-VUSs had TT2L > 24 m and OS > 40 m; one of them had a BRCA1P1464A mutation, while the other had a BRCA2 amplification. Conclusions: BRCA2, ATM and BRCA1 were the HRR genes that harbored VUSs most frequently in pts with mCRC. Majority with HRR-VUSs had left sided primaries, were MSS and had low TMB. BRCA1P1464A mutation in the ATM binding domain needs further characterization on account of prolonged TT2L with platinum based chemotherapy. Patients with HRR-VUSs that are predictive of benefit with platinum based chemotherapies could be considered for maintenance therapy with PARP inhibitors [Table: see text]
Molecular rationale for ERK and EGFR inhibition in colorectal cancer.
Authors: Yeatman Timothy Joseph , Davis Thomas , Yang Mingli , Schell Michael J. , Wang Heiman , Rocha Lima Caio Max S. , Pledger Jack 
Published: January 2019

679 Background: Mutational activation of the RAS pathway occurs in >50% of human CRC tumors, and to date has been difficult to overcome. We recently identified receptor tyrosine phosphatase-S (PTPRS) as an important regulator of the RAS pathway, which is mutated in ~11% of CRC. Methods: Global gene expression and DNA sequencing data (1321 cancer genes) were integrated across 468 CRC tumors to identify PTPRS as one of the most commonly mutated genes with a high correlation to a RAS activation score. Apoptotic responses to inhibitors of ERK, EGFR and their combination were tested in isogenic wild-type and mutant RAS cell lines where PTPRS had been knocked out by CRISPR. Results: PTPRS was in the top 15 genes correlating with RAS pathway activation scores; as expected, KRAS, BRAF were the most correlated genes. In order to determine the effect of the loss of PTPRS on RAS/ERK signaling, we used CRISPR to knockout PTPRS in an isogenic pair of CRC cell lines (HCT116) with mutant or wild type KRAS. Cell lines lacking PTPRS expression had elevated phospho-ERK activity. Interestingly, cell lines with PTPRS knockout and elevated ERK phosphorylation had an increased sensitivity to ERK inhibitors. Moreover, the loss of PTPRS allowed ERK to localize to the nucleus. Apoptosis increased dramatically from 13.1% in control cells to 53.8% in PTPRS KO cells treated with both ERK and EGFR inhibitors (Table), a synergistic effect not seen in wild type KRAS cells, where only ERK inhibitors were active. Conclusions: The loss of PTPRS allows increased activation of ERK (and the RAS pathway) which is associated with ERK addiction and increased sensitivity to ERK inhibitors. Surprisingly, ERK inhibitors synergize with EGFRi in wild type KRAS cell lines absent PTPRS. These data suggest the potential for mutant PTPRS to serve as a biomarker for ERK/EGFR inhibition. [Table: see text]
Effect of ASXL1 on the stemness of colorectal cancer initiating cells.
Authors: Isobe Taichi , Zarnegar Mark A. , Abdel-Wahab Omar Ibrahim , Clarke Michael F. 
Published: January 2019

683 Background: Impaired cellular differentiation causes uncontrolled proliferation of stem cells and can be a cause of oncogenesis. The epigenome regulates the expression of genes that are essential for cellular differentiation. On the other hand, chromosomal abnormalities are common in colorectal cancer cells. We hypothesize that epigenetic disorders caused by chromosomal abnormalities may result in oncogenesis. Methods: The Cancer Genome Atlas (TCGA) database was investigated to identify epigenetic regulating genes affected by chromosomal abnormalities. Patient-derived colorectal cancer cells were obtained from consented patients to validate these findings. Results: The amplification of Chr20q11 is the most frequent chromosomal alteration in left-sided colonic and rectal cancers. ASXL1, a recruiter of PRC2, is coded in Chr20q11 and has upregulated expression in many cases. Excessive expression of ASXL1 may cause oncogenesis as PRC2 trimethylates histone H3 on lysine 27 (H3K27me3), an epigenetic mark of transcriptional silencing. Immunofluorescence revealed that the ASXL1 protein was located in the nuclei of colorectal cancer cells that did not express differentiation markers. This finding was consistent with the finding that ASXL1 highly expressed at the bottom of crypts where undifferentiated cells exist in normal colonic epithelium. Knockdown of ASXL1 in colorectal cancer cells reduced the levels of H3K27me3 and diminished organoid formation in vitro. Knockdown of ASXL1 in patient-derived cancer cells obtained from clinical specimens impaired the tumorigenicity of cancer initiating cells in vivo and increased the expression of differentiation markers. Murine colonic tumor cells from ApcMin mice highly expressed ASXL1, while homozygous Asxl 1 knockout reduced the occurrence of tumors in vivo. Many putative genes regulated by ASXL1 are identified by gene expression analysis and ChIP-sequencing. Conclusions: High expression of ASXL1 initiates oncogenesis and maintains the stemeness of colorectal cancer cells.
CEA as a pharmacodynamic biomarker for metastatic anal cancer.
Authors: Hester Robert Harrison , Taniguchi Cullen M. , Holliday Emma Brey , Koay Eugene Jon , Das Prajnan , Minsky Bruce D. , Rashid Asif , Mehdizadeh Amir , Ohinata Aki , Messick Craig , You Y. Nancy , Chang George J. , Bednarski Brian , Rodriguez-Bigas Miguel A. , Skibber John Michael , Wolff Robert A. , Eng Cathy , Morris Van Karlyle 
Published: January 2019

684 Background: While carcinoembryonic antigen (CEA) as a tumor marker is frequently used in the management of colorectal adenocarcinoma, its clinical utility in squamous cell carcinoma of the anus (SCCA) has never been reported. Indeed, no tumor markers have been validated for monitoring tumor burden in the course of any HPV-associated malignancy like SCCA. We hypothesized that CEA levels might be preferentially elevated in patients with metastatic SCCA. Methods: Charts from 212 patients with SCCA were reviewed under an IRB-approved protocol for correlations between CEA levels and corresponding oncologic status. Clinical status was categorized as newly diagnosed non-metastatic (D), after chemoradiation with no evident remnant disease (N), recurrent/resectable SCCA (R), locally advanced/unresectable SCCA (U), metastatic SCCA to lymph nodes only (M-LN), or metastatic SCCA to visceral organs (M-V). Mean CEA levels were compared between subgroups via student t-tests, and frequencies of elevated CEA were compared via Chi-squared analyses. Results: 118 SCCA patients had metastatic disease (98 M-V, 19 M-LN). Mean CEA levels by clinical status were 5.4 (D), 2.0 (N), 2.3 (R), 4.6 (U), 6.0 (M-LN), and 22.2 (M-V), with a higher (statistically insignificant) mean CEA level in the M-V relative to other populations. However, patients with visceral metastases were more likely to have an elevated CEA at presentation (40.4%) relative to patients with newly diagnosed, non-metastatic SCCA (17.6%, p = .07) or recurrent SCCA (11.1%, p = .02). For patients with metastatic SCCA, a significant association existed between change in CEA and corresponding change in radiographic tumor dimensions (OR 24, p < 0.0001). Conclusions: Trends in CEA correlate with dynamic changes in tumor burden for patients with metastatic SCCA, and patients with metastatic SCCA were more likely to have an elevated CEA. Given that immune checkpoint blockade agents like nivolumab have proven benefit for metastatic SCCA, these data provide rationale for use of newer generation immunotherapeutic approaches like CEA-T cell bispecific antibodies, which target CEA-expressing tumors, in clinical trials for patients with metastatic SCCA.
Modulation of T cell and macrophage tumor infiltration by the TLR9 agonist lefitolimod in a murine model of colorectal cancer.
Authors: Schmidt Manuel , Oswald Detlef , Volz Barbara , Wittig Burghardt , Kapp Kerstin 
Published: January 2019

687 Background: The use of TLR9 agonists for immunotherapeutic approaches is supported by preclinical and ongoing clinical studies. Lefitolimod, a covalently-closed dumbbell-shaped DNA construct, is an immune surveillance reactivator which broadly activates cells of the innate and adaptive immune system. The conversion of non-immunogenic (cold) tumors into immunogenic (hot) tumors, characterized by their T-cell infiltration, is a pre-requisite for response to immunotherapies. By its mode-of-action lefitolimod likely provides the necessary signals for activation of immune cells and their differentiation into anti-tumor effector cells as well as their recruitment to the tumor microenvironment (TME). Methods: To support the further clinical development of lefitolimod in mCRC, the syngeneic colon carcinoma model CT26 was used to evaluate anti-tumoral efficacy of lefitolimod and its modulation of the TME. The phenotype of T cells and macrophages present within tumor-infiltrating immune cells were analyzed by flow cytometry. Their localization within the tumor was investigated by immunohistochemistry. Results: Intratumoral injection of single-agent lefitolimod in the CT26 model resulted in reduced tumor growth. This was accompanied by an increased infiltration of T cells, in particular CD8+ T cells, into the tumor center. The CD8+ T cells were activated and showed an up-regulation of the cytolytic effector Granzyme B. Correspondingly, the ratio of activated CD8+ T cells with cytolytic function to regulatory T cells was increased by lefitolimod. Moreover, lefitolimod led to the recruitment of macrophages into the tumor and, importantly, an increase of M1 macrophages and a decrease of M2 macrophages inside the TME. Conclusions: Lefitolimod treatment resulted in modulation of the TME towards an increase of effector cells with anti-tumoral functions like cytotoxic CD8+ T cells and M1-type macrophages as well as a decrease of pro-tumoral M2-type macrophages. Therefore, lefitolimod provides the essential requirements for clinical response to immunotherapeutic drugs like checkpoint inhibitors. This predestines lefitolimod as combination partner in immuno-oncological trials.
Effect of tumor progression on colon cancer stem cell plasticity.
Authors: Chiu Vi Kien , Gallupalli Rama , Osman Diaa , Zeng Zhaoshi , Shia Jinru , Paty Philip , Le Rolle Anne-France 
Published: January 2019

688 Background: Stage I colon cancer initiation is optimized through the activation of the embryonic stem cell (SC)-like program in colon adenoma cells (Le Rolle AF, et al., 2016). This malignant transformation requires cellular dedifferentiation since the embryonic SC-like program does not exist a priori in colon cells. High initial tumor plasticity provides a competitive advantage as the tumor has more intrinsic phenotypic flexibility to survive environmental challenges. Inhibition of the embryonic SC-like program represents a novel therapeutic strategy. Herein, we examine the evolution this high tumor plasticity in stage I-IV colon cancer. Methods: Human colon cancer tissues were collected prospectively under an MSKCC IRB protocol (Jan 1990-Dec 2000). RNA in situ hybridization of LGR5, a colon SC marker, was carried out on human colon tumors before and after therapeutic interventions. We performed Gene Set Enrichment Analysis (GSEA 2.0 Broad Institute software) using Affymetrix U133A expression profiles from normal colon mucosa (n = 33) and colon cancer epithelia from stage I (n = 17), II (n = 35), III (n= 39) and IV (n= 46) tumors. Statistical analyses were conducted with GraphPad Prism 5 and Microsoft Excel. Results: Putative colon SC markers and differentiation markers are increased and decreased, respectively, in stage I-IV colon cancer in comparison to normal colon. Although colon adenoma originates from LGR5+ colon SC, LGR5+ overexpression per se correlates with good prognosis stage IV colon cancer and is not a colon cancer stem cell biomarker. Maximal embryonic SC-like program enrichment occurs in stage I colon cancer. GSEA comparisons of moderately differentiated stages II-IV versus stage I colon cancer reveal progressive tumor differentiation from the stage I embryonic SC-like program toward the intestinal SC program at more advanced tumor stages. Notably, poorly differentiated stage IV colon cancer retains an embryonic SC-like program. Conclusions: We conclude that except for poorly differentiated tumors, colon cancer progression from stage I to IV involves a heterogeneous tumor differentiation process from an embryonic SC-like program towards the intestinal SC or more differentiated intestinal cell programs.
Clinical and molecular characterization of early-onset colorectal cancer patients with inflammatory bowel disease.
Authors: Willauer Alexandra Nicole , Loree Jonathan M. , Pereira Allan Andresson Lima , Lam Michael , Raghav Kanwal Pratap Singh , Morris Van Karlyle , Menter David , Shaw Kenna Rael , Broaddus Russell , Meric-Bernstam Funda , Wang Yinghong , Overman Michael J. , Kopetz Scott 
Published: January 2019

689 Background: Recent reports suggest colorectal cancer incidence is steadily increasing in adults < 50 years old. This population has a number of unique pre-disposing conditions, such as inflammatory bowel disease (IBD), that may alter the disease biology within these patients. Methods: Using a cohort of 1876 patients with metastatic CRC (mCRC), we identified 622 patients aged < 50 years and reviewed their medical records for a diagnosis of IBD. Clinical, pathologic and overall survival (OS) were compared between patients with and without IBD in this age group. Results: Twenty of 622 (3.2%) early-onset mCRC patients had IBD. These patients were more likely to have mucinous or signet ring histologic features (50.0% vs 15.6%, OR 5.43, 95% CI 2.20-13.41, P < 0.0001) and less likely to have APC mutations (15.0% vs 42.7%, P = 0.019). A trend toward an increased prevalence of right-sided location (40.0% vs 24.1%, P = 0.053) and TP53 mutations (85.0% vs 65.1%, P = 0.091) and decreased prevalence of PIK3CA mutations (0.0% vs 15.5%, P = 0.057) and KRAS mutations (35.0% vs 50.0%, P = 0.11) were noted. There were no differences in prevalence of BRAF V600 (P = 0.99), CTNNB1 (P = 0.99), NRAS (P = 0.99), PTEN (P = 0.43), or SMAD4 (P = 0.75) mutations between patients with IBD and other early-onset mCRC. The presence of IBD in early-onset mCRC patients was associated with a worse OS compared to patients without IBD but who had mCRC (HR 1.82, 95% CI 0.90-3.69, P = 0.026). Conclusions: Early-onset mCRC patients with IBD are significantly more likely to have mucinous or signet ring histologic features and have fewer mutations in canonical CRC genes such as KRAS, PIK3CA, and APC. This suggests that this population likely develops through a unique molecular pathogenesis and they may respond differently to therapy. Further molecular characterization of this population is required.