bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3991: ONCOTARGET (ONCOALVO): A custom NGS panel for therapeutic decision in solid tumors refractory to conventional therapy
Authors: Murad Andre M. , Casali-da-Rocha Jose Claudio , Carneiro Juliana G. , Godard Ana L. 
Published: August 2019

Abstract
Next-generation sequencing (NGS) of tumor biopsies of both solid tumors, as well as hematological malignancies, using commercially available platforms has broadly entered routine clinical practice in medical oncology. This molecular diagnostic approach is now used mainly to test for predictive biomarkers for patients with no available further standard therapies, as diagnostics rely on genomic testing of molecular alterations to enable effective cancer treatment. However, the high cost of large multigenic panels and especially the sequencing of the entire tumor exome is a concern, especially in a developing country such as Brazil. Here we report the clinical application of a panel of 57 genes that we call ONCOTARGET (ONCOALVO) which is based on the Thermo Fisher Oncomine Focus Assay, an integrated, commercially available NGS assay for the rapid and simultaneous detection of single nucleotide variants, short insertions and deletions, copy number variations, and gene rearrangements in 52 cancer genes with therapeutic relevance, but with 5 additional genes: the homologous recombination repair (HRR) genes BRCA1, BRCA2, ATM and CHEK2 that determine tumor sensitivity to inhibitors of the PARP enzyme and also KDR, which determines sensitivity to regorafenib. Twenty-five diagnostic samples of formalin-fixed, paraffin-embedded material submitted for molecular testing over a 8-month time period were analyzed so far. All patients had advanced solid tumors already refractory to conventional systemic therapy. Libraries were prepared from isolated nucleic acids and sequenced on the Ion Torrent S5 sequencer. Sequencing datasets were analyzed using the Ion Reporter software. From the samples of the 39 patients tested, we found 30 potential therapy target pathogenic gene aberrations in 22 (56.4%) patients: KRAS - 7 (23.3%), BRCA1 - 6 (20%), BRCA2 - 5 (16.6%), PIK3CA - 3 (10%), MAP2K1 - 2 (6.6%), BRAF-V600E - 2 (6.6%) mutations; and also one of each: ERBB2 (3.3%), mTOR (3.3%), KIT (3.3%), ALK (3.3%) mutations and one (3,3%) CCND1 amplification. In 3 (7,69%) patients there were double mutations: BRCA1 and BRCA2 in 2 cases and BRCA2 and KRAS and one case. The Oncotarget workflow enabled a turnaround of 18 frac12 days. Taken together, ONCOTARGET was found to be a convenient tool for fast, reliable, broadly applicable and cost-effective targeted NGS of tumor samples in routine diagnostics and therapeutic decisions with a potential to become an important assay for precision oncology in Brazil.
Citation Format: Andre M. Murad, Jose Claudio Casali-da-Rocha, Juliana G. Carneiro, Ana L. Godard. ONCOTARGET (ONCOALVO): A custom NGS panel for therapeutic decision in solid tumors refractory to conventional therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3991.
Abstract 4: Discovery of novel and highly potent small molecule inhibitors of chemokine receptor CXCR4
Authors: Fang Xiong , Meng Qian , Fang Xiao , Zhu Siyu , Huang Yazi , An Jing , Xu Yan , Huang Ziwei 
Published: August 2019

Abstract
Introduction: CXCR4 is a member of chemokine receptor and G protein coupled receptor (GPCR) families. Its interaction with the chemotactic ligand stromal cell-derived factor 1 (SDF-1 or CXCL12) plays important roles in physiological and pathological processes. Recent studies have showed that the blockade of CXCL12-CXCR4 interaction by small molecules can be used in several clinical applications, including sensitizing cancer cells to chemotherapy, mobilizing hematopoietic stem cells (HSCs) to the blood for HSC collection, and inhibiting the tumor metastasis. To date, AMD3100 (Plerixafor) is the only clinically approved drug used in combination with G-CSF for mobilizing HSCs. Here, we report the discovery and development of a new class of highly potent small molecule CXCR4 inhibitors which can strongly antagonize CXCL12-CXCR4 interaction and mobilizing HSCs. Methods: Based on the crystal structures of CXCR4 showing a major and minor subpockets, we applied a fragment-based combinatorial design (FBCD) strategy to design a new class of hybrid molecules to recognize these two subpockets. A series of designed compounds were chemically synthesized and tested in a panel of biological assays including competitive CXCR4 binding, chemotaxis, calcium mobilization and CXCR4 internalization to characterize their biological activities. Furthermore, site-directed mutagenesis coupled with molecular docking simulation was carried out to determine the binding modes of the most potent compounds. Results: More than 30 compounds were synthesized and characterized. Among them, compound HFX51116 showed the most potent CXCR4 binding activity (IC50 = 12.2 nM), which was more potent than AMD3100 tested in parallel (IC50 = 325.3 nM). Furthermore, HFX51116 displayed remarkable inhibition of calcium mobilization (IC50 = 1.478 nM) and chemotaxis activity (IC50 = 252.7 nM), both of which are better than those of AMD3100. In addition, mutational studies and molecular docking simulation suggested that HFX51116 recognizes the minor subpocket mainly and major subpocket partially. Conclusions: Our findings have demonstrated that HFX51116 is a promising novel lead compound for developing a new class of small molecule therapeutics targeting CXCR4.
Citation Format: Xiong Fang, Qian Meng, Xiao Fang, Siyu Zhu, Yazi Huang, Jing An, Yan Xu, Ziwei Huang. Discovery of novel and highly potent small molecule inhibitors of chemokine receptor CXCR4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4.
Abstract 4005: Glycemic microenvironment and ovarian cancer risk in underserved minority populations
Authors: Henry Desmond , Washington Crystal , Rashad Marley , Fan Guihong , Rao Veena , Frazier Monica 
Published: August 2019

Abstract
Studies have shown that ovarian cancer risk is associated with diabetes mellitus (DM). Moreover, the notion that cancer growth and progression is linked to obesity is also widely accepted. However, the impact of the glycemic and adipose microenvironment is often overlooked. Epidemiologic studies of these microenvironments in medically underserved populations are also overlooked. The aim of this study was to determine the relationship between DM and ovarian cancer incidence and progression in underserved minority populations.
A retrospective study of ovarian cancer patients diagnosed over at 10 year period (2008 – 2018) at one location was performed. Data abstracted for this study included demographic, pathologic, glycemic, DM and BMI data of 142 women with ovarian cancer. Pearson chi-square (p&lt;0.05) was used to compare variables.
26 (18%) of 141 patients had a DM diagnosis and 128 (91%) of the 141 were from an underserved minority group. There was an inverse relationship between tumor size and stage. Patients in later stages had significantly smaller tumors than those in earlier stages of ovarian cancer. There was also a direct correlation between hemoglobin a1c (HbA1c) levels and tumor staging in patients with more advanced disease having slightly higher HbA1c levels (5.2, 5.5, 5.3 and 5.8 HbA1c levels Stages 1 - 4, respectively) And although there continues to be discussion on the best glycemic indicator for determining risk, we did find a similar correlation between staging and blood glucose levels. Lastly, when investigating the relationship between BMI and ovarian cancer staging, it appears that stage 1 occurrence was irrespective of BMI measurements (range 16.3 – 63.2). However, in stages 2 (range 17 – 22.8), 3 (range 21.5 – 33.9) and 4 (range 20.9 – 41.2), there was a positive correlation between BMI and staging. This result suggests that ovarian cancer progression is associated with BMI.
Overall, when using cancer stage as an indicator of ovarian cancer progression, this data suggests that while tumor size is inversely related to progression, the glycemic microenvironment along with the increased presence of adipose tissue is positively correlated with ovarian cancer progression.
Citation Format: Desmond Henry, Crystal Washington, Marley Rashad, Guihong Fan, Veena Rao, Monica Frazier. Glycemic microenvironment and ovarian cancer risk in underserved minority populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4005.
Abstract 4027: XNA-Based OptiSeqTMlung and colorectal cancer mini panel, a high sensitivity method for cancer early detection
Authors: Sha Michael Y. , Feng Wenjing , Sun Qing , Zhan Ke , Powell Michael J. , Zhang Aiguo 
Published: August 2019

Abstract
The identification of genetic variants with low allelic frequency using next-generation sequencing method is confounded by the complexity of human genome sequence and by bias that arise during library preparation, sequencing and analysis. Herein, we introduce a novel molecule, Xenonucleic Acid (XNA) for NGS application. XNA is able to selectively suppress primer directed amplification of DNA with wild type alleles and only amplify DNA target templates containing mutant alleles. Mutants with low allelic frequency will be easily detectable without deep sequencing after enrichment by adding XNA in multiplex PCR. The 17 actionable mutants related to lung or colorectal cancer diseases at different VAF% were investigated in this study. Upon XNA blocking of wild type alleles, enriched variant allelic frequency (VAF) can be increased by ~32 fold from 10 ng of gDNA samples containing mutants as low as 0.10% VAF. Analytical sensitivity of Limit of Detection (LOD) is about 0.10% VAF. These 17 actionable mutants were tested and verified by using tissue biopsy (FFPE) and liquid biopsy (cfDNA) of lung or colon cancer patient samples. Clinical sensitivity for FFPE sample is about 100% for lung cancer and colorectal cancer samples respectively, comparing to without XNA NGS about 85.7% for lung cancer and 70% for colon cancer. For cfDNA sample its clinical sensitivity is about 100% for lung and colon cancer, but without XNA mediated enrichment NGS is only about 70% for lung cancer and undetectable for early colon cancer. This method provides a simple, robust, accurate, faster turnaround, highly sensitive and low cost alternative compared conventional NGS employing deep sequencing. This technology will greatly enhance the adaptability of NGS as a clinically useful platform for every modern pathology laboratory.
Citation Format: Michael Y. Sha, Wenjing Feng, Qing Sun, Ke Zhan, Michael J. Powell, Aiguo Zhang. XNA-Based OptiSeqTMlung and colorectal cancer mini panel, a high sensitivity method for cancer early detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4027.
Abstract 403: COX-2 expression on circulating tumor cells in nasopharyngeal carcinoma predicts a worse survival: A prospective analysis
Authors: Li Yongjiang , Xie Xiaoqi , Wang Feng 
Published: August 2019

Abstract
COX-2 expression on circulating tumor cells in nasopharyngeal carcinoma predicts a worse survival: A prospective analysis
Yong-Jiang Li1, Xiao-Qi Xie2, Feng Wang1*
1Department of Oncology, West China Hospital, Sichuan University, Chengdu, PR China
2Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, PR China
*Corresponding author
Short title: COX-2 Expression on CTCs in NPC patients
Abstract
Background and purpose: The prognostic significance of circulating tumor cells (CTCs) in head and neck cancer is still under debate, as only a few studies have been reported and limited conclusions are reached. Besides, CTCs count alone was utilized as an indicator in the previous researches. As a form of ‘liquid biopsy’, the further identification of genetic or phenotypic biomarkers on CTCs could possibly provide further clinical significance.
Materials and methods: The prospective study enrolled 131 patients with nasopharyngeal carcinoma (NPC). CTCs were isolated at baseline and at the end of concurrent chemoradiotherapy, and cyclooxygenase-2 (COX-2) expression status of CTCs was detected by RNA-in situ hybridization (ISH) method. Results were correlated with patient’s clinicopathological parameters and treatment outcomes. Univariate and multivariate survival analysis were performed to determine the prognostic significance.
Results: COX-2 expression was found in 87/131 (66.4%) patients at baseline and 53/115 (46.1%) patients at the end of concurrent chemoradiotherapy. Patients with post-therapeutic COX-2 expression had significantly poorer treatment response (P=0.011) and higher risk of tumor relapse (P=0.026) and metastasis (P=0.007). Besides, multivariate analysis revealed that post-therapeutic COX-2 expression on CTCs remained an independent prognostic indicator for poorer
progression-free survival (HR 2.17, P=0.019) and overall survival (HR 2.41, P=0.024).
Conclusion: The study demonstrated that post-therapeutic COX-2 expression on CTCs was a novel and promising prognostic indicator for NPC patients. Future studies are needed to validate our findings and further clarify the value of integrating the indicator with current clinical strategies in improving survival of NPC patients.
Note: This abstract was not presented at the meeting.
Citation Format: Yongjiang Li, Xiaoqi Xie, Feng Wang. COX-2 expression on circulating tumor cells in nasopharyngeal carcinoma predicts a worse survival: A prospective analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 403.
Abstract 4081: Efficacy of MERTK inhibitor in combination with pembrolizumab in lung cancer
Authors: Pyo Kyoung-Ho , Cho Ha-Ni , Xin Chun-Feng , Cho Jae Seok , Kang Han Na , Yun Jiyeon , Kim Hye Ryun , Cho Byoung Chul 
Published: August 2019

Abstract
Introduction: MERTK is thought to play a role in cancer immune evasion mechanism based on M2 type macrophage-driven immunosuppression in tumor microenvironment (TME). Thus, MERTK is a highly promising target for anti-cancer therapy under high tumor associated macrophages (TAMs) condition. We evaluated the anti-tumor effects and immune reaction of combination or single MERTK inhibitor in two lung squamous patients derived xenograft (PDX) tumor engrafted Hu-CD34-NSG models.
Methods: The aPD-1 sensitive (YHIM2004) and aPD-1 non-sensitive (YHIM2009) squamous cell carcinoma PDX models were selected from pre-test with pembrolizumab. The selected two models were composed four groups; control, pembrolizumab, MERTK inhibitor, and combination. We applied pembrolizumab as aPD-1 blockade (10 mpk, q2w, i.p. inj.). The dose of MERTK inhibitor was 50 mpk, q1d by orally. The treatment was started when tumor size reached 100 mm3. Whole exome sequencing (WES), microarray (mRNA), flow cytometry, and multispectral image analysis were performed on the tumors. To elucidate the involvement of MERTK inhibitor in tumor, the tumor mutation burden, tumor microenvironment and immune cell phenotype were deconvoluted.
Results: The TMB of YHIM2004 and YHIM2009 was 3.23 and 2.64 (mutations/Mb) respectively. The PD-L1 and TIL level of YHIM2004 were relatively higher than YHIM2009. Both two models were observed high macrophage in tumor. The two PDX-models, YHIM2004 (aPD-1 sensitive), YHIM2009 (aPD-1 non-sensitive) were observed anti-tumor effects in MERTK inhibitor single treatment groups (TGI = 44.23%, 67.40% respectively, p &lt; 0.05, t-test). Especially, YHIM2004 tumor was reduced after combination therapy more than single treatment. Of note, the NOG-PDX model demonstrated no anti-tumor effect in MERTK inhibitor monotherapy, suggesting that this drug involves anti-cancer immune responses. Flow cytometry data showed increased PD-1+ and granzyme B+ T cells (p &lt;0.05, t-test) in the combined group (YHIM2004) and MERTK inhibitor monotherapy group (YHIM2009) as much as the tumor suppressive effect.
Conclusion: We concluded that MERTK signaling involves regulation of anti-cancer immune responses. Our results suggest an anti-cancer therapeutics of MERTK selective inhibitor on aPD-1 sensitive or non-sensitive tumors under high TAM tumor microenvironment.
Citation Format: Kyoung-Ho Pyo, Ha-Ni Cho, Chun-Feng Xin, Jae Seok Cho, Han Na Kang, Jiyeon Yun, Hye Ryun Kim, Byoung Chul Cho. Efficacy of MERTK inhibitor in combination with pembrolizumab in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4081.
Abstract 4097: TMV vaccine inhibits growth of squamous cell carcinoma of head and neck in mice
Authors: Bommireddy Ramireddy , Munoz Luis , Pack Chrstopher D. , Ramachandiran Sampath , Reddy Shaker JC , Kim Janet , Chen Georgia , Saba Nabil F. , Shin Dong M. , Selvaraj Periasamy 
Published: August 2019

Abstract
Introduction: Head and neck cancer is a leading cause of cancer related deaths accounting for approximately 3% of all cancer related mortalities in the US. Currently, there is no cure for the advanced squamous cell carcinoma of the head and neck (SCCHN) thus development of efficacious therapies is urgently needed. To test whether vaccine-induced immunity inhibits tumor growth, we investigated efficacy of a tumor membrane-based vaccine immunotherapy in a murine SCCHN (SCC VII) model.
Materials and Methods: The SCC VII tumors grown subcutaneously in C3H/HeJ mice were harvested to generate tumor membrane vesicles (TMVs). TMVs were then protein transferred with glycolipid-anchored immunostimulatory molecules mouse GPI-B7.1 and mouse GPI-IL-12 to generate the TMV vaccine. Mice were vaccinated with TMV vaccine either before (prophylactic) or after SCC VII tumor cell challenge (therapeutic) and tumor growth was monitored every 3 days. Survival was then assessed using a Kaplan-Meier survival curve and significance determined using a Log-rank test for comparison analysis.
Results: SCCVII cells express MHC I, CD44, CD47 and respond to IFN-γ in vitro. The therapeutic TMV vaccine inhibited tumor growth and improved the survival of mice challenged with SCCVII tumor cells. Tumor-free mice remained protective from rechallenge with SCCVII cells.
Conclusions: These observations suggest that tumor tissue-based vaccines can be harnessed to develop an effective immunotherapy for SCCHN.
Funding: Supported by Head and Neck SPORE pilot funding from Emory Winship Cancer Institute.
Citation Format: Ramireddy Bommireddy, Luis Munoz, Chrstopher D. Pack, Sampath Ramachandiran, Shaker JC Reddy, Janet Kim, Georgia Chen, Nabil F. Saba, Dong M. Shin, Periasamy Selvaraj. TMV vaccine inhibits growth of squamous cell carcinoma of head and neck in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4097.
Abstract 4114: NPM1 upregulates the transcription of PD-L1 and suppresses T-cell activity in triple negative breast cancer
Authors: Long Qian , Li Yizhuo , Qin Ge , Zhang Changlin , Shi Dingbo , Chen Miao , Shi Shuihan , Zhang Kefang , Deng Wuguo 
Published: August 2019

Abstract
Programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) interaction plays a crucial role in tumor-associated immune escape. Here we verified that triple-negative breast cancer (TNBC) had higher PD-L1 expression than other subtypes. We then discovered that nucleophosmin (NPM1) bound to PD-L1 promoter specifically in TNBC cells and activated PD-L1 transcription, thus inhibiting T cell activity in vitro and in vivo. Furthermore, we demonstrated that PARP1 suppressed PD-L1 transcription through its interaction with the nucleic acid binding domain of NPM1, which was required for the binding of NPM1 at PD-L1 promoter. Consistently, the PARP1 inhibitor olaparib elevated PD-L1 expression in TNBC and exerted a synergistic effect with anti-PD-L1 therapy. Together, our research has revealed NPM1 as a novel transcription regulator of PD-L1 in TNBC, which could lead to potential therapeutic strategies to enhance the efficacy of cancer immunotherapy.
Citation Format: Qian Long, Yizhuo Li, Ge Qin, Changlin Zhang, Dingbo Shi, Miao Chen, Shuihan Shi, Kefang Zhang, Wuguo Deng. NPM1 upregulates the transcription of PD-L1 and suppresses T-cell activity in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4114.
Abstract 4115: Naturally circulating anti-LAG3 antibodies exist in cancer patients
Authors: Tsimafeyeu Ilya , Ershov Pavel , Kaluzhskiy Leonid , Couture Jean-Philippe , Gagnon Hugo , Kuznetsov Vladimir , Kalachev Aleksei , Ivanov Alexis , Bratslavsky Gennady 
Published: August 2019

Abstract
To date there was no evidence of existence of the naturally circulating antibodies to checkpoint receptors in humans. LAG3 checkpoint is crucial in modulation of immune response that is altered in humans with inflammatory and malignant conditions. We have previously described novel methodology in identification of diagnostic and therapeutic antibodies (US Patent #9810694). Here we report identification of novel potentially therapeutic fully human anti-LAG3 antibodies in cancer patients.
Anti-LAG3 antibody presence was evaluated in 25 individuals: 11 healthy donors (controls) and 14 cancer patients in two different laboratories blinded to clinical information. Surface plasmon resonance analysis was done using the optical biosensor BiacoreT200 where LAG3 protein was covalently immobilized on the optical chip and biosensor signals from human serum samples were analyzed. Western Blotting used recombinant LAG3 loaded on a 10% SDS PAGE followed by blotting with plasma samples followed by biotinylated anti-human IgA/IgG/IgM and IrDye 800 streptavidin. Plasma anti-LAG3 IP utilized recombinant LAG3 crosslinked to MagResyn Carboxyl beads followed by incubation with plasma, followed by a biotinylated anti human IgA/IgG/IgMand IrDye streptavidin. No anti-LAG3 antibodies were detected in control group.
Among three assays there was complete correlation for presence of anti-LAG3 antibody in 3 cancer patients. One of these patients had sufficient plasma quantity and anti-LAG3 concentration (21 - 33 µg/ml) that should allow for the antibody purification and de novo sequencing. The novel fully human anti-LAG3 antibody will be identified, purified, and the sequence will be determined.To our knowledge this is the first report of checkpoint antibody presence in humans. Further study with cloning and evaluation of therapeutic properties of novel fully human anti-LAG3 antibody in xenograft models will be performed.
Citation Format: Ilya Tsimafeyeu, Pavel Ershov, Leonid Kaluzhskiy, Jean-Philippe Couture, Hugo Gagnon, Vladimir Kuznetsov, Aleksei Kalachev, Alexis Ivanov, Gennady Bratslavsky. Naturally circulating anti-LAG3 antibodies exist in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4115.