bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4121: ORIC-101 overcomes resistance to diverse chemotherapeutics across cancer types
Authors: Zhou Haiying , Barkund Shravani , Pankov Aleksandr , Hegde Ganapati , Kong Wayne , Narayanan Padmini , Sun Jessica D. , Kabbarah Omar , Friedman Lori S. , Daemen Anneleen 
Published: September 2020

Abstract
Preclinical studies have shown that GR activation leads to decreased response to antimetabolites, taxanes, and platinum agents, while GR inhibition enhances therapeutic efficacy. The novel, selective GR antagonist ORIC-101 is under clinical evaluation in combination with anticancer therapies. In this study we set out to assess which cancer types and chemotherapeutics are responsive to combination with ORIC-101. Specifically, we employed caspase assays, in vitro and in vivo tumor growth inhibition studies, and transcriptional profiling in a panel of preclinical models spanning triple-negative breast, ovarian, non-small cell lung cancers, pancreatic ductal adenocarcinoma, hepatocellular carcinoma, sarcoma, and renal cell carcinoma. We found that ORIC-101 reverses GR-mediated antiapoptosis effects towards diverse chemotherapeutics, including paclitaxel, gemcitabine, and cisplatin, across the seven cancer types. Furthermore, ORIC-101 completely overcomes GR-driven chemoprotection and tumor growth in colony formation assays in vitro and in xenograft studies in vivo. At the molecular level, transcriptional profiling and pathway enrichment analysis showed that ORIC-101 fully reverses GR-activated pathways that are directly involved in drug resistance, such as epithelial-to-mesenchymal transition and antiapoptosis, supporting a pan-cancer role of GR as a mediator of therapy resistance. Altogether, ORIC-101, a selective and potent GR antagonist, overcomes resistance to common chemotherapeutics across multiple cancer models. Clinical evaluation of ORIC-101 in combination with nab-paclitaxel is currently ongoing in advanced solid tumors.
Citation Format: Haiying Zhou, Shravani Barkund, Aleksandr Pankov, Ganapati Hegde, Wayne Kong, Padmini Narayanan, Jessica D. Sun, Omar Kabbarah, Lori S. Friedman, Anneleen Daemen. ORIC-101 overcomes resistance to diverse chemotherapeutics across cancer types [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4121.
Abstract 4174: Anticancer activity of a novel small molecule krct-1 through inhibition of Trk-A signaling in breast cancer cells
Authors: Kim Ah-Young , Kim Jae-Sung 
Published: September 2020

Abstract
The small molecule krct-1 was synthesized as a structurally novel compound. Krct-1 inhibited cell proliferation and tumor growth of breast cancer. In addition, Krct-1 had a capacity to induce activation of several apoptotic markers and downregulate anti-apoptotic markers in various breast cancer cell lines. Furthermore, Krct-1 increased the radiosensitivity of breast cancer cells by promoting DNA damage responses. By performing the kinase profile analysis, we found that Krct-1 inhibited tropomyosin receptor kinase A (Trk-A) and further demonstrated inhibition of its downstream signaling such as ERK and STAT3 in breast cancer cells. Thus, our results suggest that a novel compound Krct-1 have an antitumor activity through Trk-A regulation in breast cancer.
Citation Format: Ah-Young Kim, Jae-Sung Kim. Anticancer activity of a novel small molecule krct-1 through inhibition of Trk-A signaling in breast cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4174.
Abstract 4191: Characterization of a novel anti-glucose transporter inhibitor as a pan-anticancer therapeutic in vitro and in vivo
Authors: Shriwas Pratik , Bergmeier Stephen , Chen Xiaozhuo 
Published: September 2020

Abstract
Cancer has surpassed cardiovascular diseases as the top killer in many US counties. Opportunistic uptake of extracellular nutrients has recently been named as an emerging hallmark of cancer metabolism. Glucose is a key nutrient taken in by cancer cells for satisfying their high energy and biosynthesis needs. Drastic upregulation of glucose uptake and metabolism, a phenomenon called the Warburg effect, is prevalent among cancers. Cancer cells overexpress specific glucose transporters (GLUTS), particularly GLUT1, on their cell surface for uptaking glucose via facilitated diffusion. Considering the addiction of cancer cells to glucose and their sensitivity and vulnerability to changes in glucose supply, Gluts, have been recognized as an attractive anticancer target. Previously, our first-generation GLUT-inhibitor, WZB117, had been characterized in vitro and in vivo as an anticancer therapeutic. In this study, DRB18, a novel and proprietary lead inhibitor of glucose transporters, is characterized in vitro and in vivo by bioassays. DRB18 inhibits growth and proliferation in about 90% of the 60 different cancer cell lines in 9 major cancer types. It shows IC50 values in high nM range in some cell lines in several different cancer types. DRB18 treatment leads to significant changes in glucose-based metabolism in A549 lung cancer cells, including cell death via ER/oxidative stress and necrosis. The docking and Seahorse studies reveal the surprising contributions of macropinocytosis in DRB18 internalization, ultimately leading to better GLUT1 binding and increase in potency in killing cancer cells. DRB18 (10mg/kg) treatment thrice a week significantly reduces growth in Xenograft A549 tumors. Comprehensive in vitro and in vivo metabolomics analysis would be presented to better describe anti-glucose metabolism of activity of DRB18. Further, GLUT1-KO A549 (A549glut1ko) cell lines, in which Glut1 gene has been knocked out, were generated using CRISPR-Cas9 system for further studying GLUT1's roles in A549 cells. Immunoblotting analysis revealed the upregulation of other GLUTs after GLUT1 is knocked out, strongly suggesting the need for a pan-GLUT inhibitor for better inhibition of tumor growth.
Citation Format: Pratik Shriwas, Stephen Bergmeier, Xiaozhuo Chen. Characterization of a novel anti-glucose transporter inhibitor as a pan-anticancer therapeutic in vitro and in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4191.
Abstract 4198: Role of receptor tyrosine kinase AXL in mediating DNA damage response
Authors: Yeo Xun Hui , Tam Wai Leong , Huang Ruby Yun-Ju 
Published: September 2020

Abstract
AXL is a receptor tyrosine kinase that is often overexpressed in many cancers. It contributes to tumor progression, metastasis and drug resistance through activating downstream signaling cascades, making it an emerging therapeutic target. Moreover, the first-in-class AXL inhibitor R428 (BGB321) was lately approved by the FDA for the treatment of relapsed or refractory acute myeloid leukemia. Previously, R428 (BGB321) was also reported to show selective sensitivity towards ovarian cancers with a Mesenchymal molecular subtype. Recently, a novel role of AXL in the regulation of DNA damage responses has been brought to light. Here, we further explored AXL's role in mediating DNA damage responses by using ovarian cancer as a disease model. AXL inhibition using R428 resulted in the increase DNA damage foci in ovarian cancer cells SKOV3 and HeyA8. This occurred concurrently with the upregulation of classic DNA damage response signaling molecules such as γH2Ax, ATM and ATR. RNA sequencing results further validated this observation, that R428-treated cells showed downregulation of genes involved in cell cycle control and DNA replication, suggesting the decrease in proliferation. Through SILAC co-immunoprecipitation mass spectrometry, we uncovered a novel binding partner of AXL that could potentially regulate the DNA damage repair upon the inhibition of AXL, giving us insights to how AXL inhibition might contribute to DNA damage. Furthermore, our results showed that AXL inhibition rendered cells more sensitive to the inhibition of ATR, a crucial mediator for replication stress, paving ways to the rationale for potential combinatory use of AXL and DNA damage repair inhibitors.
Citation Format: Xun Hui Yeo, Wai Leong Tam, Ruby Yun-Ju Huang. Role of receptor tyrosine kinase AXL in mediating DNA damage response [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4198.
Abstract 4223: Combination therapy of BCR-ABL-positive B cell acute lymphoblastic leukemia by tyrosine kinase inhibitor dasatinib and c-Jun N-terminal kinase inhibition
Authors: Xiao Xinhua , Jiao Bo , Ren Ruibao 
Published: September 2020

Abstract
The Philadelphia chromosome (Ph), which leads to creation and expression of the fusion gene product BCR-ABL, underlines the pathogenesis of chronic myelogenous leukemia (CML) and a fraction of adult and pediatric acute B-lymphoblastic leukemia (B-ALL). The BCR-ABL tyrosine kinase inhibitors (TKIs) has shown a remarkable clinical activity in patients with CML, but their efficacy in treating Ph+ B-ALL is limited. Identifying additional therapeutic targets is important for the effective treatment of Ph+ B-ALL. In this study, we found that the c-Jun N-terminal kinase (JNK) signaling pathway is abnormally activated in both human and mouse BCR-ABL+ B-ALL cells, but the BCR-ABL TKI does not inhibit JNK activation in these cells. Inhibition of JNK, either by RNAi-mediated downregulation or by JNK inhibitors, could significantly reduce viability of Ph+ B-ALL cells. JNK inhibition by RNAi-mediated downregulation or JNK inhibitors also showed a synergistic effect with the BCR-ABL TKI, dasatinib, in killing Ph+ B-ALL cells in vitro. Furthermore, a potent JNK inhibitor, JNK-IN-8, in combination with dasatinib markedly improved the survival of mice with BCR-ABL induced B-ALL, as compared to the treatment with dasatinib alone. Our findings indicate that simultaneously targeting both BCR-ABL and JNK kinase might serve as a promising therapeutic strategy for Ph+ B-ALL.
Citation Format: Xinhua Xiao, Bo Jiao, Ruibao Ren. Combination therapy of BCR-ABL-positive B cell acute lymphoblastic leukemia by tyrosine kinase inhibitor dasatinib and c-Jun N-terminal kinase inhibition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4223.
Abstract 4239: Immunomodulatory effects of topotecan augment the effectiveness of chemotherapy-immunotherapy combination
Authors: Lee Jeong-Mi , Shin Kwang-Soo , Koh Choong-Hyun , Jeon Insu , Kang Tae-Seung , Song Boyeong , Kang Chang-Yuil 
Published: September 2020

Abstract
Combination therapy is a cornerstone of anticancer therapy, suggesting potential therapeutic benefit to nonresponders to single-agent treatment. BVAC, a B-cell-and-monocyte-based vaccine loaded with alpha-galactosylceramide(α-GC) and tumor antigen as reported in our previous studies, can be successfully combined with other treatments. Here we found out a novel synergistic regimen in TC-1 tumor model which combines BVAC with topotecan, a chemotherapeutic agent as a topoisomerase I inhibitor. We demonstrated some significant alteration in the immunoprofiles of topotecan-treated mice. We observed increased tumor recruitment of monocytes and CD8+ T cells, and decreased frequencies in regulatory T cells in tumor. Accordingly, we are currently investigating how topotecan-induced changes in immune cell composition could lead to improvement of antitumor effect. These data indicate that topotecan not only has cytotoxicity to tumor but can contribute to modulating tumor immune microenvironment. We anticipate that this study could provide a rationale for combination of cancer vaccine and chemotherapy and define future optimal treatment regimens in cancer patients.
Citation Format: Jeong-Mi Lee, Kwang-Soo Shin, Choong-Hyun Koh, Insu Jeon, Tae-Seung Kang, Boyeong Song, Chang-Yuil Kang. Immunomodulatory effects of topotecan augment the effectiveness of chemotherapy-immunotherapy combination [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4239.
Abstract 4241: Regorafenib and nivolumab or pembrolizumab combination and ctDNA response assessment in refractory colorectal cancer
Authors: Fakih Marwan , Chevalier Dawnyel , Saluja Janelle , Lau Cecilia , Wang Chongkai 
Published: September 2020

Abstract
Introduction: Patients with microsatellite stable (MSS) metastatic colorectal cancer (MCRC) are considered resistant to immunotherapy with PD-1 and PD-L1 inhibitors. However, a recent study of regorafenib and nivolumab (REGONIVO) reported high response rates and a median progression free survival (PFS) of more than 6 months (mo) in a cohort of 24 Japanese patients (pts) with MSS chemo-resistant MCRC.
Methods: We evaluated the outcome of advanced MSS MCRC pts who were treated on a compassionate basis with PD-1 inhibitors in combination with regorafenib 80 mg PO QD x 21 days every 28 days in a single US center. We report their response rate (RR), PFS, and overall survival (OS).
Results: 16 pts (15 males) were treated with a combination of regorafenib + PD-1 inhibitors and were evaluable for response. 14 pts received regorafenib + nivolumab (5 with prior anti-PD-1 treatment) and 2 pts received regorafenib + pembrolizumab (both following pembrolizumab treatment). No treatment-related G3 or above toxicities were attributed to the combination therapy. No objective responses were noted on treatment. 11 pts had progressive disease (PD) and 5 pts experienced stable disease (SD) as best response at 2 mo. The duration of SD was 4 mo in 2 pts (1 pt with prior anti-PD1 exposure), 6 mo in 1 pt (prior anti-PD1 exposure), 5 mo+ in 2 pt (1 with prior anti-PD1 exposure). When limiting the analysis to the 9 regorafenib and checkpoint-inhibitor naïve patients, 2 pts were noted to have SD (4 months and 5 mo+). ctDNA assays were evaluated at baseline and at 4 weeks of treatment in 11 patients. All 9 patients with a rise in ctDNA at 4 weeks had PD at the 2-mo imaging point. 2 patients with declining ctDNA at 4 weeks experienced SD for 4 mo 5 mo+, each. OS analysis remains immature as the median follow-up is only 5 mo.
Conclusions: Regorafenib and nivolumab combination was associated with modest clinical activity in patients with MSS chemotherapy-resistant MCRC. This US-based small retrospective trial is at odds with the Japanese REGONIVO trial. ctDNA may represent a powerful tool for predicting progression prior to radiographic staging.
Citation Format: Marwan Fakih, Dawnyel Chevalier, Janelle Saluja, Cecilia Lau, Chongkai Wang. Regorafenib and nivolumab or pembrolizumab combination and ctDNA response assessment in refractory colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4241.
Abstract 4254: Quality assessment platform for molecular pathology from non small cell lung cancer histopathology images using deep learning: A nationwide study of central laboratory in South Korea
Authors: Kim Tae-Jung , Kang Ho Chul , Lee Yonggeun , Seo Seokman , Kim Donghwan 
Published: September 2020

Abstract
Molecular testing became the most important part of lung cancer diagnostics. Integration of various molecular testing such as real-time PCR, fluorescent in situ hybridization (FISH) and next-generation sequencing into routine clinical practice and their systemic quality control is challenging to a pathologist and even more in the central laboratory. In this study, we trained a variant of DenseNet, a convolutional neural network model with the highest performance in image classification and suitable for quality assessment. Train dataset is composed of the arbitrarily classified dataset made and assessed by a professional pathologist during routine molecular test using whole-slide tissue images and molecular profiles including DNA density and the signal intensity of FISH obtained from 15,000 tests from lung cancer biopsies and resections, which were sent to the central laboratory for molecular studies from 45 hospitals nationwide. The performance of our platform is tested and compared to the quality assessment dataset made from each a general pathologist and a technician. The performance of our method for classifying DNA concentration and the signal intensity of FISH is comparable to that of a general pathologist and we are under improving its average area under the curve (AUC) over 0.95. This result suggests that deep learning model based on a convolutional neural network can assist pathologists for rigorous assessing quality of tissue morphology and signal of FISH for tissue samples with various molecular quality before or during the molecular test and, furthermore, can be applied to quality control of lung cancer molecular testing in a central laboratory.
Citation Format: Tae-Jung Kim, Ho Chul Kang, Yonggeun Lee, Seokman Seo, Donghwan Kim. Quality assessment platform for molecular pathology from non small cell lung cancer histopathology images using deep learning: A nationwide study of central laboratory in South Korea [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4254.
Abstract 4264: Liquid biopsy and FFPE tissue based somatic BRCA1/2 variant screening in breast and ovarian cancer
Authors: Boga Ibrahim , Sonmezler Ozge , Bisgin Atil 
Published: September 2020

Abstract
Next generation sequencing (NGS) has widened its use since it provides highly precise and accurate genetic testing with reasonable costs in tumor genetic profiling from somatic materials such as FFPE (formalin fixed paraffin embedded) tissue and liquid biopsy [circulating cell free DNA (ccfDNA)]. It has a high value in differentiating treatment strategies especially in BRCA1/2 genomic profiling in breast and ovarian cancer. However, somatic BRCA1/2 testing still remains unclear algorithm versus germ-line testing approved in human genetics for many decades. Thus, we sum up our testing results in relation with clinical diagnosis. FFPE samples from 89 and 74 liquid biopsy samples from breast and/or ovarian cancer patients were collected and sequenced via the GeneReader NGS system for BRCA1 and BRCA2 genes. QCI-Analyze and QCI-Interpret bioinformatics tools were used for bioinformatics analyses. We detected 56 actionable variants in 48 patients (29.5%) out of 163 patients. The 46.4% (nvariant=26) of the mutations were detected in BRCA1 gene while 53.6% (nvariant=30) of them were in BRCA2 gene. The allele frequencies vary from 1.43% to 100% with an average of 43% in 89 FFPE tissue samples with the positivity rates of 30% (nsample=27) while the rate is 28.4% (nsample=21) in 74 liquid biopsy samples. Interestingly, 8 patients had more than one actionable variant and 5 of them had mutations both in BRCA1 and BRCA2 genes. To sum up, genetic testing for targeted treatments has become first-line clinical testing in cancer and taken its place in international guidelines. Thus, somatic testing to profile BRCA genes should be considered in breast and ovarian cancer algorithm since 5% percent of the patients additionally carry somatic actionable mutation with regarding 15% positivity in germ-line BRCA1/2 studies.
Citation Format: Ibrahim Boga, Ozge Sonmezler, Atil Bisgin. Liquid biopsy and FFPE tissue based somatic BRCA1/2 variant screening in breast and ovarian cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4264.
Abstract 4271: Standardized approach for monitoring plasma cell disorders
Authors: Johansson Ulrika , Li Na , Saksena Suraj , Golts Natalie , Gaylord Brent 
Published: September 2020

Abstract
Multi-color flow cytometry using consensus surface markers (CD138, CD38, CD19, CD45, CD27, CD56, CD81, and CD117), intracellular kappa and lambda, as well as other auxiliary markers is routinely being used for the identification and characterization of plasma cells. Here, we describe the development of a modular 10-color plasma cell panel for immunophenotyping of the plasma cell compartment. The panel was developed as an 8-color dried backbone, which can be supplemented with 2 liquid (drop in) reagents.
Lyophilized or dried reagent cocktails in a unit test format are known to drive workflow efficiency in clinical settings by eliminating the need for manual cocktailing (of reagents), and frequent batch to batch verification procedures. Longer shelf life and room temperature storage are additional appealing features for lyophilized and dried products. We have developed a dried-down 8-color plasma cell panel, which is manufactured in a single test-per-tube, ready to use format, and can be supplemented with liquid (drop in) reagents. The flexibility of being able to add 2 liquid reagents to the dried backbone provides the option of using intracellular kappa and lambda to examine clonality or using CD38-multi-epitope and/or anti-p63 (VS38c) reagent(s). The single test-per-tube format is ideally suited for MRD applications, where sample size is limited and there is a need for acquiring a large number of events for data analysis. Also, the dried reagent panel is comprised of multiple high performing polymer dyes, which are brighter than conventional dyes, and afford high resolution of the relevant cell populations. Furthermore, the dried reagent tubes have a long shelf life (12 months) and significantly enhance the workflow efficiency.
Comparison of the liquid and dried versions of the 10-color plasma cell panel using peripheral blood from healthy donors (as well as control cell lines) showed similar staining patterns, comparable population statistics, and fluorochrome brightness. The dried plasma cell tube(s) were also tested on bone marrow samples from healthy and diseased subjects in conjugation with intracellular staining for kappa and lambda. Our results demonstrate that the 10-color plasma cell panel can be used for identification of the plasma cell compartment (based on CD38 & CD138 expression), assessment of aberrant marker expression (CD19, CD27, CD81, CD117, CD45, CD56) for the identification of normal and abnormal plasma cells, and examining clonality in multiple patient samples.
Citation Format: Ulrika Johansson, Na Li, Suraj Saksena, Natalie Golts, Brent Gaylord. Standardized approach for monitoring plasma cell disorders [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4271.