bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5471: Integrating tumor-intrinsic and immunological factors to identify immunogenic breast cancers from a low-risk cohort; results from the randomized SweBCG91RT trial
Authors: Tullberg Axel Stenmark , Sjöström Martin , Niméus Emma , Killander Fredrik , Chang Laura , Feng Felix Y. , Speers Corey W. , Pierce Lori J. , Kovács Anokó , Lundstedt Dan , Holmberg Erik , Karlsson Per 
Published: June 2023

Abstract
Purpose: The local immune infiltrate’s influence on tumor progression may be linked to tumor-intrinsic factors. This study aimed to investigate whether integrating immunological and tumor-intrinsic factors could identify patients who may be candidates for de-escalation of radiotherapy (RT).Experimental
Design: The practice-changing SweBCG91RT trial included 1178 patients with stage I-IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT with sparse use of systemic therapy (95% without systemic therapy) and followed for a median time of 15.2 years. We developed two gene expression models to capture immunological activity and immunomodulatory tumor-intrinsic qualities, respectively. We then analyzed if combining these two variables could identify a subgroup where RT de-escalation is feasible.
Results: The immunomodulatory model correlated with proliferation and was named Proliferative Index. The immunological model was enriched for T cell signatures and was named Immunescore. Increased Proliferative Index predicted an increased prognostic benefit from Immunescore (pinteraction=0.01). Combining the two models stratified patients who may be recommended an escalated RT (RT boost) by RT benefit and prognosis. Patients with a low predicted risk benefited from standard RT (HR: 0.28, CI 95% 0.09-0.85, p=0.025) and had a 5.4% 10-year incidence of ipsilateral breast tumor recurrence (IBTR) after radiation. In contrast, the group with a high predicted risk, characterized by rapidly proliferating tumors without an immune infiltrate, had a clinically meaningful high 10-year incidence of IBTR despite RT treatment (19.5% (CI 95% 12.2-30.3)).
Conclusions: Integrating tumor-intrinsic and immunological factors may identify immunogenic tumors in early-stage breast cancer populations and identify patients for whom de-escalated RT may be appropriate. Patients with rapidly proliferating tumors and an immune infiltrate may be candidates for RT de-escalation.
Citation Format: Axel Stenmark Tullberg, Martin Sjöström, Emma Niméus, Fredrik Killander, Laura Chang, Felix Y. Feng, Corey W. Speers, Lori J. Pierce, Anokó Kovács, Dan Lundstedt, Erik Holmberg, Per Karlsson. Integrating tumor-intrinsic and immunological factors to identify immunogenic breast cancers from a low-risk cohort; results from the randomized SweBCG91RT trial. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5471.
Abstract 5489: Synergistic activity of SCD1 blockade in combination with tyrosine kinase inhibitors lenvatinib and cabozantinib in hepatocellular carcinoma (HCC)
Authors: Gleba Justyna J. , Alasonyalilar-Demirer Aylin , Pawlush Matthew L. , Bilgili Ahmet , Hickman Peyton G. , Mody Kabir , Roberts Lewis R. , Alberts Steven R. , Truty Mark J. , Patel Tushar C. , Tun Han W. , Copland John A. 
Published: June 2023

Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Tyrosine kinase inhibitors (TKIs) are approved as a first-line treatment for unresectable HCC. Lenvatinib and cabozantinib are two of the most used TKIs, but the therapeutic duration is limited due to the development of drug resistance. Therefore, understanding the mechanisms of resistance and combining TKIs with other drugs antagonizing resistance should lead to antitumor synergy, eliminating drug resistance. It turns out that the simultaneous use of TKIs together with an inhibitor of stearoyl-CoA desaturase 1 (SCD1) prevents the development of drug resistance, leading to a durable response. SCD1 is the enzyme responsible for de novo fatty acid (FAs) synthesis, converting saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs). MUFAs are an alternative energy source to glucose, integral to cellular membranes, and prevent endoplasmic reticulum (ER) stress and other signaling pathways. In our laboratory, we developed a novel, highly specific SCD1 inhibitor - SSI-4. We have tested the biological activity of SSI-4 against different HCC cell lines and patient-derived xenografts (PDX) mouse models. Of the twelve tested HCC cell lines, four were highly sensitive to SSI-4 (IC50 1-50 nM). Other cell lines showed moderate or no sensitivity to SSI-4. We tested the concomitant use of SSI-4 with lenvatinib and cabozantinib, tyrosine kinase inhibitors (TKIs) FDA-approved for HCC, in HCC cell lines in vitro and using HCC PDX in vivo mouse models. Our studies showed that the combination of the SCD1 inhibitor with both lenvatinib and cabozantinib showed a highly synergistic effect and no development of drug resistance i.e. durable response versus single TKI therapy. Ongoing mechanistic studies are examining whether known molecular targets of tested TKI’s such as VEGFR1, 2, and 3, PDGFRα, FGFR, KIT, and RET dominate in HCC drug resistance to lenvatinib and cabozantinib, and how the use of SSI-4 overcomes the phenomenon of resistance.
Citation Format: Justyna J. Gleba, Aylin Alasonyalilar-Demirer, Matthew L. Pawlush, Ahmet Bilgili, Peyton G. Hickman, Kabir Mody, Lewis R. Roberts, Steven R. Alberts, Mark J. Truty, Tushar C. Patel, Han W. Tun, John A. Copland. Synergistic activity of SCD1 blockade in combination with tyrosine kinase inhibitors lenvatinib and cabozantinib in hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5489.
Abstract 555: Gene expression profiling in recurrence of oral cancer involved in tumor microenvironment change and cancer stem cells
Authors: Kioi Mitomu 
Published: June 2023

Abstract
Background: Local recurrence or lymph node metastasis is one of the critical events for the mortality of patients with oral cancer. Thus, it is essential to elucidate the mechanism of recurrence of oral cancer after treatment. It is recently thought that the cause of recurrence in advanced oral cancer is involvement of microenvironmental changes after treatment and signaling from cancer stem cells. In this study, we aimed to elucidate the molecular mechanism of cancer stem cell signaling that causes microenvironmental changes and the influx of bone marrow-derived cells that lead to revascularization following radiation.
Materials and Methods: In order to analyze the function of cancer stem cells, we used YCUOC, a primary tissue obtained from biopsy sample of oral cancer. YCUOC and OSC-19 cell line as a control were inoculated at pre-irradiated site where local blood vessels were eradicated (recurrence model) and non-irradiated sites, and gene expression analysis in cancer tissues was performed.
Results: Induction of CD11b-positive bone marrow-derived cells was observed in YCUOC cells, and the higher influx of Tie2-positive cells was observed at the pre-IR site, consistent with activation of HIF-1α. We identified several genes that were up-regulated only in YCUOC at pre-IR site, but neither OSC-19 nor non-IR site.
Conclusion: The development of new therapies targeting tumor vasculogenesis is expected by elucidation of cancer stem cell-specific signals.
Citation Format: Mitomu Kioi. Gene expression profiling in recurrence of oral cancer involved in tumor microenvironment change and cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 555.
Abstract 5556: Lemur tyrosine kinase 3 serves as a predictor of patient outcome and a target for the treatment of ovarian cancer
Authors: Kirsch-Mangu Thea K. , Tullberg Axel S. , Portela Anna , Helou Khalil , Saed Ghassan M. 
Published: June 2023

Abstract
The objective of these in vitro and in vivo studies was to validate Lemur Tyrosine Kinase 3 (LMTK3) as a specific target and predictor of clinical outcome in ovarian cancer. LMTK3 belongs to a family of regulated tyrosine kinases with three structurally related isoforms, LMTK1, LMTK2, and LMTK3. Both nuclear and cytoplasmic LMTK3 expressions correlated with tumor grade and patient survival in cancers such as breast and colorectal cancer. We tested the clinical significance of the LMTK3 gene by immunohistochemistry (IHC) using LMTK3 monoclonal antibody on formalin-fixed paraffin-embedded sections (FFPE) collected from 204 early-stage (stage I-II) ovarian cancer patients. Results from this IHC LMTK3 study revealed a higher cytoplasmic to nuclear localization of LMTK3 correlated with worse overall survival (P&lt;0.01). Further investigation of LMTK3’s prognostic value by screening LMTK3 signaling in 270 stage III-IV ovarian cancer patients is ongoing. We utilized the MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay for testing the killing efficacy of targeting LMTK3 by a monoclonal antibody, siRNA, and specific LMTK3 binding peptides (LMTK3BP) in ovarian cancer cell lines SKOV3, MDAH-2774, A2780, and TOV-21G. Treatment with LMTK3 specific monoclonal antibody, siRNA, and LMTK3BP significantly induced killing of both chemosensitive and chemoresistant ovarian cancer cells without affecting normal cells in vitro. Moreover, we observed this killing as synergistic with both Cisplatin and Taxotere treatment in vitro. Lastly, we used an A2780 cell line derived orthotopic xenograft mouse model of ovarian cancer to test the efficacy of specific LMTK3BP in vivo. Strikingly, LMTK3BP 20 mg/kg IV dose given three times a week for three weeks showed a 35% tumor reduction. Furthermore, in vivo safety studies showed no signs of toxicity of the LMTK3BP, even at a very high dose of 40 mg/kg. Thus, with dose optimization in ongoing experiments, we could expect a higher efficacy. In conclusion, this study highlighted the importance of LMTK3 as a predictor of patient clinical outcome and potential target for treatment in ovarian cancer.
Citation Format: Thea K. Kirsch-Mangu, Axel S. Tullberg, Anna Portela, Khalil Helou, Ghassan M. Saed. Lemur tyrosine kinase 3 serves as a predictor of patient outcome and a target for the treatment of ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5556.
Abstract 5605: Ambient storage and stabilization of proteins and cell-free nucleic acids in whole blood samples
Authors: Li Jing , Bartron Lisa , LaRue Jordan , Mehta Sama , George Nicholas M. 
Published: June 2023

Abstract
Introduction: Highly anticipated advancements in biotechnology and instrumentation now allows for simultaneous detection of multiple biomarkers. This is accelerating the cancer research field towards the development of multianalyte-based in vitro diagnostic tests for early detection and/or monitoring of cancer. These multianalyte liquid biopsy tests are often based on detection of cancer-related proteins and/or tumor-specific genomic and transcriptomic changes (circulating cell-free nucleic acids) in plasma. A specialized and proprietary stabilization reagent has been developed for use in a blood collection tube with the capability to simultaneously stabilize protein biomarkers of interest and cell-free nucleic acids.
Methods: Blood samples from self-proclaimed healthy donors were drawn into evacuated blood collection tubes containing a new stabilization reagent and stored at room temperature. Plasma was isolated using a general double-spin protocol (1800 × g for 15 min and 2800 × g for 15 min) and frozen at -80 °C until use. Plasma levels of proteins of interest including cancer markers and immuno-oncology checkpoint markers were measured by Ella Simple Plex Assays (Bio-Techne) and Luminex xMAP® Technology Assays (Bio-Techne, samples tested by LuminexPLORE Lab). Total cell-free nucleic acids were isolated using the QIAamp Circulating Nucleic Acid Kit and the resultant cfDNA or cfRNA was analyzed with fluorometric-based assay (quantitative) and Bioanalyzer/Tapestation (qualitative).
Results: Compared with blood samples collected in EDTA and ACD-A tubes, the new stabilization reagent maintained the draw time levels of plasma proteins of interest such as TGF-β1, MMP-9, IL-8/CXCL8, CCL5/RANTES, Granzyme B, CEA and PD-L1 for up to 5 days of room temperature storage in whole blood. The reagent also effectively maintained draw time levels of plasma cell-free nucleic acids to near draw time levels. In addition, the new reagent also minimized in vitro hemolysis during room temperature storage.
Conclusion: This new and breakthrough stabilization reagent simultaneously maintains the draw time levels of proteins of interest and cell-free nucleic acids for an extended period of time in whole blood. It provides cancer researchers and clinical assay developers confidence in blood sample integrity and flexibility in sample storage, transport, and processing at ambient temperature for multianalyte analysis or multiomics profiling.
Citation Format: Jing Li, Lisa Bartron, Jordan LaRue, Sama Mehta, Nicholas M. George. Ambient storage and stabilization of proteins and cell-free nucleic acids in whole blood samples. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5605.
Abstract 5831: CD200R signaling contributes to unfavorable tumor microenvironment through regulating production of chemokines by tumor associated macrophages
Authors: Lin Cho-Hao , Talebian Fatemeh , Li Yang , Zhu Jianmin , Zhao Bolin , Liu Jin-Qing , Basu Sujit , Pan Xueling , Chen Xi , Yan Pearlly , Carson William E. , Xin Gang , Wen Haitao , Wang Ruoning , Li Zihai , Ma Qin , Bai Xue-Feng 
Published: June 2023

Abstract
CD200 is overexpressed in human solid tumors such as neuroblastoma and melanoma and is considered as an immune checkpoint molecule for dampening cancer immunity. However, how CD200 affects tumor microenvironment (TME) and host immunity is incompletely understood. In the present study, we evaluated the role of the CD200-CD200R pathway in TME using loss-of-function CD200R-/- mice, along with two clinically relevant, CD200-positive murine tumor models: the mouse neuroblastoma NB9464D and melanoma Yummer1.7. We found that comparing with the wild type mice, CD200R-/- mice were significantly more potent in rejecting these CD200+ tumors. Transcriptome analysis by single cell RNA sequencing demonstrated that tumors from CD200R-/- mice had more infiltration of CD45+ immune cells, including CD4+ and CD8+ T cells, and NK cells but less infiltration of neutrophils. Antibody depletion experiments revealed that immune effectors including CD8+ T cells and NK cells in combination, are crucial in inhibiting tumor growth in CD200R-/- mice. Mechanistically, we found that CD200R signaling differentially regulates the expression of chemokines in tumor-associated macrophages (TAMs). In the absence of CD200R, TAMs up-regulate CCL24 and CCL8 and down-regulate CXCL3, CXCL2, and CCL3 via activation of ERK and/or p38 MAP kinases. Increased expression of CCL24 in CD200R-deficient tumors resulted in increased infiltration of eosinophils, which also contributes to anti-tumor activity. Overall, we conclude that CD200R-mediated signaling, via interaction with CD200 on tumor cells, contributes to unfavorable TME primarily through chemokine-dependent recruitment of immune suppressive neutrophils and exclusion of anti-cancer immune effectors. Our study has significant implications in developing CD200-targeted immunotherapy of solid tumors.
Citation Format: Cho-Hao Lin, Fatemeh Talebian, Yang Li, Jianmin Zhu, Bolin Zhao, Jin-Qing Liu, Sujit Basu, Xueling Pan, Xi Chen, Pearlly Yan, William E. Carson, Gang Xin, Haitao Wen, Ruoning Wang, Zihai Li, Qin Ma, Xue-Feng Bai. CD200R signaling contributes to unfavorable tumor microenvironment through regulating production of chemokines by tumor associated macrophages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5831.
Abstract 5832: Integrinα5 mediates the direct heterocellular interaction between cancer cells and cancer-associated fibroblasts and promotes peritoneal metastasis of diffuse-type gastric carcinoma
Authors: Yamaguchi Hideki , Miyamoto Shingo , Nagano Yoshiko , Miyazaki Makoto , Nagamura Yuko 
Published: June 2023

Abstract
Diffuse-type gastric carcinoma (DGC) is an aggressive subtype of gastric cancer characterized by rapid infiltrative growth and frequent peritoneal metastasis. Peritoneal metastasis is the main cause of poor prognosis and decreased quality of life for patients with DGC. Histologically, DGC tumor lesions are associated with massive fibrotic stroma caused by the extensive proliferation of cancer-associated fibroblasts (CAFs). Peritoneally metastasized tumors of DGC are also accompanied by abundant fibrotic stroma and CAFs. CAFs are known to promote the progression of DGC by enhancing the growth, invasion, and dissemination of tumor cells. Previously, we reported that the direct heterocellular interaction between cancer cells and CAFs is necessary for the invasion and peritoneal metastasis of DGC. In this study, we aimed to identify and target the molecules that mediate such direct heterocellular interaction. Monoclonal antibodies (mAbs) against intact DGC cells were generated and subjected to high-throughput screening to obtain mAbs that block the adhesion of DGC cells to CAFs. As a result, several such inhibitory mAbs were obtained. Immunoprecipitation and mass spectrometry revealed that all mAbs recognized integrin α5 complexed with integrin β1. Blocking integrin α5 in DGC cells abrogated the adhesion of DGC cells to CAFs. Similarly, blocking fibronectin, a ligand of integrin α5β1, deposited on CAFs blocked the heterocellular adhesion. Furthermore, administration of mAbs or knockout of integrin α5 in DGC cells suppressed their invasion led by CAFs in vitro and peritoneal metastasis in a mouse xenograft model. Analysis of the public database revealed that integrin α5 and fibronectin were highly expressed in DGC. In addition, integrin α5 and fibronectin expression levels were correlated with worse overall survival in DGC patients. Taken together, these results show that integrin α5 mediates the heterotypic cancer cell-CAF interaction during peritoneal metastasis of DGC and may thus be a promising therapeutic target.
Citation Format: Hideki Yamaguchi, Shingo Miyamoto, Yoshiko Nagano, Makoto Miyazaki, Yuko Nagamura. Integrinα5 mediates the direct heterocellular interaction between cancer cells and cancer-associated fibroblasts and promotes peritoneal metastasis of diffuse-type gastric carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5832.
Abstract 6240: The potent quadruplex-binding compound QN-302 shows anti-tumor activity as a monotherapy in an orthotopic in vivo model of pancreatic cancer
Authors: Williams Nicole , Santos Danielle , Worthington Jenny , Ahmed Ahmed , Arshad Tariq , Neidle Stephen 
Published: June 2023

Abstract
The compound QN-302, a tetra-substituted naphthalene diimide derivative has single-digit nM anti-proliferative activity in a panel of human pancreatic cancer (PDAC) cell lines (Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644). It has significant anti-tumor activity in the MIA-PACA2 xenograft model for PDAC and in the genetic KPC model. We now report that this compound also shows significant mono-therapy anti-tumor activity in an orthotopic model for PDAC. Female athymic nude mice bearing orthotopically implanted pancreatic BxPC-3 cells were dosed with 1 x weekly IV QN-302 at 0.5 and 1.0 mg/kg, over a period of 21 days. A separate group of mice was treated with Gemcitabine twice weekly IV during this period, at a dosage of 15 mg/kg. Blood samples from animals were collected on a weekly basis and were used to detect and quantify circulating tumor DNA as a method of following treatment efficacy. In line with previous studies QN-302 was well-tolerated at 0.5 and 1.0 mg/kg with no adverse effects on animal health or behavior noted during the study. Circulating tumor DNA levels were significantly less than vehicle controls in gemcitabine-treated animals from day 7 and QN-302 (1.0 mg/kg) treated animals from day 14 of treatment. Survival was significantly increased in gemcitabine and QN-302 (1.0 mg/kg) QW treatment groups. Statistically significant efficacy was observed in gemcitabine and QN-302 (1.0 mg/kg) treated animals. Examination of blood chemistry and biochemistry of treated animals did not indicate any adverse effects due to QN-302. This orthotopic model is the 4th in vivo study in a pancreatic cancer model showing anti-tumor activity for QN-302, further confirming the potential of this compound for human disease. QN-302 is currently in an advanced stage of pre-IND development by Qualigen Inc.
Citation Format: Nicole Williams, Danielle Santos, Jenny Worthington, Ahmed Ahmed, Tariq Arshad, Stephen Neidle. The potent quadruplex-binding compound QN-302 shows anti-tumor activity as a monotherapy in an orthotopic in vivo model of pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6240.
Abstract 6287: Selective CBP degradation shows superior potency and differentiated biological activity compared to small molecule inhibitors
Authors: La Bonte Laura , Sappal Darshan 
Published: June 2023

Abstract
CREB binding protein (CBP) and E1A binding protein (p300) are paralog histone acetyltransferases involved in many cellular processes via their activity as transcription factor co-activators. Dysregulation of one or both proteins has been implicated in a variety of cancers, and functional genomic screens have exhibited a bidirectional synthetic lethal relationship between the two genes in many cancer indications. Due to the high homology between CBP and p300, identification of selective chemical matter that specifically and directly targets CBP has proven challenging. Small molecule inhibitors (SMIs) targeting the HAT or bromodomain of CBP/p300 have been developed, however these agents are not selective for either paralog and inhibit both proteins equally, potentially limiting their clinical application. Herein, we describe the biological activity of selective, potent CBP degraders and show differentiation from SMIs.
Citation Format: Laura La Bonte, Darshan Sappal. Selective CBP degradation shows superior potency and differentiated biological activity compared to small molecule inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6287.