bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3938: Anti-angiogenic therapy combination with hypoxia-regulating agent leads to improved tumor regression in a murine model or renal carcinoma
Authors: Nafia Imane , Chaibi Assia , Bortolotto Doriane , Rey Christophe , Bessede Alban 
Published: September 2020

Abstract
Background: While antiangiogenic therapies have been shown effective in preclinical and clinical trials, tumors can acquire resistance conferring them the ability to survive and grow under hypoxic conditions, even, induced by antiangiogenic drugs themselves.
Methods: This study investigated the effects of an antiangiogenic strategy and hypoxia-regulating agent, each alone and in combination. Here, we have tested the synergistic activity of the anti-angiogenic agent Sunitinib and the mTOR inhibitor Everolimus in murine syngeneic renal cancer model - renal carcinoma being known as angiogenesis-dependent and hypoxia-driven malignancy. Anti-tumor effects were investigated on tumor growth and survival. Flow cytometry-based immunoprofiling was performed at the peripheral level - blood and spleen - while immunohistofluorescence and quantitative image analysis served to characterize and evaluate tumor immune cell infiltrate, tumor hypoxia, and tumor vascular density/features.
Results: While Sunitinib and more importantly Everolimus led to a significant tumor growth inhibition as single agents, their combination was more effective on tumor regression. At the peripheral level, Sunitinib, but also Everolimus, led each to declines in circulating and splenic myeloid-derived suppressor cells (MDSCs) - depicted as CD11b+/Gr1+, an event that was further optimized upon combination of both agents. In addition, tumor sections analyses showed decreased microvessel density under Sunitinib and combination treatment. Differential modulations of correlative endothelium/pericytes staining and hypoxia degree were also observed upon the different treatments. This study confirms the preclinical efficacy of Sunitinib and a hypoxia regulator in renal tumor model and suggests that limitation of Sunitinib-induced hypoxia through mTOR targeting or with hypoxia regulators represents a suitable strategy to enhance effect of anti-angiogenic agent thereby limiting tumor growth.
Citation Format: Imane Nafia, Assia Chaibi, Doriane Bortolotto, Christophe Rey, Alban Bessede. Anti-angiogenic therapy combination with hypoxia-regulating agent leads to improved tumor regression in a murine model or renal carcinoma [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 3938.
Abstract 3951: Age-dependent loss of HAPLN1 affects vascular integrity and metastasis in melanoma
Authors: Marino Gloria E. , Almeida Filipe V. , Liu Ying , Alicea Gretchen M. , Fane Mitchell E. , Weeraratna Ashani T. 
Published: September 2020

Abstract
Older melanoma patients (&gt;55 years) have worse prognoses than younger patients (&lt;45 years) independent of other clinical prognostic factors. Further, while younger patients have more lymph node metastases, older patients have more distal metastases which significantly impacts their survival. We have shown that age-dependent loss of a secreted factor from dermal fibroblasts, HAPLN1, contributes to increased distal metastasis in vivo via ECM reorganization. Previous work from our lab has shown that age-dependent loss of HAPLN1 confers fewer lymphatic metastases but more lung metastases, consistent with clinical observations. We have demonstrated that this is due to ECM structural degradation and loss of lymphatic vasculature integrity. However, the biological mechanisms by which dermal ECM structure influences metastatic spread and localization are still largely unknown. Here we report that age-dependent loss of HAPLN1 contributes to increased intratumoral neoangiogenesis and decreased vascular integrity. Using immunohistochemistry, we have shown that tumors from aged mice treated with recombinant HAPLN1 have significantly fewer neoangiogenic blood vessels than untreated aged mice, suggesting that HAPLN1 may signal to inhibit neoangiogenesis. Additionally, the intratumoral blood vessels in aged mice treated with recombinant HAPLN1 have increased levels of the adherens junction protein VE-cadherin consistent with levels seen in the tumor vasculature of young mice. Given the pivotal role of intratumoral vasculature in metastasis, we hypothesize that these changes in vessel number and permeability contribute to the increased incidence of lung metastasis in older patients. Further, our data utilizing two-photon microscopy indicate that aged mice have aberrant collagen structure surrounding intratumoral vessels, but that treatment with recombinant HAPLN1 is sufficient to restore a collagen pattern similar to what is seen in young mice. We have additionally demonstrated using an in vitro impedance-based assay that endothelial cell monolayers have a reduced ability to maintain barrier function in the context of ECM without HAPLN1. Given that dermal ECM structural complexity is essential for maintaining vascular integrity, loss of HAPLN1 seems to contribute to this “leaky” vasculature phenotype. In all, these data may provide clues as to why young and aged patients exhibit differential routes of metastases via lymphatic vs. hematogenous dissemination.
Citation Format: Gloria E. Marino, Filipe V. Almeida, Ying Liu, Gretchen M. Alicea, Mitchell E. Fane, Ashani T. Weeraratna. Age-dependent loss of HAPLN1 affects vascular integrity and metastasis in melanoma [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 3951.
Abstract 3961: Influence of hyaluronic acid in tumor microenvironment on glioblastoma (GBM) invasive behavior
Authors: Solomon Itay , Sohrabi Alireza , Seidlits Stephanie K. 
Published: September 2020

Abstract
Glioblastoma invasion is mediated by distinct interactions between tumor cells and the extracellular matrix. Engineered biomaterial platforms allow for systemic examination of the influence of the microenvironment HA content on GBM cell activity. In this study, high molecular weight hyaluronic acid (700 kDa) was photopolymerized within three-dimensional (3D) polyethylene-glycol (PEG) hydrogels and patient-derived, primary GBM cell migration in the HA-hydrogels was investigated. Hydrogel polymerization conditions were tuned to achieve orthogonal control of HA content in a series of hydrogels (0.1 - 0.75 wt% HA) with conserved poroelastic properties (i.e. storage moduli and diffusivity). GBM cell migration was strongly influenced by microenvironment HA content. Knockdown of HA-dependent cell surface receptors (CD44 and RHAMM) modulated GBM cell activity. Our results demonstrate that alterations in microenvironment HA content and inhibition of HA-dependent signaling produced distinct molecular and phenotypic differences in GBM migratory behavior. These results demonstrate the differential effect of tumor microenvironment HA content on the invasive phenotype of GBM in a physiologically relevant 3D culture environment.
Citation Format: Itay Solomon, Alireza Sohrabi, Stephanie K. Seidlits. Influence of hyaluronic acid in tumor microenvironment on glioblastoma (GBM) invasive behavior [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 3961.
Abstract 3962: Differential extracellular matrix remodeling induced by VEGF-A and TGF-β activated fibroblasts
Authors: Nuñez Muriel A. , Cerda-Infante Javier , Nualart Francisco , Cerda Gustavo , Yussef Isabel M. , Montecinos Viviana P. 
Published: September 2020

Abstract
Introduction: Tumor progression is modulated by the presence within the tumor microenvironment of activated fibroblasts called cancer-associated fibroblasts (CAFs). CAFs exhibit an increase in the production of collagen (COL), tenascin C (TNC) and fibronectin (FN), resulting in a remodeling of the extracellular matrix (ECM) within the tumor mass. CAFs-derived ECM guides the cancer cells to migrate directionally increasing metastasis. TGF-β and VEGF-A are highly express in tumors and promote progression, however, their role in ECM remodeling is poorly understood. This study seeks to analyze the ECM protein remodeling mediated by TGF- β o VEGF-A activated fibroblasts.
Materials and methods: In vitro and in vivo ECM protein remodeling mediated by TGF- β o VEGF-A activated fibroblasts was analyzed through expression of TNC, FN and COL using immunofluorescence and second harmonic generation (SHG); alignment and thickness of the fibers; Organoleptic invasion and 2D migration assay were conducted to study the effect of the stiffness of collagen gels generated by VEGF-A and TGF-β activated fibroblasts in the migration/invasion of tumor cells.
Results and discussion: ECM derived from VEGF-A and TGF-β activated fibroblasts have differential ECM remodeling patterns, including differences in the secretion of TNC, FN, and COL; alignment and thickness of the fibers, and migration/invasion rate. These changes results in a differential stiffness of the ECM, which would alter the directional migration of cancer cells within tumor microenvironment.
Citation Format: Muriel A. Nuñez, Javier Cerda-Infante, Francisco Nualart, Gustavo Cerda, Isabel M. Yussef, Viviana P. Montecinos. Differential extracellular matrix remodeling induced by VEGF-A and TGF-β activated fibroblasts [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 3962.
Abstract 3963: Physical confinement induces malignant transformation in mammary epithelial cells
Authors: Lu Yen-Chun 
Published: September 2020

Abstract
The physical microenvironment of tumor cells plays an important role in cancer initiation and progression. Here, we present evidence that confinement - a new physical parameter that is apart from matrix stiffness - can also induce malignant transformation in mammary epithelial cells. We discovered that MCF10A cells, a benign mammary cell line that forms growth-arrested polarized acini in Matrigel, transforms into cancer-like cells within the same Matrigel material following confinement in alginate shell hydrogel microcapsules. The confined cells exhibited a range of tumor-like behaviors, including uncontrolled cellular proliferation and invasion. Additionally, 4-6 weeks after transplantation into the mammary fad pads of immunocompromised mice, the confined cells formed large palpable masses that exhibited histological features similar to that of carcinomas. Taken together, our findings suggest that physical confinement represents a previously unrecognized mechanism for malignancy induction in mammary epithelial cells and also provide a new, microcapsule-based, high throughput model system for testing new breast cancer therapeutics.
Citation Format: Yen-Chun Lu. Physical confinement induces malignant transformation in mammary epithelial 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 3963.
Abstract 4017: Biochemical and biophysical characterization of a covalent inhibitor of Src kinase
Authors: Gurbani Deepak , Westover Kenneth , Bera Asim 
Published: September 2020

Abstract
Background: c-Src was among the first oncogenes discovered. It encodes a non-receptor tyrosine kinase that regulates many cancer-related cellular processes including mitogenesis, angiogenesis, adhesion, invasion, migration, and survival. Src activity drives malignant phenotypes in hematologic and solid cancers including breast, prostate, lung, colorectal, and pancreatic cancer. However, no specific Src-directed targeted therapies are in clinical use. Various Src inhibitors such as dasatinib, bosutinib and others have been tested in human trials, but with variable outcomes including dose-limiting toxicity, which is due to the multi-targeted nature of these compounds, which also hit Src, SFKs, BCR-ABL, c-KIT, PDGFR, c-FMS, EPHA2 and others. Improved selective Src inhibitors may overcome these challenges to enable Src-directed therapies. Engineering selectivity into Src inhibitors is challenging because of the high degree of sequence homology between Src family members and other receptor tyrosine kinases. The selective, covalent Src inhibitor DGY-06-116, which targets a relatively unusual targetable cysteine near the active site in the p loop, was recently reported. Here, we further characterize DGY-06-116.
Methods: We characterized the inhibitory activity DGY-06-116 using an enzymatic assay and surface plasmon resonance (SPR). We also determined the co-crystal structure of DGY-06-116 bound to Src.
Results: DGY-06-116 showed a substantial improvement over both SM171 and bosutinib for inhibition of Src kinase activity: SM1-71 (IC50, 26.6 nM); bosutinib (IC50, 9.5 nM); DGY-06-116 (IC50, 2.59 nM). Determination of kinact using SPR showed a value of 5.7 x 10-7 (s-1) for DGY-06-116, slower than FDA-approved neratinib (2 x 10-3 s-1) and afatinib (1 x 10-3 s-1). A 2.15 Å resolution co-crystal structure of DGY-06-116 bound to Src (PDB ID: 6E6E) showed a covalent bond with Cys-280 and bending of the p-loop relative to other Src-inhibitor structures.
Conclusions: DGY-06-116 demonstrates a slow inactivation rate that likely reflects the need for repositioning of the p-loop for a covalent bond to occur. Src inhibitors based on DGY-06-116 may benefit from optimization of p-loop, inhibitor interactions.
Citation Format: Deepak Gurbani, Kenneth Westover, Asim Bera. Biochemical and biophysical characterization of a covalent inhibitor of Src kinase [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 4017.
Abstract 4021: Assessing the sensitivity of LSF inhibitors against liver cancer
Authors: Pokharel Niranjana , Kavouris John , Biagi Jessica , Hansen Ulla , Schaus Scott E. 
Published: September 2020

Abstract
Introduction: Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the second leading cause of cancer mortality. The transcription factor Late SV40 Factor (LSF) functions as an oncogene in HCC, making it a potential protein target for HCC therapy. LSF overexpression correlates with pathogenesis of liver, colorectal and pancreatic cancers, for which there are limited molecularly targeted therapy options. A library of dihydroquinolinones, termed Factor Quinolinone Inhibitors (FQIs), inhibits LSF-DNA binding and specific LSF-protein interactions in in vitro and in cellular assays. The initial lead compound FQI1 causes dramatic mitotic defects in HCC cell lines but has no toxic consequences on immortalized human hepatocytes or primary mouse hepatocytes. Additionally, FQI1 has proven efficacious in endogenous HCC mouse models, with no evidence of associated toxicity.
Methods: A series of dihydroquinolinone compounds were synthesized and tested for potency in two HCC cell lines, Huh7 and SNU423, by a cell proliferation assay. The FQI analogs, FQI34, N-oxide FQI34 and FQI37, were separated by chiral chromatography to the corresponding R and S enantiomers. Direct target engagement of the three lead compounds, FQI1, FQI34 and FQI37, is shown with cellular thermal stability assays on Huh7 cells.
Results: More than 20 compounds were synthesized and characterized. Among them, FQI37 showed the most potent activity (GI50 = 70 nM) against Huh7 HCC cells. Structure-activity-relationship studies suggest that the amide portion of quinolinone core is important for optimal activity. Growth inhibition assays revealed enantiomeric specificity; the (S)-enantiomers are more potent than the (R)-compounds and the racemate. The cellular thermal shift assay in Huh7 cells demonstrated the direct target binding of FQIs to LSF in cells at micromolar concentrations. Growth inhibition assays also identified colorectal cancer and pancreatic cancer lines to be sensitive to the dihydroquinolinones treatment.
Conclusions: Aryl-dihydroquinolinones are promising small molecule chemotherapies for LSF-driven cancers such as HCC, colorectal cancer, and pancreatic cancer.
Citation Format: Niranjana Pokharel, John Kavouris, Jessica Biagi, Ulla Hansen, Scott E. Schaus. Assessing the sensitivity of LSF inhibitors against liver 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 4021.
Abstract 4024: NAMPT inhibitor decreases NAMPT capture by an antibody directed against the 5-phosphoribosyl-1-pyrophosphate-binding loop: Rationale for an NAMPT occupancy assay
Authors: Shomali Maysoun , Hilairet Sandrine , Duhamel Marianne , Nardi Frederico , Bertrand Thomas , Penarier Geraldine , Debussche Laurent , Bouaboula Monsif 
Published: September 2020

Abstract
Nicotinamide phosphoribosyl transferase (NAMPT) catalyzes the rate-limiting step of nicotinamide adenine dinucleotide (NAD) biosynthesis. As NAMPT inhibitors (NAMPTi) have been shown to be substrates of NAMPT, binding of NAMPTi to NAMPT results in the NAMPTi-phosphoribose adduct (RP) that binds tightly and strongly inhibits the NAMPT enzyme. Structural analyses performed in this study unveiled the proximity of the NAMPTi-RP complex to the phosphoribosyl diphosphate (PRPP)-binding loop within the NAMPT catalytic site. The PRPP-binding loop of NAMPT is subject to conformational flexibility. The PRPP-binding loop domain is oriented to the outer side of the NAMPT dimer and can potentially serve as an antigen-binding site for antibodies. Interestingly, we show that the NAMPTi-RP adduct bound to NAMPT decreases NAMPT capture by an antibody that is directed against the c-terminal 5-phosphoribosyl-1-pyrophosphate-binding loop in NAMPT. This finding was then used to explore cellular NAMPT occupancy. The NAMPTi-RP complex displays a sustained, cellular NAMPT occupancy that correlates with the inhibition of NAMPT activity. Moreover, a good correlation between NAMPT occupancy, NAD decrease, and NAMPTi efficacy was observed in-vivo in a NCI-H82 small cell lung cancer (SCLC) xenograft model. NAMPT-occupancy assay can be used in clinical settings to better define the optimal dose levels and dose regimen for effective NAMPT inhibition.
Citation Format: Maysoun Shomali, Sandrine Hilairet, Marianne Duhamel, Frederico Nardi, Thomas Bertrand, Geraldine Penarier, Laurent Debussche, Monsif Bouaboula. NAMPT inhibitor decreases NAMPT capture by an antibody directed against the 5-phosphoribosyl-1-pyrophosphate-binding loop: Rationale for an NAMPT occupancy assay [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 4024.
Abstract 4038: ABM-1310, A novel BRAF Inhibitor, combined with EGFR and MEK inhibitors, inhibits colorectal tumor growth and increases overall survival in vivo
Authors: Hu Yong , Chen Chen , Huang Charles , Xu Min , Chen Youqin , Zhao Xiyuan , Zhao Li 
Published: September 2020

Abstract
Colorectal cancer (CRC) is a cancer that starts in the colon or the rectum, and the current treatment mainly relies on chemotherapies. For example, ERBITUX® /cetuximab is an FDA approved targetedtherapy drug to treat CRC with wild-type KRAS, the 11% low response rate limits its clinical application. BRAF inhibitors have been widely used clinically for melanoma and lung cancer, however, they have dismally low response rate at only approximately 5% of colorectal cancer patients with BRAFv600 mutation.
Here, we report that ABM-1310, a novel small molecule inhibitor of BRAF (specifically inhibit BRAFv600 mutant), has shown good potency in colon cancer xenograft models, when combined with a MEK inhibitor and EGFR antibody. In the HT-29 xenograft subcutaneous model, 10 to 25mg/kg/day oral dose of ABM-1310 combined with cetuximab (0.1mg/dose, twice a week) and 3 mg/kg/day of Binimetinib (MEK inhibitor) significantly inhibited HT-29 tumor growth with TGI of 85% to 92% after 34-days treatment. As a monotherapy or combined with cetuximab alone, ABM-1310 also brought the TGI of 74% and 82% at 25mg/kg/day, which indicates ABM-1310 played a key role in tumor growth inhibition in the combinations. Beside with Binimetinib, we also tested combination of ABM-1310 with other different MEK inhibitors in this model.
ABM-1310 is highly water-soluble small molecule with high cell permeability and blood brain barrier penetration. ABM-1310 shown good efficacy in melanoma A375 (luciferase labelled cells) in the subcutaneous/intracranial/intracardiac xenograft models (brain metastasis models). In the HT-29 colon intracranial model, ABM-1310 also demonstrated significant tumor inhibition effect and increased animal overall survival. Compared with vehicle or marketed BRAF inhibitor vemurafenib, the median survival time of ABM-1310 group was &gt;90 days vs 51 days (vemurafenib) and 38 days (vehicle), respectively.
In Summary, ABM-1310, as a novel small molecule BRAF inhibitor, combined with EGFR and MEK inhibitors, has shown strong anti-tumor effect in preclinical in vivo models of colon cancer with BRAFv600 mutation, especially with brain metastasis.
Citation Format: Yong Hu, Chen Chen, Charles Huang, Min Xu, Youqin Chen, Xiyuan Zhao, Li Zhao. ABM-1310, A novel BRAF Inhibitor, combined with EGFR and MEK inhibitors, inhibits colorectal tumor growth and increases overall survival 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 4038.