bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4601: Vitamin D supplementation attenuates resistance to anti-angiogenic therapy in colorectal cancer liver metastases
Authors: Rada Miran , Krzywon Lucyna , Kapelanski-Lamoureux Audrey , Petrillo Stephanie , Lazaris Anthoula , Metrakos Peter 
Published: April 2023

Abstract
Colorectal cancer liver metastasis (CRCLM) is one of the deadliest cancers. CRCLM tumours have two distinct histopathological growth patterns (HGPs) including desmoplastic HGP (DHGP) and replacement HGP (RHGP). The DHGP tumours are angiogenic, while their RHGP counterparts are vessel co-opting. The patients with RHGP tumours showed poor response to anti-angiogenic agents, as well as a worse prognosis. Herein, we conducted a retrospective cohort study that comprised 106 CRCLM patients to examine the effect of vitamin D supplementation on the HGPs of the tumours and the 5-year overall survival (OS). Interestingly, we found an inverse correlation between vitamin D supplementation and the presence of RHGP tumours in CRCLM patients. Additionally, the population who used vitamin D supplementation had significantly better 5-year OS. Moreover, our in vivo results suggested that vitamin D supplementation significantly improves the response of CRCLM tumours to anti-angiogenic therapy. Mechanistically, we found that vitamin D can suppress cancer cell motility, which is essential for the development of vessel co-option tumours and resistance to anti-angiogenic therapy. Collectively, this study suggests vitamin D supplementation is a promising way to attenuate resistance to anti-angiogenic therapy and improve the prognosis of CRCLM patients.
Citation Format: Miran Rada, Lucyna Krzywon, Audrey Kapelanski-Lamoureux, Stephanie Petrillo, Anthoula Lazaris, Peter Metrakos. Vitamin D supplementation attenuates resistance to anti-angiogenic therapy in colorectal cancer liver metastases. [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 4601.
Abstract 4602: Differences in tumor vascular density between smoker and non-smoker cancer patients
Authors: Singh Shubhangi , Khan Mohammad Aslam , Herrera Elba T. , Singh Seema , Singh Ajay P. , Dasgupta Santanu 
Published: April 2023

Abstract
Smoking is among the most significant preventable risk factors associated with cancer and other benign diseases. Cancer development is a multi-step process in which transforming cells gradually gain malignant properties through a series of oncogenic genetic alterations. Successful cancer progression also depends on the remodeling of the surrounding stroma, which feeds the cancer cells in a host-parasite interaction. Tumor angiogenesis, the process of blood vessel formation, is an essential feature of solid tumors that ensures that they have the needed supply of food and oxygen to sustain their proliferative growth. We previously demonstrated that nicotine, an addictive component of tobacco smoke, promoted tumor angiogenesis by impacting the growth of endothelial cells. In the present work, we examined the differences in tumor vasculature between smoker and non-smoker patients to find clinical support for our laboratory findings. After searching the available tumor cases in the repository for the patient’s smoking history, I selected 27 smokers (12 lung and 15 prostate adenocarcinomas) and 19 non-smokers (4 lung and 15 prostate adenocarcinomas) cases. The tissue blocks were sectioned and subjected to hematoxylin and eosin staining and immunohistochemistry using an antibody against CD31, a biomarker for endothelial cells. Following digital scanning, all slides were reviewed to identify tumor areas and CD31+ tubular structures (blood vessels). We observed that lung and prostate tumor tissues from smoker patients had a significantly higher number of blood vessels than those from non-smoker patients. Thus, increased tumor vascularization appears to be a common feature of smoking cancer patients providing clinical support for a novel mechanism by which smoking may contribute to tumor pathobiology.
Citation Format: Shubhangi Singh, Mohammad Aslam Khan, Elba T. Herrera, Seema Singh, Ajay P. Singh, Santanu Dasgupta. Differences in tumor vascular density between smoker and non-smoker cancer patients. [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 4602.
Abstract 4607: TRPS1 inhibits angiogenesis in triple negative breast cancer down regulating JAG1 and TYMP genes involved in angiogenesis pathways
Authors: Guzman Liliana 
Published: April 2023

Abstract
Background. Triple-negative breast cancer (TNBC), the most difficult subtype to treat, is defined as estrogen receptor, HER2, and progesterone receptor negative. TNBC constitutes 10-20% of all breast cancer and has a higher rate of distal recurrence and a poorer prognosis than other breast cancer subtypes. Less than 30% of women with metastatic TNBC survive 5 years and almost all die from their disease despite adjuvant chemotherapy. Angiogenesis is a critical factor in the development of tumors and metastases in numerous cancers. Clinical trials with anti-angiogenic drugs showed to be inadequate, with moderate response rates and insignificant survival gains for patients. To understand the genetic forces involved in TNBC, we performed a transposon mutagenesis screen in Pten mutant mice that identified several candidate trunk drivers and progression genes. A major finding of our screen was the discovery and functional validation of, Trichorhinophalangeal syndrome type 1 (TRPS1), a GATA-like transcription factor, which functions as a transcriptional repressor or activator, depending on cell type, stage of development, or pathological conditions. Based on this data, we explored the role of TRPS1 in angiogenesis.
Methods and Results. Tube formation and sprouting assays were performed using overexpression and inactivation of TRPS1 in MDA-MD-231 and HCC70 cells, respectively. Interestingly, inactivation of TRPS1 expression accelerates tube formation structures compared to the vector control as well as cell branching in the sprouting assay. Overexpression of TRPS1 prevents tubing and branching formation in vitro assays. Moreover, immunohistochemistry staining of CD31 detected a reduced number of blood vessels in MDA-MB-231 tumor xenografts overexpressing TRPS1, and an increase of angiogenic vasculature in HCC70 TRPS1-shRNA tumor xenografts. In vitro and in vivo assays demonstrate the role of TRPS1 in tumor angiogenesis. Furthermore, human ChIP qPCR angiogenesis array identified 10 top candidate genes potentially regulated by TRPS1 transcription factor. Of these candidates, JAG1 and TYMP showed to have a higher fold enrichment compared to other angiogenic related genes. Finally, we validated its direct functional binding by using luciferase reporter assay, such demonstrated that TRPS1 is a direct transcriptional regulator of JAG1 and TYMP.
Conclusion. TRPS1 is a tumor suppressor involved in the mechanisms regulating tumor angiogenesis by repressing the expression of JAG1 and TYMP genes in TNBC.
Citation Format: Liliana Guzman. TRPS1 inhibits angiogenesis in triple negative breast cancer down regulating JAG1 and TYMP genes involved in angiogenesis pathways. [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 4607.
Abstract 461: Targeting glucose metabolism in lung cancer
Authors: Telang Sucheta , Chang Simone , Sanders Nicole 
Published: April 2023

Abstract
Positron emission tomographic studies with 2-18F-fluoro-deoxy-glucose (FDG-PET) consistently demonstrate that non-small cell lung cancers (NSCLC) take up significantly more glucose than normal lung. NSCLCs preferentially utilize glucose to support their rapid growth- a phenotype driven by several oncogenic alterations among which mutations of the oncoprotein Ras are frequently observed. Oncogenic Ras is shown to activate downstream effectors (e.g. HIF-1α) that stimulate glycolysis - in part by activation of the 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase family of enzymes (PFKFB1-4). The PFKFBs produce fructose-2,6-bisphosphate (F26BP) which activates a key rate-limiting glycolytic enzyme, 6-phosphofructo-1-kinase (PFK1). In preliminary studies, we found that the PFKFB4 family member was highly expressed relative to other PFKFB isoforms (by multiplex RT-PCR) in a series of patient-derived NSCLCs relative to paired normal lung tissue. We further explored PFKFB4 protein expression by immunohistochemistry in NSCLCs derived from a cohort of patients and found markedly elevated PFKFB4 in the majority of tumors relative to adjacent normal tissue. We then determined that silencing PFKFB4 markedly reduced F26BP, glycolysis and cell survival in NSCLC cell lines and inhibited xenograft lung tumor growth in vivo. In order to target PFKFB4, we conducted a virtual screen of compounds that fit into the active site of PFKFB4 and discovered a first-in-class small molecule selective PFKFB4 inhibitor, termed 5MPN, that selectively inhibits recombinant PFKFB4 activity and decreases F26BP, glycolysis and proliferation in multiple NSCLC cell lines, with significantly higher anti-proliferative effects in Ras-driven cell lines. 5MPN also caused marked suppression of growth in established NSCLC xenograft tumors, importantly without systemic toxicity. We have developed an inducible, pan-tissue homozygous floxed Pfkfb4 knockout mouse and crossed it with a Cre recombinase mouse driven by a tamoxifen-inducible β-actin promoter to produce Cre/Pfkfb4fl/fl mice. We crossed Cre/Pfkfb4fl/fl mice with a Ras-driven lung cancer model, induced Pfkfb4 deletion by tamoxifen administration and found significantly lower total lung tumor burden in these mice accompanied by decreased PFKFB4 expression in tumors and lung tissue. Taken together, these data provide strong rationale for the further evaluation of small molecule inhibitors of PFKFB4 as a potential therapeutic strategy against NSCLC.
Citation Format: Sucheta Telang, Simone Chang, Nicole Sanders. Targeting glucose metabolism in lung 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 461.
Abstract 4613: Inhibition of myosin II in triple-negative breast cancer cells limits macrophage recruitment in a 3D environment
Authors: Cho Youngbin , Li Ruxuan , Zervantonakis Ioannis 
Published: April 2023

Abstract
Among all breast cancer subtypes, triple-negative breast cancer (TNBC) exhibits the least favorable outcomes with a complex tumor microenvironment that facilitates metastatic progression. Remodeling of the extracellular matrix at the tumor invasive front is associated with increased cancer cell motility and poor outcomes. Myosin II, a key cytoskeletal regulator, plays a central role in cancer cell metastatic potential. In the clinic, high expression of myosin II in breast tumors has been associated with distant metastasis and lower survival rates. Interestingly, breast tumors overexpressing myosin II exhibited a higher density of tumor-associated macrophages and an immunosuppressive microenvironment. However, the relationship between myosin II activation in TNBC cancer cells and macrophage recruitment remains poorly understood. Here we employed a novel 3D microfluidic model of tumor-macrophage co-culture to study macrophage infiltration toward cancer cells with high spatiotemporal resolution. Using a panel of TNBC cell lines we found that high myosin II expression in cancer cells correlated with higher macrophage recruitment in a 3D matrix. Pharmacologic or genetic inhibition of myosin II reduced macrophage recruitment. Furthermore, using our microfluidic devices, we controlled the spatial distribution of cancer cells in a 3D matrix and separated the role of cancer cell-secreted paracrine factors from cancer cell-mediated matrix remodeling on macrophage recruitment. Analysis of matrix remodeling over time revealed that targeting myosin II in cancer cells limited the establishment of migratory tracks that facilitated macrophage recruitment. In sum, our studies revealed the critical role of cancer cell-driven matrix remodeling in promoting macrophage infiltration that can be therapeutically targeted to reverse the establishment of an immunosuppressive microenvironment.
Citation Format: Youngbin Cho, Ruxuan Li, Ioannis Zervantonakis. Inhibition of myosin II in triple-negative breast cancer cells limits macrophage recruitment in a 3D environment. [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 4613.
Abstract 4630: Deep Immuno-profiling of syngeneic tumor mouse models for preclinical studies
Authors: Joachim Anais , Maturin Emilie , Mello Marielle , Hadjem Lillia , Grange Magali , Deas Olivier , Zarubica Ana , Malissen Bernard , Luche Hervé 
Published: April 2023

Abstract
Identification of major cellular players involved in progression of cancer is key to success of new immunotherapies. It is however a daunting challenge due to the complex interplay between tumor cells and the immune system. Component of innate and adaptive immunity may be directed to a pro- or anti-tumor function. In order to cope with the complexity of the tumor microenvironment (TME), it is necessary to use an experimental approach characterizing the heterogeneity of cell types, the evolution of their relative proportion and their fine-tuned functional specificity. This approach should lead to the identification of new cellular biomarkers characteristics of different stages of tumor cancer progression.
To decipher the impact of immunotherapy treatments, cellular phenotyping of leukocytes infiltrating TME but also those present in peripheral organs is necessary. In order to increase our understanding in the precise mode of action of anti-PD1 treatment at the cellular level in sensitive and unsensitive syngeneic models, we investigated immunophenotypes and responses to immune checkpoint inhibitor (ICI) of several hallmark tumor models (MC38, CT26, B16F10, B16-OVA, RENCA, EMT6) in immunocompetent mouse models by flow and mass cytometry. We compared growth kinetics and profiled the immune cell composition of tumor microenvironment (TME), draining lymph node (dLN) and blood in order to establish immune-phenotypic cell signatures that correlates with treatment efficacy. Supervised, unsupervised and integrative data analysis arewere used to identify significant changes across different experimental settings. Our results indicate that each model possesses a unique tumor-immune infiltrate profile that can be modulated with immunotherapies. Overall, these studies provide an important resource of highly well-characterized syngeneic tumor model and highlight the importance of tumor immune landscape changes across models that will drive selection of the most appropriate model to test novel immunotherapeutic agents and enhance our translation of knowledge from syngeneic models to human tumors.
Citation Format: Anais Joachim, Emilie Maturin, Marielle Mello, Lillia Hadjem, Magali Grange, Olivier Deas, Ana Zarubica, Bernard Malissen, Hervé Luche. Deep Immuno-profiling of syngeneic tumor mouse models for preclinical studies. [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 4630.
Abstract 4667: Establishment of patient-derived human cell lines using PDX mouse model for intrahepatic cholangiocarcinoma
Authors: Matsumoto Takashi 
Published: April 2023

Abstract
Background: In recent years, patient tumor transplant models (PDX models) have attracted method that can predict the effects of anticancer drugs on patients. The PDX model is a technique in which the patient's tumor tissue is directly transplanted into immunodeficient mice. Tumors can grow three-dimensionally in a living mouse, so compared to culturing in petri dishes, the situation is like the growth of tumors in the patient's body. In addition, there are reports that the efficacy of anticancer drugs in patients and the results of administration of anticancer drugs in PDX show a high concordance rate, and it is attracting attention as a model that can predict efficacy in patients. In this time, we report on the establishment of cell lines using PDX mice for resected cases of intrahepatic cholangiocarcinoma in our hospital.
Methods: Twelve patients who underwent surgical resection between September 2019 and December 2021 were included. After resected the tumor, the tumor was transplanted into up to 10 PDX mice, and cell lines were established from the formed tumor tissue.
Results: Of the 12 cases, tumors formed in PDX mice after transplantation in 6 cases, and the median time to engraftment after the first transplantation was 133 days (75-188). Furthermore, among the 6 cases, 3 cases achieved the establishment of cell lines.Case1:moderately differentiated adenocarcinoma, tumor diameter 50mm, single, vascular invasion positive, no lymph node metastasis, Stage IIIA (UICC 8th)Case2:well differentiated adenocarcinoma, tumor diameter 60mm, single, vascular invasion negative, no lymph node metastasis, Stage II (UICC 8th)Case 3:moderately differentiated adenocarcinoma, tumor diameter 55mm, single, vascular invasion positive, no lymph node metastasis, Stage IIIA (UICC 8th)
Conclusion: The cell line we established this time is a case of advanced cancer, and we would like to continue to increase the number of cases and continue to establish cell lines, which will lead to future research.
Citation Format: Takashi Matsumoto. Establishment of patient-derived human cell lines using PDX mouse model for intrahepatic cholangiocarcinoma. [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 4667.
Abstract 474: Preclinical development of an oral selective estrogen receptor degrader (SERD) TFX06 for the treatment of ER+HER2− breast cancer
Authors: Wu Jinping , An Ke , Fang Douglas D. , Lu Jianyu , Hu Lihong , Wang Jing , Zhang Kaili , Xia Yuanfeng , Ding Charles , Chen Shuhui , Wei Sha 
Published: April 2023

Abstract
Breast cancer (BC) has recently surpassed lung cancer to become the most commonly diagnosed cancer in women worldwide. Approximately 70% of BC was ER+, in which estrogen receptor α (ERα, encoded by ESR1 gene) drives dysregulated cell proliferation. In clinic, ER+ BC has been effectively treated by endocrine therapy targeting estrogen or ER. As the first approved ERα degrader, fulvestrant has proven to be effective for locally advanced or metastatic BC. However, its clinical utilization is hampered by inconvenience of intramuscular injection, as well as its poor PK/PD profile and limited efficacy, especially in the patient population that developed ESR1 mutation-conferring drug resistance after the earlier line of treatment with an aromatase inhibitor. Thus, developing an oral and more effective therapy for ER+ BC remains an unmet medical need. We report herein discovery and preclinical investigation of a novel orally bioavailable SERD TFX06. TFX06 demonstrated potent binding affinity to ERα with a Ki of 0.10 nM and preferably antagonized ERα to ERβ with an IC50 value of 0.086 nM and 2.83 nM, respectively. TFX06 potently induced ERα degradation in ER+ BC cells and substantially inhibited cell proliferation in BC cell lines with ER wild type (WT), and MCF-7 cells expressing Y537S or D538G mutants. Oral administration of TFX06 demonstrated impressive antitumor efficacy in ER WT (TGI = 101%) and ER D538G-expressing (TGI = 99%) MCF-7 cell line-derived xenograft (CDX) models in mice. Similarly, in an ER+ BC patient-derived xenograft (PDX) model (HCI-013) with ER Y537S mutation, TFX06 also exerted excellent antitumor activity (TGI = 99%). Furthermore, TFX06 in combination with palbociclib achieved synergistic activity in MCF-7 CDX model. Moreover, TFX06 exhibited an excellent correlation between systemic/local drug exposure, pharmacodynamic modulation (i.e., ERα downregulation) and antitumor activity. Collectively, these findings demonstrate that TFX06 is a novel, orally bioavailable SERD. TFX06 demonstrates substantial antitumor activity in both in vitro and in vivo preclinical tumor models, including those expressing ESR1 mutations, through downregulation of ERα. The preclinical data warranted the clinical evaluation of TFX06 in human with an IND application submitted to the China NPMA.
Citation Format: Jinping Wu, Ke An, Douglas D. Fang, Jianyu Lu, Lihong Hu, Jing Wang, Kaili Zhang, Yuanfeng Xia, Charles Ding, Shuhui Chen, Sha Wei. Preclinical development of an oral selective estrogen receptor degrader (SERD) TFX06 for the treatment of ER+HER2− breast 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 474.
Abstract 4751: The function of bromodomain containing protein 4 (BRD44) in hematopoiesis
Authors: Nihozeko Francine 
Published: April 2023

Abstract
Bromodomain containing protein 4 (BRD4) is an epigenetic transcription regulator that reads acetylated chromatin and is involved in the recruitment of transcriptional factors to initiate gene transcription. BRD4 is functionally versatile and has extensively been studied for its role in cell cycle progression, gene transcription regulation, chromatin organization and remodeling, as well as DNA replication and repair. In addition, BRD4 has been implicated in many solid and liquid tumors, and its inhibition shows promising preclinical activity, especially in hematopoietic malignancies. BRD4 is overexpressed in Leukemia and has been reported to play a role in hematopoietic stem cell expansion and progenitor development. However, the mechanisms of BRD4 in hematopoietic stem cell functions and disease development remain poorly understood. Using BRD44 knockout (BRD44 Δ/Δ, driven by Mx1 Cre to delete BRD44 in hematopoietic system) mouse model, we found that BRD4 is required for HSCs self-renewal and the loss of BRD44 impaired erythroid differentiation and skewed myeloid differentiation. BRD44 Δ/Δ HSPCs showed G0/G1 arrest, decreased S-phase, and increased senescence compared to wild type (WT) HSPCs. Our study demonstrates that BRD4 is essential for normal hematopoiesis. To further investigate the role of BRD4 in hematopoiesis, we generated BRD44 transgenic mice (driven by Vav1 promoter, to assure all BRD44 transgene expression is instructed in the hematopoietic system). Ongoing studies focus on determining the impact of BRD4 overexpression on hematopoietic stem cell functions.
Citation Format: Francine Nihozeko. The function of bromodomain containing protein 4 (BRD44) in hematopoiesis. [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 4751.