bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2994: A new ER+Her2- Palbociclib resistant breast cancer PDX model
Authors: Melton Michele , Hyddmark Emma M. , Jiang Hongmei , Bast Athena , Semanik Nicole , Deeds Stacy , Brown Andrew 
Published: July 2021

Abstract
One out of eight women will get breast cancer during their lifetime with over 250000 new cases of invasive breast cancer diagnosed yearly. The majority of breast cancer medicines (94%) were initially approved in the metastatic setting for patients that have been heavily pre-treated and resistant to the standard of care1. Thus, it is crucial that pre-clinical models are representative of this patient population in order for results to be translational. One recently approved class of drugs are the CDK4/6i which increase progression free survival for many patients. However, some tumors are intrinsically resistant, and others develop resistance over time. Hence, there is a need for new pre-clinical models that mimic these resistance features to test new therapies. WHIM81 and WHIM84 are two new ER+Her2- breast cancer PDX models from the Washington University Human in Mouse collection derived from heavily pretreated tumors. WHIM81 was derived from a patient with liver metastasis consistent with breast primary after she received treatment with Palbociclib, first as a monotherapy for 20 days and later in combination with letrozole for 2 months. During treatment, the patient developed the liver metastasis, whereas the WHIM84 model was grafted from a second patient with a bone metastasis prior to the patient seeing Palbociclib, but once she did, the tumor was unresponsive.
In this PDX study, athymic nude mice bearing either WHIM81 or WHIM84 tumors were treated with 3 different concentrations of Palbociclib (10 mg/kg, 25 mg/kg and 75 mg/kg) administered daily for the duration of the experiment and also included an arm with Fulvestrant administered once weekly through a subcutaneous injection of 3 mg/dose. Our results showed that although WHIM81 tumors were responsive to a very high dose of Palbociclib (75 mg/kg), those tumors showed resistance to Palbociclib doses of 10 mg/kg and Palbociclib 25 mg/kg group as well as Fulvestrant, consistent with what was seen in the clinic for the tumor from which this PDX is derived. On the contrary WHIM84, while still showing resistance at the 10 mg/kg dose, was sensitive to treatment with Palbociclib at a dose of 25 mg/kg.
Loss of pRb is an unlikely driver of resistance as WHIM81 retains pRb expression based on the presence of both pRb and phospo-pRb in the tumor. Thus, we believe that WHIM81 will provide a valuable new model to test novel therapies aimed to treat patients with CDK4/6i resistant cancers.
1. Leo and Szucs. (2020). Nature Reviews Drug Discovery. 19, 10.
Citation Format: Michele Melton, Emma M. Hyddmark, Hongmei Jiang, Athena Bast, Nicole Semanik, Stacy Deeds, Andrew Brown. A new ER+Her2- Palbociclib resistant breast cancer PDX model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2994.
Abstract 3013: Orthotopic patient-derived xenografts (O-PDX) are effective precision oncology models that can predict therapeutic response, recurrence, and acquired drug resistance
Authors: Nakashima Jonathan , Sperry Jantzen , Carapia Bianca , Yan Deborah , Chin Angelina , Shahsafaei Aliakbar , Chen Joan , Chien Yuan-Hung , Pedros Christophe , Federman Noah , Singh Arun , Eilber Fritz C. , Datnow Brian 
Published: July 2021

Abstract
Patient-derived xenografts provide a functional test system in a living organism, making them the leading assay for precision oncology and drug development. In vivo pharmacology studies are widely performed using subcutaneous implantation; however, due to significant changes in the tumor microenvironment, this methodology falls short of modeling the full complexities of human cancer. We use quantitative magnetic resonance imaging (MRI) to report differences in growth kinetics and pharmacological response between orthotopic and subcutaneous implantation of patient-derived xenografts. We demonstrate that O-PDX models can predict effective treatment strategies for individual patients and forecast tumor recurrence after therapy. Furthermore, we use this approach to develop in vivo models of acquired drug resistance to strategize future treatment options and aid in drug development.
Citation Format: Jonathan Nakashima, Jantzen Sperry, Bianca Carapia, Deborah Yan, Angelina Chin, Aliakbar Shahsafaei, Joan Chen, Yuan-Hung Chien, Christophe Pedros, Noah Federman, Arun Singh, Fritz C. Eilber, Brian Datnow. Orthotopic patient-derived xenografts (O-PDX) are effective precision oncology models that can predict therapeutic response, recurrence, and acquired drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3013.
Abstract 3066: DNA ligase IV inhibitor and X-ray exert a synthetic lethal in loss-of-function p53 cells
Authors: Lin Tingting , Zhou Zhilian , Zhu Lifeng , Fan Yandan , Ding Xiaofen , Sun Yingming 
Published: July 2021

Abstract
The majority of lung cancer patients receive radiotherapy during the treatment process. Dysfunction of DNA ligase IV impaired non-homologous end joining (NHEJ) and sensitized cells to X-ray. p53 regulated DNA damage repair and was mutated in various lung cancer cells. This study aimed to investigate the synergic effects of DNA ligase IV inhibitor SCR-7 and radiation on both wild-type and p53-deficient lung cancer cells. In the p53 wild-type cell, X-ray and SCR-7 triggered G2/M checkpoint, induced BRCA1, RAD18 activation, and promoted PCNA ubiquitination, facilitating homologous recombination (HR) and translesion synthesis (TLS) rather than NHEJ. In p53-deficient cells, SCR-7 and X-ray exerted a synthetic lethal via inducing more DNA damage, muting TLS, and impairing G2/M checkpoint as dysfunction of Cdc2 and Cyclin B1. Moreover, many cells were collapsed in mitosis catastrophe as a large number of disintegrating chromosomes, and apoptosis was significantly increased. Furthermore, the synergic effects of SCR-7 and X-ray were diminished by exogenous p53 overexpression. Therefore, we hypothesized p53 should be a major regulator of HR and TLS activation when HNEJ deficiency. Our studies indicated that patients with a loss function of p53 might benefit from SCR-7 and radiotherapy with fewer side effects.
Citation Format: Tingting Lin, Zhilian Zhou, Lifeng Zhu, Yandan Fan, Xiaofen Ding, Yingming Sun. DNA ligase IV inhibitor and X-ray exert a synthetic lethal in loss-of-function p53 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3066.
Abstract 3106: Roles of extracellular ATP in inducing cancer stem cell (CSC)-like changes in non-small lung cancer cell line
Authors: Song Jingwen , Chen Xiaozhuo 
Published: July 2021

Abstract
Cancer is a major death-causing disease worldwide, and metastasis, a hallmark of cancer, is associated with up to 90% of all cancer-related deaths. Metastasis requires ATP, and the tumor microenvironment (TME) has much higher concentrations of intratumoral and extracellular ATP (eATP) than healthy tissue, implying that eATP may have potential roles in tumor development and progression. Our previous ATP studies, cited by a Nature Review Cancer paper in 20181 showed that eATP is internalized by cancer cell through macropinocytosis, and it promotes cancer cell growth, survival, and drug resistance. However, how intratumoral eATP plays roles in metastasis remains largely unclear. Our 2019 published results show that eATP promotes cancer migration and invasion, initiates epithelial to mesenchymal transition (EMT), alters expression level of EMT related protein markers such as ZEB1, SNAIL, SLUG in human non-small lung cancer cell (NSCLC) lines2. It has been reported that the EMT and cancer stem cells (CSCs) share some molecular links, but the detailed mechanisms involved are still unknown. Recently, we have found the eATP significantly induces the protein expression level of CSC related makers in A549 cells. We have also found that, after A549 cells were treated with 0.5mM and 0.75mM ATP for 6 and 24 hours, the ATP treated A549 cells were able to show significantly increased colony numbers by soft agar colony formation assay. Based on all these results, we hypothesize that extracellular ATP functions as a messenger, a signal facilitator, an energy molecule, and a transcription cofactor to induce CSC-like features to promote metastasis in NSCLC. RNAseq and metabolomics studies are being used to determine the transcriptional and metabolic changes associated with the ATP induced CSC process in NSCLC. The completion of the study will not only unravel eATP's roles in CSC induction and early steps of tumor metastasis, but also potentially provide novel promising therapeutic targets for inhibiting tumor metastasis.(1) Di Virgilio, F., Sarti, A. C., Falzoni, S., De Marchi, E., & Adinolfi, E. (2018). Extracellular ATP and P2 purinergic signaling in the tumor microenvironment. Nature Reviews Cancer, 18(10), 601-618. (2) Cao, Y., Wang, X., Li, Y., Evers, M., Zhang, H., & Chen, X. (2019). Extracellular and macropinocytosis internalized ATP work together to induce epithelial-mesenchymal transition and other early metastatic activities in lung cancer. Cancer Cell International, 19(1).
Citation Format: Jingwen Song, Xiaozhuo Chen. Roles of extracellular ATP in inducing cancer stem cell (CSC)-like changes in non-small lung cancer cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3106.
Abstract 3127: A transcriptional lineage tracing approach to unravel crucial gene expression patterns in breast cancer progression
Authors: Roda Niccolò , Hillje Roman , Cheloni Stefano , Gambino Valentina , Blandano Giada , Falvo Paolo , Bertolini Francesco , Pelicci Pier Giuseppe 
Published: July 2021

Abstract
Breast cancer represents a major clinical hurdle, with intra-tumor heterogeneity and metastatic outcome accounting for poor prognosis. Traditionally, its poly-clonal structure was investigated through the genetic barcoding of cells followed by the tracing of the offspring. However, this analysis does not allow a solid investigation of the transcriptional profile associated to clones throughout tumor progression. In this work, we exploited a recently published library of expressed barcodes to perform both clonal and transcriptional tracing in breast cancer by single-cell RNA sequencing. To this aim, human breast cancer cell line MDA-MB-231 was transduced with the above mentioned library and orthotopically transplanted in immune-deficient mice. To analyze our data we generated a pipeline aimed at identifying the barcodes at single-cell level and subsequently sequenced more than 20000 cells in six independent primary tumors. Our clonal distribution analysis strongly suggested that clones within the same tumor possess different growth potential. Furthermore, we found that breast tumors show a transcriptional heterogeneity characterized by two major transcriptional patterns: highly proliferating cells on one side, and stressed and dormant cells on the other. Notably, breast cancer clones were shown to belong to one of these two patterns, therefore suggesting that primary tumors are composed of both proliferative and non-proliferative clones. Interestingly, although the non-proliferative clones outnumbered the proliferative ones, the two different transcriptional patterns do not differ in terms of absolute number of cells. Analyses of breast cancer metastases to lungs and liver revealed that the clones that spread metastases belong to both the transcriptional patterns identified in the primary tumor. Interestingly, the metastatic clones were found to be rare in the primary tumors and shared between the two colonized organs. In addition, metastases recapitulated the same transcriptional heterogeneity of primary tumors, despite being composed of a much lower number of clones. Altogether, these findings represent an intriguing launching pad for the identification of the transcriptional markers whose inhibition may counter the metastatic outcome.
Citation Format: Niccolò Roda, Roman Hillje, Stefano Cheloni, Valentina Gambino, Giada Blandano, Paolo Falvo, Francesco Bertolini, Pier Giuseppe Pelicci. A transcriptional lineage tracing approach to unravel crucial gene expression patterns in breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3127.
Abstract 3154: Host and neoplastic cell Axl inhibition impair prostate and breast cancer bone metastasis
Authors: Tanaka Mai , Siemann Dietmar W. 
Published: July 2021

Abstract
Prostate and breast cancers are the most prevalent and the second leading causes of cancer-deaths for men and women in the United States. Cancer survival rates generally worsen significantly with advanced and disseminated disease with nearly 90% of all cancer deaths resulting from metastasis. For breast and prostate cancers, bone is the most common site of metastasis. A key signaling pathway involved in metastatic dissemination of tumor cells is the receptor tyrosine kinase Axl. Axl belongs to the Tyro3, Axl, and MerTK (TAM) subfamily, is expressed in a variety of tumor types, including breast and prostate, and is associated with poor prognosis, metastasis, and outcome. The goal of the present study was to characterize the role of Axl signaling in prostate and breast cancer cell dissemination to bone. This was accomplished using Axl knockdown neoplastic cells, a selective small molecule Axl inhibitor (BGB324), and osteoclast progenitor cells in vitro, as well as intracardiac injection of Axl knockdown tumor cells in vivo. The results showed that Axl inhibition significantly decreases tumor cell migration and invasion in vitro, and suppression of Axl signaling in osteoclast precursor cells reduces the formation of mature osteoclasts. In vivo, Axl knockdown in prostate and breast cancer cells significantly suppressed the formation of neoplastic bone lesions. Taken together our findings indicate that therapeutic targeting of Axl may impair tumor metastasis to the bones through neoplastic and host cell signaling axes.
Citation Format: Mai Tanaka, Dietmar W. Siemann. Host and neoplastic cell Axl inhibition impair prostate and breast cancer bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3154.
Abstract 3195: Hijacked senescence secretomes as 'immune primers' of antiangiogenic TKI efficacy
Authors: Dolan Melissa , Shi Yuhao , Hill James W. , Mastri Michalis , Vaghi Cristina , Barbi Joseph , Benzekry Sebastien , Ebos John M. 
Published: July 2021

Abstract
VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) and immune checkpoint inhibitors (ICIs) are approved together as a treatment regimen for multiple metastatic cancers, yet the mechanistic basis for this combinatory benefit remains unclear. Previously we have shown that resistance to VEGFR TKI treatment can transiently hijack the secretory machinery typically associated with senescence - the process of cellular aging. Here we report that these senescence-associated secretory programs can also drive immune cell activation, potentially ‘priming' the tumor for PD-1 pathway inhibition. Using a novel live-cell sorting method based on C12FDG - a substrate for senescence-associated beta-galactosidase activity - we isolated senescence-marker (SM) expressing VEGFR TKI-treated cells for transcriptomic analysis. SM+ cell populations were enriched for senescence, immune, and interferon secretory processes, with a unique gene signature validated using published preclinical and clinical datasets. Notably, SM+ cells were found to be more sensitive to CD8 T-cell mediated tumor inhibition in vivo and ex vivo and be sensitive to PD-L1 blockade and inhibitors of mTOR, a key secretory regulator. Together, these results suggest VEGFR TKI controlled secretory programs contributing to resistance can simultaneously prime the tumor microenvironment for immune cell activation, providing an explanation for improved effects of antiangiogenic and immunotherapy combinations in patients.
Citation Format: Melissa Dolan, Yuhao Shi, James W. Hill, Michalis Mastri, Cristina Vaghi, Joseph Barbi, Sebastien Benzekry, John M. Ebos. Hijacked senescence secretomes as 'immune primers' of antiangiogenic TKI efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3195.
Abstract 326: Structural dynamics-based hit generation to disrupt YAP/TAZ-TEAD protein-protein interaction
Authors: Du Lin , Liu Jing , Zeng Qinglong , Xu Ming , Lu Jiting , Zheng Qiangang , Zhu Jidong 
Published: July 2021

Abstract
The Hippo pathway is an evolutionarily conserved pathway involved in developmental biology. The biological functions of Hippo pathway are executed by the downstream transcriptional coactivator YAP/TAZ, which shuttle between the cytoplasm and the nucleus and have to interact with TEADs in nucleus for transcription activation. YAP/TAZ are master transcriptional factors widely activated in human cancers to promote cancer initiation, progression, metastasis and therapy resistance. It has been shown that aberrant YAP/TAZ activation is also associated with the adapted tumor microenvironment (TME) for tumor growth. Dysregulation in Hippo pathway and YAP/TAZ-TEADs transcriptional activity is pervasively associated with various types of cancers, including mesothelioma, squamous cell cancers, liver cancer and lung cancer, making it an attractive target for cancer therapy. Therefore, inhibition of YAP/TAZ oncogenic activity by blocking YAP/TAZ-TEADs interaction is an effective approach for cancer treatment. In this study, we aim to discover small molecule inhibitors that bind to TEADs and disrupt YAP/TAZ-TEADs interaction for cancer therapy. With superposition of all the available crystal structures of four TEAD subtypes in the public database, we found the YAP Ω loop binding site of TEADs is relatively rigid (of backbone atoms), but the side chain flexibility of K289, K265 and V406 in TEAD1 affects the shape of the binding site significantly. Notably, in two TEAD2 structures, e.g. PDB ID: 5dqe and 5dq8, K301 (K274 of TEAD1) adopts an open conformation and accommodates a flufenamic acid to bind in an induced pocket. Using 5dq8 as the protein model, we virtually screened a fragment library, and identified a hit compound that is suitable to combine with flufenamic acid. Interaction between the hit compound and TEAD1 was confirmed by 1D-NMR (STD). Based on the docking poses, we combined the hit and flufenamic acid, designed and synthesized several compounds. Interaction with TEAD1 of the compounds were confirmed by 1D-NMR, SPR and HTRF. Crystal structures of representative compounds confirmed the predicted binding mode in TEAD1. With further medicinal chemistry efforts, we have discovered a series of novel YAP/TAZ-TEAD PPI inhibitors bound at the Ω loop site of TEAD1.
Citation Format: Lin Du, Jing Liu, Qinglong Zeng, Ming Xu, Jiting Lu, Qiangang Zheng, Jidong Zhu. Structural dynamics-based hit generation to disrupt YAP/TAZ-TEAD protein-protein interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 326.
Abstract 329: Targeting an emerging oncogenic biomarker, heparanase
Authors: Cui Lina 
Published: July 2021

Abstract
Heparan sulfate proteoglycans (HSPGs), major components in the extracellular matrix (ECM) of all tissue types, maintain ECM structural integrity and regulate cellular signaling via binding with ECM components and protein ligands such as growth factors and chemokines. Heparanase, the only known enzyme that can cleave the heparan sulfate (HS) side chains of HSPGs, regulates many cellular processes including ECM remodeling and homeostasis of cell-associated HS, and controls the bioavailability and activity of molecules attached to HS. The expression of heparanase is significantly elevated in almost all cancer types, and increased heparanase activity is mostly linked with increased angiogenesis, metastasis, and shortened post-surgery survival. Our research focuses on the development of molecular tools that can target and visualize the spatiotemporal activities of heparanase in both cells and living organisms. We have applied our molecular probes of heparanase towards cancer diagnostics and drug discovery.
Citation Format: Lina Cui. Targeting an emerging oncogenic biomarker, heparanase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 329.