bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2977: Organoid-T-cell co-cultures for preclinical testing of adoptive cell and cancer immunotherapy
Authors: Hombrink Pleun , Mardpour Soura , Spaan Ewout , Hanrath Jarmil , Pourfarzad Farzin , Mullenders Jasper , Overmeer Rene , Robert G.J , Vries  , Sylvia F , Boj  
Published: July 2021

Abstract
Recent advances in cancer immunotherapy had a positive impact on the life expectancy of patients with a large range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy. Challenges range from lack of confidence in animal cancer models, inter-tumor heterogeneity and the absence of cellular microenvironment. Hubrecht Organoid Technology (HUB) offers an innovative alternative, build on the discovery that adult stem cells proliferate and organize into three-dimensional organotypic structures when they are embedded into Matrigel. HUBOrganoids™ are generated from healthy and disease tissues and stored as “living” biobanks with high quality and reproducibility. HUB Organoids recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity, and morphological and functional traits. HUB has developed organoid-T-cell co-culture systems that allow a physiologic representation of the complexity of interactions in the tumor microenvironment, which is important for evaluating the effects of novel therapies. HUB offers an innovative platform combining image-based analysis with flow cytometry to visualize and quantify T-cell-tumor interactions as well as measurements of T-cell cytotoxicity against tumor (and normal-matched) organoids for colorectal and several other cancers. Our platform offers a powerful strategy for the development and validation of cancer immunotherapy and may help to screen the efficacy of immune checkpoint blockade or bispecific antibodies. In addition, cancer organoid-T-cell co-culture may also predict the functionality of tumor-infiltrating lymphocytes (TIL) and chimeric antigen receptor (CAR)-engineered T cells. As such, our platform offers opportunities in preclinical development and could become a diagnostic tool to predict individual patient response to immunotherapy.
Citation Format: Pleun Hombrink, Soura Mardpour, Ewout Spaan, Jarmil Hanrath, Farzin Pourfarzad, Jasper Mullenders, Rene Overmeer, G.J Robert, Vries, F Sylvia, Boj. Organoid-T-cell co-cultures for preclinical testing of adoptive cell and cancer immunotherapy [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 2977.
Abstract 2993: Intraductal xenografts model ERα-positive invasive lobular carcinoma of the breast
Authors: Sflomos George , Battista Laura , Aouad Patrick , De Martino Fabio , Scabia Valentina , Stravodimou Athina , Ayyanan Ayyakkannu , Ifticene-Treboux Assia ,   RLS, Bucher Philipp , Fiche Maryse , Ambrosini Giovanna , Brisken Cathrin 
Published: July 2021

Abstract
Invasive lobular carcinoma (ILC) is the most frequent special histological subtype of breast cancer, typically characterized by loss of E-cadherin. It has clinical features distinct from other estrogen receptor-positive (ER+) breast cancers but the molecular mechanisms underlying its characteristic biology are poorly understood because we lack experimental models to study them. By xenografting lobular cells to the milk ducts, we recapitulate the human disease, including invasion and metastasis to clinically relevant organs. Using patient-derived intraductal xenografts from lobular and non-lobular ER+ HER2- tumors to compare global gene expression we identify extracellular matrix modulation as a lobular carcinoma cell-intrinsic trait. Analysis of TCGA patient datasets shows matrisome signature is enriched in lobular carcinomas with overexpression of elastin, collagens, and the collagen modifying enzyme LOXL1. Pharmacological treatment and silencing of LOXL1 expression decrease tumor growth, invasion, and metastasis by disrupting ECM structure resulting in decreased ER signaling. We conclude that LOXL1 inhibition is a promising therapeutic strategy for ILC. This is the first study of a hormone-responsive ER+ preclinical lobular model that mimics their clinical counterparts and opens opportunities for the development and evaluation of therapies.
Citation Format: George Sflomos , Laura Battista, Patrick Aouad, Fabio De Martino, Valentina Scabia, Athina Stravodimou, Ayyakkannu Ayyanan, Assia Ifticene-Treboux, RLS, Philipp Bucher, Maryse Fiche, Giovanna Ambrosini, Cathrin Brisken. Intraductal xenografts model ERα-positive invasive lobular carcinoma of the breast [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 2993.
Abstract 305: ELU001, a targeted C'Dot drug conjugate (CDC) for the treatment of folate receptor alpha (FRα) overexpressing cancers
Authors: Adams Gregory Paul , Ma Kai , Venkatesan Aranapakam , Chen Feng , Wu Fei , Turker Melik , Gardinier Thomas , Chen Peiming , Patel Vaibhav , Bayever Eliel , Rudick Paul , Germano Geno 
Published: July 2021

Abstract
CDCs are novel ultra-small (6-7 nm) nanoparticle drug conjugates that have been demonstrated to be capable of faster tumor targeting and deeper tumor penetration than antibody drug conjugates in animal models. CDCs are capable of targeting tumors in the brain and pancreas that are difficult to access, while exhibiting limited exposure to normal tissues due their efficient renal elimination. CDCs are composed of a silica core, in which Cy5, a far red dye is covalently encapsulated. The silica core is covalently coated with a layer of polyethylene glycol which is then functionalized with targeting moieties and payloads. ELU001 is a CDC functionalized with ~20 molecules of the topoisomerase-1 inhibitor exatecan linked via a proteolytic cleavable linker as a payload and ~15 folic acids to provide targeting to FRα overexpressing cancers. ELU001 is rapidly internalized into FRα expressing cells and is trafficked to the lysosome where the payload is released from the CDC. ELU001 exhibits potency in the low single digit nanomolar to sub-nanomolar range against cancer cells that express 3+ (KB, IGROV-1) and 2+ (SK-OV-3, HCC827 and OVCAR-3) levels of FRα after a 6-hr exposure in a 7-day viability study. In contrast, an anti-FRα ADC based ADC mirvetuximab soravtansine exhibits lower potency (&gt;100 nM IC50) against SK-OV-3 and HCC827 cells and 40 nM IC50 against OVCAR-3 cells. ELU001 exhibits potent efficacy against established s.c. KB human cervical tumor xenografts in immunodeficient mice with significantly better efficacy and safety than free exatecan payload. It is also effective in treating established SK-OV-3 tumors with lower (2+) FRα expression, a setting where the ADC is again less effective. IND-enabling nonclinical studies are currently underway to prepare for initiation of a first-in-human phase 1 clinical trial in subjects with FRα overexpressing cancers in the second half of 2021.
Citation Format: Gregory Paul Adams, Kai Ma, Aranapakam Venkatesan, Feng Chen, Fei Wu, Melik Turker, Thomas Gardinier, Peiming Chen, Vaibhav Patel, Eliel Bayever, Paul Rudick, Geno Germano. ELU001, a targeted C'Dot drug conjugate (CDC) for the treatment of folate receptor alpha (FRα) overexpressing cancers [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 305.
Abstract 3070: Lung cancer TTFields treatment planning sensitivity to errors in torso segmentation
Authors: Atya Hadas Ben , Peles Oren , Shamir Reuben , Bomzon Zeev 
Published: July 2021

Abstract
Introduction: Tumor Treating Fields (TTFields) is a treatment modality for glioblastoma multiforme (GBM) and other malignant tumors, utilizing low-intensity, intermediate frequency (100-300kHz) alternating electric field delivered through noninvasive transducer arrays. TTFields are currently being tested in a phase III clinical trial for the treatment of advanced Non-Small Cell Lung Cancer (NSCLC). Previous studies have demonstrated that the treatment efficacy increases when the dose of TTFields delivered to the tumor is at least 1 V/cm. Thus, personalized simulations to estimate the dose are performed as part of the patient treatment planning. For NSCLC treatment, these simulations require the segmentation of torso tissues. We are currently developing a semi-automatic software for the segmentation of these tissues. Achieving highly accurate segmentation is time consuming and not always necessary. Therefore, in this study we assess the level of segmentation accuracy that is required for TTFields dose estimation.
Methods: We introduce a novel pipeline for evaluating the sensitivity of TTFields treatment planning errors in the segmentation of torso tissues. To this end, we incorporated an expert-segmented torso volume and artificially placed NSCLC tumors of different sizes in the vicinity of the tested torso tissue. We employed relaxations to the segmentation algorithm and derived the TTFields distribution with and without the simulated segmentation errors. We then computed the treatment planning error as the per-voxel average deviation of the TTFields dose computed over the erroneous segmentation from the reference one. The dose was calculated over the simulated tumor location and over the entire lung volume.
Results: We have evaluated our sensitivity analysis pipeline on 9 different test cases. Based on previous analysis, we have set our tolerable target error to be 0.1 V/cm. Our results show that 6 out of the 9 tests were within the target, whereas the other 3 exceeded the target, requiring algorithmic refinements.
Conclusions: We have presented a method for estimating the sensitivity of lung cancer TTFields treatment planning to segmentation errors. This method is used to evaluate the required accuracy of the semi-automatic torso segmentation tool that we are currently developing. Our method can be further extended to other types of tumors in different regions of the body.
Citation Format: Hadas Ben Atya, Oren Peles, Reuben Shamir, Zeev Bomzon. Lung cancer TTFields treatment planning sensitivity to errors in torso segmentation [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 3070.
Abstract 3170: Targeting tumor-associated astrocyte dependence in glioblastoma treatment
Authors: Domino Joseph S. , Alvarado Anthony , Arnold Levi , Gunewardena Sumedha , Akhavan David , Thomas Sufi M. 
Published: July 2021

Abstract
Glioblastoma (GBM) is the most common malignant primary brain tumor and remains challenging to treat due to its aggressive nature with high rate of recurrence. Despite advances in therapy, prognosis is poor with median survival of 19 months with maximal therapy. The normal astrocytes within the GBM TME undergo a phenotypic shift, promoting alterations supportive of tumor growth. There is increasing attention on the role of tumor-associated astrocytes (TAA) in GBM progression and resistance to therapy. Previous studies assessing astrocyte support of GBM employ astrocytes derived from murine or fetal sources. We have isolated TAAs from patients with GBM as well as normal human astrocytes (NHA) from cancer-free patients undergoing surgical treatment of epilepsy. The cells are maintained at a low passage number (&lt;10 passes). Our data emphasize the supportive role these cells in GBM progression and resistance to GBM therapy. Briefly, conditioned media (CM) from non-malignant, GFAP positive TAAs, demonstrate a propensity to induce invasion and migration of U87 GBM cells compared to the NHA CM. In addition, TAA CM significantly increased the IC50 dose of U87 cells treated with temozolomide from 536 μM to 1351 μM demonstrating treatment resistance (p&lt;0.001). TAA CM induced temozolomide resistance of the GBM cells can be abolished with supra-therapeutic dosing. RNA sequencing (RNAseq) of two TAA and three NHA samples revealed 399 differentially expressed genes identified with 38 of those upregulated genes coding extracellular products. Expression data was verified by quantitative polymerase chain reaction (qPCR), thus validating the differential expression profile generated by RNAseq. The differential expression data was explored further using Ingenuity Pathway Analysis (IPA) and gene set enrichment analysis (GSEA). Attention was focused on genes with excreted factors as products or involved in the regulation of critical excreted products. We identified and validated high expression of IL1β in TAAs compared to NHAs. RNAseq data revealed multiple potential pathways for targeted therapies aimed at modulating the effect of TAAs in the tumor microenvironment. In ongoing studies, we will determine the efficacy of IL1β in attenuating the TAA-induced temozolomide resistance in GBM. These studies reveal for the first time a highly clinically relevant approach to attenuate TAA-facilitated GBM progression and therapy resistance.
Citation Format: Joseph S. Domino, Anthony Alvarado, Levi Arnold, Sumedha Gunewardena, David Akhavan, Sufi M. Thomas. Targeting tumor-associated astrocyte dependence in glioblastoma treatment [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 3170.
Abstract 336: Gut microbiome predicts response to CDK4/6 inhibitor and immune check point inhibitor combination in patients with hormone receptor positive metastatic breast cancer
Authors: Wong Chi Wah , Yost Susan E. , Lee Jin Sun , Highlander Sarah K. , Yuan Yuan 
Published: July 2021

Abstract
Background: CDK4/6 inhibitors (CDK4/6i) have been shown to modulate immune responses in the preclinical setting. Palbociclib is a front-line therapy for hormone receptor positive (HR+) metastatic breast cancer (MBC), and the combination with immune check point inhibitors (ICI) is increasingly being studied. An ongoing phase I trial was designed to test the safety and efficacy of palbociclib, pembrolizumab, and letrozole in postmenopausal women with HR+ HER2- MBC (NCT02778685). Stool microbiome was collected and analyzed. The aim of this study is to determine the association of gut microbiota and response using metagenome sequencing data through a machine learning model.
Methods: Postmenopausal women with histologically proven stage IV HR+ HER2- MBC were enrolled. Stool samples were collected at baseline and during treatment for analysis using metagenome sequencing. Response per RECIST 1.1 were grouped into: responders (complete response or partial response) and non-responders (stable disease or progressive disease). Using metagenomic relative abundance data, a gradient-boosted tree model was developed with leave-one-patient-out cross validations to predict patient response at baseline. Kruskal-Wallis tests were used to assess the differences of the most important microbiota relative abundance (generated from the machine learning model) between responders and non-responders.
Results: Forty-seven stool samples from 11 patients were collected at baseline and during treatment, and metagenome sequencing was performed. For predictive modeling, the validation Area Under the Receiver Operating Characteristic Curve (AUROC) and Area Under the Precision Recall Curve (AUPRC) were 0.71 and 0.83, respectively. Among the top 5 features from the model, patients with a larger relative abundance of Gemmiger formicillis have increased probability of responding to therapy (p&lt;0.05 uncorrected), whereas an increase of Bacteroides vulgatus have reduced probability of responding to therapy (p&lt;0.05 uncorrected). The relative abundance of Gemmiger formicillis at baseline has been reported in recent studies to be higher in patients with long term benefit (Aarnoutse et al. 2017). Thus, there is increasing evidence that gut microbiota plays a role in the pathogenesis of breast cancer and response of MBC patients to systemic cancer therapy.
Citation Format: Chi Wah Wong, Susan E. Yost, Jin Sun Lee, Sarah K. Highlander, Yuan Yuan. Gut microbiome predicts response to CDK4/6 inhibitor and immune check point inhibitor combination in patients with hormone receptor positive metastatic breast cancer [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 336.
Abstract 39: APOBEC3A drives acquired resistance to targeted therapies in non small cell lung cancer
Authors: Isozaki Hideko , Abbasi Ammal , Nikpour Naveed , Langenbucher Adam , Su Wenjia , Stanzione Marcello , Sequist Lecia V. , Buisson Rémi , Lawrence Michael S. , Hata Aaron N. 
Published: July 2021

Abstract
Acquired drug resistance to even the most effective anti cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes or simply provides the selective pressure necessary for the outgrowth of drug resistant clones remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy induced A3A mutagenesis either by gene deletion or RNAi mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non small cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.
Citation Format: Hideko Isozaki, Ammal Abbasi, Naveed Nikpour, Adam Langenbucher, Wenjia Su, Marcello Stanzione, Lecia V. Sequist, Rémi Buisson, Michael S. Lawrence, Aaron N. Hata. APOBEC3A drives acquired resistance to targeted therapies in non small cell lung cancer [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 39.
Abstract 43: Discovery of ARV-110, a first in class androgen receptor degrading PROTAC for the treatment of men with metastatic castration resistant prostate cancer
Authors: Snyder Lawrence B. , Neklesa Taavi K. , Chen Xin , Dong Hanqing , Ferraro Caterina , Gordon Deborah A. , Macaluso Jennifer , Pizzano Jennifer , Wang Jing , Willard Ryan R. , Vitale Nicholas , Peck Ron , Moore Marcia Dougan , Crews Craig M. , Houston John , Crew Andrew P. , Taylor Ian 
Published: July 2021

Abstract
Prostate cancer is the second leading cause of cancer death in men in the United States. The androgen receptor (AR) plays critical roles in both early disease and advanced prostate cancer. Current therapeutic approaches targeting the androgen/AR axis are initially effective, but castration resistant prostate cancer (CRPC) inevitably develops. CRPC is tightly linked with increased AR activity via gene overexpression, amplification, and gain-of-function mutations. To address these mechanisms of AR-dependent prostate tumor growth, we have developed a novel therapeutic agent, ARV-110, a proteolysis targeting chimera (PROTAC®) that induces a protein-protein interaction between the AR and E3 ubiquitin ligase complexes, leading to the ubiquitination of AR and its subsequent degradation via the proteasome. In vitro, ARV-110 robustly degrades AR in various prostate cancer cell lines with a half-maximal degradation concentration (DC50) of ~1 nM. Whole cell lysate proteomics and ubiquitin proteomics demonstrated high selectivity for AR in VCaP cells. ARV-110 potently downregulates androgen responsive genes, inhibits proliferation and induces apoptosis in AR dependent prostate cancer cells. In vivo, ARV-110 is orally bioavailable and robustly degrades AR with a &gt;90% observed maximum degradation (Dmax) at efficacious doses. ARV-110 significantly and dose-dependently inhibits tumor growth in murine LNCaP and VCaP xenograft models, including enzalutamide-resistant VCaP and enzalutamide-insensitive patient-derived xenograft models. These preclinical data supported the clinical development of ARV-110 for the treatment of men with metastatic CRPC. The discovery, chemical structure and initial clinical data of ARV-110 will be presented
Citation Format: Lawrence B. Snyder, Taavi K. Neklesa, Xin Chen, Hanqing Dong, Caterina Ferraro, Deborah A. Gordon, Jennifer Macaluso, Jennifer Pizzano, Jing Wang, Ryan R. Willard, Nicholas Vitale, Ron Peck, Marcia Dougan Moore, Craig M. Crews, John Houston, Andrew P. Crew, Ian Taylor. Discovery of ARV-110, a first in class androgen receptor degrading PROTAC for the treatment of men with metastatic castration resistant prostate cancer [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 43.