bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1665: Humanized mice for preclinical efficacy evaluation of drugs targeting CD73
Authors: Liu Xing , Ju Cunxiang , Sun Hongyan , Zhao Jing , Gao Xiang , Li Zhiying 
Published: June 2022

Abstract
CD73 expressed in Treg surface facilities the hydrolysis of AMP into adenosine which inhibits the activation, expansion and homing of T effector cells.Therapeutic efficiency of CD73 mAb had been studied in C57BL/6 and BALB/C mice xenografted with several murine cancer cell lines. However, for human CD73 mAb with no binding to murine CD73, CD73 humanized mouse models are essential for medicinal development.We established CD73 humanized mouse model (hCD73) on C57BL/6 and BALB/c background in which the mCD73 was replaced with hCD73. Similar expression level of hCD73 in peripheral blood was observed compared with mCD73 in wildtype mice. Besides, the proportion of T, B and NK cells in spleen of hCD73 mice were also analogy to that in wildtype mice. After treating with anti-hCD73 antibody, tumor growth was inhibited in our CT-26-hCD73 tumor model.Furthermore, hPD1/hPDL1/hCD73 mouse models were also established on C57BL/6 and BALB/c backgrounds based on hCD73 mice. However, a better anti-tumor effect of anti-CD73 antibody was found on BALB/c-hPD1/hPDL1/hCD73 bearing CT26 than that on B6-hPD1/hPDL1/hCD73 bearing MC38. Besides, Combination of anti-CD73 and anti-PD1 significant elevated anti-tumor effect comparing with anti-CD73 and anti-PD1 mono therapy in BALB/c-hPD1/hPDL1/hCD73 mice bearing CT26-hPDL1hCD73.In conclusion, BALB/c-hPD1/hPDL1/hCD73 is a well efficient mouse model for therapeutic effect study of anti-CD73 and relevant combination therapy.
Citation Format: Xing Liu, Cunxiang Ju, Hongyan Sun, Jing Zhao, Xiang Gao, Zhiying Li. Humanized mice for preclinical efficacy evaluation of drugs targeting CD73 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1665.
Abstract 167: Pre-clinical characterization of a novel series of FGFR2 selective inhibitors with potency against clinically relevant mutations
Authors: Fischer John , Bouhana Karyn , Chicarelli Mark J. , Dahlke Josh , Fell Brad , Fulton Jennifer , Guarnieri Anna , Jalluri Ravi , Johnson Amber , Mclean Brent , Mejia Max , Rieger Rob , Robinson John , Rodriguez Mareli , Sullivan Francis , Wang Yang , Winski Shannon , Zhou Yeyun 
Published: June 2022

Abstract
The fibroblast growth factor receptor (FGFR) family of protein tyrosine kinases plays a role in many physiological processes including angiogenesis and wound healing. FGFR mutations, fusions, rearrangements, and amplifications have been linked to the pathogenesis of multiple tumor types. For example, approximately 10-15% of patients with intrahepatic cholangiocarcinoma have FGFR2 fusions, and amplification of FGFR2 is prevalent in gastric cancer and implicated in tumor growth. Approved FGFR inhibitors produce responses in patients that harbor FGFR genetic alterations but show reduced activity against key mutations (e.g., V565, N550, etc.). These pan-FGFR inhibitors also frequently show dose-limiting toxicities including hyperphosphatemia which can be linked to the inhibition of FGFR1. To address these issues, a novel series of FGFR inhibitors that are potent and selective reversible inhibitors of FGFR2 with selectivity over FGFR1 have been identified. This series also maintains activity against clinically relevant mutations in the FGFR2 protein. Inhibition of cellular FGFR phosphorylation was measured using engineered cell lines to demonstrate that the inhibitors target both wild-type FGFR2 and activating FGFR2 mutations while sparing FGFR1. In addition, CDX tumor models showed in vivo target engagement and FGFR isoform selectivity. Herein, the in vitro and in vivo characterization of a representative selective reversible FGFR2 inhibitor is described.
Citation Format: John Fischer, Karyn Bouhana, Mark J. Chicarelli, Josh Dahlke, Brad Fell, Jennifer Fulton, Anna Guarnieri, Ravi Jalluri, Amber Johnson, Brent Mclean, Max Mejia, Rob Rieger, John Robinson, Mareli Rodriguez, Francis Sullivan, Yang Wang, Shannon Winski, Yeyun Zhou. Pre-clinical characterization of a novel series of FGFR2 selective inhibitors with potency against clinically relevant mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 167.
Abstract 1691: The landscape of intra-tumor heterogeneity (ITH) and its association with actionable mutation and blood tumor mutation burden (bTMB) in patients with non-small cell lung cancer (NSCLC) assessed by circulating tumor DNA (ctDNA)
Authors: Kim Leeseul , Lee Yeun Ho , Kim Hye Sung , Choi Horyun , Kim Jinah , Chae Young Kwang 
Published: June 2022

Abstract
Background: ITH, which is caused by subpopulations of cells with distinct genomic alterations within the same tumor is known to have an impact on the biological profile and natural history of the tumor. However, assessment of ITH is mostly done tissue-based. Herein, we investigated the correlation of ITH assessed by ctDNA with bTMB and the presence of actionable mutations.
Method: Blood samples were collected from consecutive 53 patients with NSCLC seen at Northwestern Memorial Hospital. For each sample, SNV, indel, and CNV results generated by sequencing of all plasma ctDNA (Guardant360) were formatted for PyClone. ITH scores were calculated using the number of clusters identified in the sample divided by the number of variants detected in the sample.
Result: bTMB was evaluable for 22 patients (41%). 7 patients (13%) had actionable mutations associated with FDA-approved therapies. Cluster number was positively correlated with bTMB (Pearson r 0.69, p-value 0.0004, CI 0.38 to 0.86) and was negatively correlated with the presence of actionable mutations (median 2 vs 5, p-value 0.01). ITH scores were not significantly correlated with bTMB (Pearson r 0.03, p-value 0.89, CI -0.39 to 0.44).
Conclusion: Higher cluster number was inversely correlated with the presence of actionable mutations and positively correlated with bTMB. Our study illustrates the importance of utilizing liquid biopsy to assess ITH with tissue-based ITH in clinics for a better understanding of the biological profile of tumor.
Citation Format: Leeseul Kim, Yeun Ho Lee, Hye Sung Kim, Horyun Choi, Jinah Kim, Young Kwang Chae. The landscape of intra-tumor heterogeneity (ITH) and its association with actionable mutation and blood tumor mutation burden (bTMB) in patients with non-small cell lung cancer (NSCLC) assessed by circulating tumor DNA (ctDNA) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1691.
Abstract 1701: Single-cell multi-omic profiling and clonal tracing of the human gynecological tumor microenvironment
Authors: Liu Vincent , Sandor Katalin , Daniel Bence , Berthoin Lionel , Sabri Shan , Panagiotopoulou Sofia , Yin Yajie , Hiam-Galvez Kamir , Sit Rene , Fan Zi , Galvin Brendan , Khan Omar , Bezman Natalie , Grogan Jane , Howitt Brooke , Zheng Grace , Lareau Caleb , Satpathy Ansuman 
Published: June 2022

Abstract
Tumor initiation and progression are the result of a close interplay between malignant cells and immune cells. While single-cell genomics has enabled the molecular dissection of the cellular heterogeneity underlying complex cancers, many facets of tumor microenvironments remain unresolved. In particular, the ontogeny of myeloid cells have not been fully understood in human tumors, although the source and expansion of macrophages have been suggested to underlie tumor development and metastasis in mice. In an effort to comprehensively characterize these tumor microenvironments, we profiled endometrial, ovarian, and metastatic tumors from 16 patients using CITE-seq (an atlas of 258,810 cells) and mitochondrial single-cell ATAC-seq (mtscATAC-seq; consisting of 173,820 cells). Our multi-omic analyses reveal the heterogeneity of tumor-infiltrating immune cells at clonal, epigenetic, transcriptomic, and proteomic levels. Notably, all tumor types harbored diverse exhausted T cell subsets, including terminal and precursor exhausted T cells, and gamma/delta T cells. Clonal somatic variant analysis between tumor tissues and peripheral blood mononuclear cells identified blood-derived monocytes, rather than embryonically derived cells, as the origin of macrophages within gynecological tumors. Further, our analyses show that macrophages expand minimally within the tumor microenvironment, suggesting that they may be continuously replenished by blood, an observation that may facilitate new approaches for cancer immunotherapy. In total, our dataset represents the first multi-modal single cell atlas of gynecologic tumors and reveals distinct features of T cell heterogeneity and myeloid expansions in complex tumor microenvironments.
Citation Format: Vincent Liu, Katalin Sandor, Bence Daniel, Lionel Berthoin, Shan Sabri, Sofia Panagiotopoulou, Yajie Yin, Kamir Hiam-Galvez, Rene Sit, Zi Fan, Brendan Galvin, Omar Khan, Natalie Bezman, Jane Grogan, Brooke Howitt, Grace Zheng, Caleb Lareau, Ansuman Satpathy. Single-cell multi-omic profiling and clonal tracing of the human gynecological tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1701.
Abstract 1762: A novel antibody drug conjugate linker enabling production of ADCs with high drug to antibody ratios and fast payload release for improved efficacy
Authors: Luong Noemie , Bellocq Nathalie , Marx Leo , Pantin Mathilde , Tchumi Benjamin , Roubaudi-Fraschini Marie-Claude , Riff Camille , Mutter Manfred , Attinger Antoine 
Published: June 2022

Abstract
Antibody drug conjugates (ADCs) represent an attractive approach to bring very cytotoxic drugs into tumors while avoiding systemic toxicities. Currently, most commercially available ADCs come with toxicities associated with the nonspecific release of the payload in the circulation. We have developed a novel drug multi-linker technology that enables the generation of stable and potent ADCs. It is selectively recognized and cleaved by the carboxydipeptidase activity of Cathepsin B that has been shown to be overexpressed in cancer cells. The technology allows for a fast and specific cleavage, which results in efficient drug release in the tumor. Different payloads can be attached to antibodies, and the drug to antibody ratio (DAR) can be modulated up to DAR16, resulting in customed cytotoxic activity. Here we characterize the properties of the multi-linker using different payloads, different DARs, and trastuzumab as the targeting antibody. Trastuzumab based multi-linker ADCs were generated and tested in vitro and in vivo. The linker-payload kinetic release and the cytotoxicity of these ADCs were assessed in vitro. Pharmacokinetic (PK) and pharmacodynamic properties of selected multi-linker ADCs were then investigated in relevant in vivo models and compared to trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-Dxd). Trastuzumab based multi-linker ADCs were shown to efficiently target Her2 expressing cells. In vitro, increasing the DAR had a positive effect on cytotoxicity. In a breast cancer model expressing low levels of Her2, a trastuzumab based multi-linker ADC with mertansine (DM1) at DAR8 showed superior activity, including complete tumor regressions, as compared to T-DM1 and T-Dxd and was well tolerated. In addition, the trastuzumab based multi-linker ADCs showed total antibody PK profiles comparable to T-DM1 and good stability in plasma. In conclusion, these results demonstrate that this novel linker technology can be used to produce stable and high DAR ADCs with improved efficacy.
Citation Format: Noemie Luong, Nathalie Bellocq, Leo Marx, Mathilde Pantin, Benjamin Tchumi, Marie-Claude Roubaudi-Fraschini, Camille Riff, Manfred Mutter, Antoine Attinger. A novel antibody drug conjugate linker enabling production of ADCs with high drug to antibody ratios and fast payload release for improved efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1762.
Abstract 1797: Bcl-2 up-regulation mediates taxane resistance downstream of APC loss
Authors: Maloney Sara , Zabala Sarah , Richmond Grace , Prosperi Jenifer R. 
Published: June 2022

Abstract
Patients with triple negative breast cancer (TNBC) are treated with traditional chemotherapy, such as paclitaxel (PTX). Despite the efficacy of taxanes, many tumors will recur due to drug resistance. Therefore, the need to understand the mechanism behind drug resistance is critical to improve patient outcome and survival. Our lab was the first to show that loss of the Adenomatous Polyposis Coli (APC) tumor suppressor caused resistance to PTX in the MDA-MB-157 human TNBC cell line. In the absence of APC, apoptosis induction was decreased, as measured through cleaved caspase 3 and annexin/PI staining. To understand the molecular mechanisms behind APC-mediated PTX response, we analyzed the BCL-2 family of proteins and found a robust increase of the pro-survival family member, Bcl-2. The BH3 mimetic, ABT-199 (Venetoclax), which specifically targets Bcl-2, has been used as a single or combination therapy in multiple hematologic malignancies. In addition, ABT-199 has shown promise in multiple subtypes of breast cancer. Therefore, we used ABT-199 in combination with PTX to address the hypothesis that APC-induced Bcl-2 increase is responsible for PTX resistance. Combination treatment in three CRISPR-mediated APC knockout TNBC cell lines (MDA-MB-157, MDA-MB-231, and SUM159) caused changes in cell proliferation and apoptosis. Combined, these data suggest restored sensitivity to PTX using ABT-199. Our studies are the first to show that Bcl-2 inhibition can restore PTX-sensitivity in APC mutant breast cancer cells. These studies are critical to advance better treatment regimens in patients with TNBC.
Citation Format: Sara Maloney, Sarah Zabala, Grace Richmond, Jenifer R. Prosperi. Bcl-2 up-regulation mediates taxane resistance downstream of APC loss [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1797.
Abstract 1915: Addressing cancer health disparities among US minority populations with patient-derived xenografts
Authors: Sanderson Brian J. , Lott Paul , Srivastava Anuj ,   PDXNet Consortium, Chuang Jeffrey H. , Carvajal-Carmona Luis G. 
Published: June 2022

Abstract
Despite the tremendous advances in cancer prevention and treatment strategies that have been achieved since the war on cancer plan in the 1970’s, it is clear that not all communities are equally benefiting from such advances and that minority populations nearly always have worse cancer health outcomes. These cancer health disparities are the result of complex interactions between social determinants of health, population-specific cultural behaviors and lifestyles, and unique biological differences that associate with ancestry. Two major limitations to the advancement of precision medicine in minority groups include the lack of: i) race/ethnic appropriate genomic data, which will facilitate identifying priority targets for therapeutic development, and ii) patient-derived models, such as patient-derived xenografts (PDXs) that recapitulate the unique interactions of germline and somatic genetics that exist in minority patients. In this presentation we describe the development of an analytical pipeline to quantify continental genetic ancestry that we have developed for the Cancer Genomics Cloud as part of the PDX Development and Trials Center Research Network (PDXnet). This pipeline leverages a novel reference panel for the program SNPweights, which includes a greater representation of genomic data from Native and Latin American populations than previously published reference panels, and thus provides improved assignment of American continental ancestry. We use this pipeline to characterize the diversity of the PDX models in PDXnet, which represent a manifold increase in models with African and American continental genetic ancestry compared with those available in other public resources. Finally, we present power analyses to demonstrate that additional PDX models derived from patients from minority populations are critically needed to effectively address health equity goals in the US.
Citation Format: Brian J. Sanderson, Paul Lott, Anuj Srivastava, PDXNet Consortium, Jeffrey H. Chuang, Luis G. Carvajal-Carmona. Addressing cancer health disparities among US minority populations with patient-derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1915.
Abstract 1916: Using systems medicine for comprehensive metabolic profiling of tumors: how tumor metabolism shapes prognosis and response to chemotherapy
Authors: Cook Daniel , Cole John A. , Carrigan Patricia , Peterson Joseph R. ,   The SimBiosys Team
Published: June 2022

Abstract
Background: Metabolic disfunction is one of the hallmarks of cancer, and metabolism-based therapies are a key class of chemotherapeutics. Despite this, there has previously been no systematic way to identify metabolism-based targets for therapeutic intervention. This is especially concerning when considering that targeting tumor metabolism has been shown to increase the efficacy of standard chemotherapy in pre-clinical studies. We therefore developed a systems medicine approach to interrogate tumor metabolism systematically, identify the effects of metabolic heterogeneity on overall survival prognosis, and gain insights into new metabolism-associated targets or therapies to complement standard of care for cancer patients. Method: Our systems medicine framework statistically integrates metabolic network modeling with RNA-sequencing data (RNA-seq). This allows us to integrate molecular data about individual tumors (from RNA-seq) with a curated knowledge base of how these molecules interact within a patient’s tumor (using metabolic network models). This results in a mathematical description, or model, of a specific tumor’s metabolism that is able to be interrogated (i.e., it is high-dimensional like RNA-seq data) and able to be simulated (i.e., we can “drug” the model and investigate downstream effects). Results: We applied this systems medicine approach across a range of tumor types, including lung adenocarcinoma, pancreatic adenocarcinoma, metastatic melanoma, clear cell renal cell carcinoma, and salivary cystic adenoid carcinoma. Within each cancer type, we found significant patient-to-patient metabolic heterogeneity. Across cancer types, a consistent pattern that emerged was that the metabolic systems with the most patient-to-patient heterogeneity were also the systems most associated with patient overall survival. This result suggests that metabolic variability is a key driver of tumor response to therapy and overall patient survival. Furthermore, targeting metabolic pathways in a patient-specific manner could enhance chemotherapy in tumors with metabolic profiles associated with poor prognosis. Conclusion: This study shows that the specific metabolic profiles of tumors are key drivers of overall survival. We therefore believe that metabolic tumor characterization and intervention could be a useful strategy to enhance chemotherapy efficacy and overall survival in patients across tumor types.
Citation Format: Daniel Cook, John A. Cole, Patricia Carrigan, Joseph R. Peterson, The SimBiosys Team. Using systems medicine for comprehensive metabolic profiling of tumors: how tumor metabolism shapes prognosis and response to chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1916.
Abstract 1954: Circulating tumor cell kinetics and rare cell morphology monitor disease progression in patients with metastatic colorectal cancer
Authors: Narayan Sachin 
Published: June 2022

Abstract
As the world’s third most common cancer and second leading cause of oncology-related deaths, colorectal cancer (CRC) poses a variety of clinical challenges. CRC is marked by its extensive solid tumor heterogeneity and the difficulties in longitudinally monitoring a patient’s disease status. Being a minimally invasive prognostic tool, the liquid biopsy has immense potential to improve current clinical practice by providing real-time personalized information over the course of treatment. Utilizing the High-Definition Single Cell Assay (HDSCA) workflow, we employed a “no cell left behind approach” to analyze peripheral blood samples from metastatic CRC (mCRC) patients at various timepoints during treatment. We highlight the circulating rare cell population present in the liquid biopsy of mCRC patients, showing the spatial and temporal heterogeneities of CTCs. We observed a significant association between CTC subcategorization based on morphological differences and survival, emphasizing the heterogeneity within the CTC classification. Moreover, considering the time of sample collection in relation to the clinical scenario is critical in determining the prognostic relevance of static cellular enumerations as well as the change in cell populations over time. Through the integration of cellular morphology in a time-based analysis, the liquid biopsy can provide insight into the pathophysiology of mCRC by highlighting the complexity of the disease to monitor treatment response.
Citation Format: Sachin Narayan. Circulating tumor cell kinetics and rare cell morphology monitor disease progression in patients with metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1954.