bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1242: Foxa1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma
Authors: Gillis Katherine , Orellana Walter , Wilson Emily , Fort Gabriela , Dadzie Headtlove Essel , Parnell Timothy , Zhang Xiaoyang , Snyder Eric 
Published: March 2024

Abstract
The ability of cancer cells to alter their identity is essential for tumor survival and progression. Loss of the pulmonary lineage specifier NKX2-1 within KRAS-driven lung adenocarcinoma (LUAD) enhances tumor progression and results in a pulmonary-to-gastric lineage switch that is dependent upon the activity of pioneer factors FoxA1 and FoxA2; however, the underlying mechanism remains largely unknown. Here, we perform transcriptional and epigenetic assays to show that FoxA1/2 reprogram the chromatin landscape of NKX2-1-negative LUAD to facilitate a gastric differentiation program. Using sequential recombination models, we find that FoxA1/2 are required for demethylation of gastric-defining genes after Nkx2-1 deletion. FoxA1 colocalizes with TET3, an enzyme that mediates DNA demethylation, in NKX2-1-negative tumors. Deletion of Foxa1/2 results in loss of TET3 occupancy at key gastric marker genes, indicating that FoxA1/2 recruit TET3 to lineage-specific sites. H3K27ac ChIP-seq and HiChIP show that FoxA1/2 also control the activity of enhancers and promoters as well as their 3D interactions at gastric target genes following NKX2-1 loss. Furthermore, oncogenic KRAS is required for the FoxA1/2-dependent epigenetic reprogramming in NKX2-1-negative LUAD. This work demonstrates the role of FoxA1/2 in rewiring the methylation and histone landscape and cis-regulatory dynamics of NKX2-1-negative LUAD to drive cancer cell lineage switching.
Citation Format: Katherine Gillis, Walter Orellana, Emily Wilson, Gabriela Fort, Headtlove Essel Dadzie, Timothy Parnell, Xiaoyang Zhang, Eric Snyder. Foxa1/2-dependent epigenomic reprogramming drives lineage switching in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1242.
Abstract 1297: Patient engagement: Improving the at home care for cancer patients in treatment
Authors: Blomquist Robert 
Published: March 2024

Abstract
CareBOX Program is an Austin-based non-profit founded in 2014 to address a serious gap in cancer care for patients in the Central Texas area. It provides essential nutritional supplements and supplies to help prevent malnutrition, infections, and injuries from falls as patients continue at-home recovery during treatment and following surgery. About 80 percent of the supplies CareBOX Program provides are not covered by insurance. Many patients could not afford to purchase these items on their own. Volunteers deliver the CareBOXes to the clients’ homes. CareBOX Program has always been an inclusive organization. We operate on the basis that all cancer patients in Central Texas in need of our services will receive them as long as we have the funding to do so. Our youngest patient has been 3 months old and our oldest patient has been 93 years old. Currently we are serving more women (61%) than men (39%). Approximately 67% of patient households report annual income of less than $35,000. To date, CareBOX program volunteers have delivered more than 3,800 CareBOXes
Citation Format: Robert Blomquist. Patient engagement: Improving the at home care for cancer patients in treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1297.
Abstract 1314: SCHEQ Foundation (STEMM & Cancer Health Equity): Increasing STEMM diversity and outcomes for patients navigating cancer
Authors: Manley Eugene 
Published: March 2024

Abstract
Health inequities are estimated to cost $320B annually, while racial and ethnic disparities are estimated to cost $42B in productivity. There are systemic issues at play that contribute to these disparities. These include lack of diversity in Science, Technology, Engineering, Mathematics, and Medicine (STEMM) fields; bias in healthcare delivery and access; underinsurance in patients from low-income backgrounds; and lack of training that advances those from historically underrepresented groups. The SCHEQ Foundation (STEMM & Cancer Health Equity) is a black-founded nonprofit organization that seeks to increase STEMM workforce diversity and improve outcomes for underrepresented, underserved, marginalized, and invisible populations across the cancer care continuum. Herein we describe the formation of SCHEQ Foundation and our core domains that we seek to make change. We seek to increase STEMM access and exposure, increase STEMM workforce diversity, and improve outcomes for underserved populations navigating the cancer care continuum. This will be accomplished in part by 1) engaging professional in STEMM from their lived background and experiences, 2) developing training, mentoring, and professional developing programs across the academic continuum to increase success of minoritized scholars; and 3) providing information and resources in culturally responsive manners to help underserved patient navigate cancer and advocate for the standard of care they deserve. We will change how we convey content, information, and resources to underserved populations by utilizing a combination of multimedia, infographics, webinars, info sheets, and community engagement. The goal is to increase survival for groups that historically have the greatest cancer disparities.
Citation Format: Eugene Manley. SCHEQ Foundation (STEMM & Cancer Health Equity): Increasing STEMM diversity and outcomes for patients navigating cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1314.
Abstract 1339: Pre-clinical development of IAMA-004, a tri-specific antibody targeting innate immune receptors and tumor targets
Authors: Liu Liming , Han Zhen , Fan Yang , Pan Qi 
Published: March 2024

Abstract
Immune check-point inhibitor (ICI) such as anti-PD1 or anti-PDL1 antibody, which enhances the adaptive immunity via re-energizing exhausted T cells, has become the foundational therapy for many cancers. However, due to variety of other immunosuppressive tumor microenvironments, it is efficacious only in 15-30% of the patients. It is well known both the innate immunity and the adaptive immunity are required for full control of cancer growth. Thus, therapeutics harnessing the innate immunity will be complementary to ICI and improve the cancer response rate when used in combination. Currently therapeutics harnessing the innate immunity mainly involve bispecific antibodies with one arm targeting tumor antigen and one arm connecting to innate effector cells such as NK cells or macrophages, represented by CD30-CD16a bispecific and Her2-CD47 bispecific respectively. Considering that cancer patient’s immune status are heterogenous, varying from T cell exhaustion, macrophage disfunction (M2 bias), Treg cell presence to NK cell deficiencies, it would be advantageous to combine several innate immunity enhancers into one therapeutic molecule. Here we describe a long-acting tri-specific antibody termed IAMA-004 that targets Her2 as the primary target and CD47 and CD16a as effector cell engagers. CD47 is also a co-target on some tumor cells (CD47-Her2 double positive tumors). We have characterized this molecule both in vitro and in vivo. The in vitro experiments tested the molecule’s ability to kill Her2 high, Her2 low and Her2 negative tumor cell lines including BT-474, SK-OV-3, NCI-N87, OE19, HCC1954, MDA-MB-231, MDA-MB-468, in human PBMC ADCC assays with DS-8201 and Trastuzmab as the comparator molecules. In all of these ADCC experiments, IAMA-004 showed superior tumor cell killing activities to those mediated by DS-8201 or Trastuzmab. When combined with IAMA-005 (a Fc-IL2-IFN-α fusion cytokine), the tumor cell killing activities were dramatically increased. In addition, IAMA-004 was also tested in patient-derived Ex-Vivo fluids (one malignant pleural effusion and one malignant asities) and demonstrated tumor cell killing efficacies; and the killing activity could be attributed to the specific arms of the molecule. These results suggest that it is feasible to combine more than one innate engager in one molecule to carry out specific functions in the heterogeneous immune status for the treatment of advanced cancer patients.
Citation Format: Liming Liu, Zhen Han, Yang Fan, Qi Pan. Pre-clinical development of IAMA-004, a tri-specific antibody targeting innate immune receptors and tumor targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1339.
Abstract 1354: Anti-CTLA-4 generates memory T-cells with greater expansion and functionality than anti-PD-1
Authors: Mok Stephen , Liu Huey , Anang Nana-Ama A.S. , Mancuso James J. , Çobanoğlu Didem Ağaç , Allison James P. 
Published: March 2024

Abstract
Distinct effects on T-cell differentiation arise from immune checkpoint inhibition targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1). However, the effect of these immunotherapies on the immunological memory response remains unclear. Our investigation into the effects of anti-CTLA-4 and anti-PD-1 on memory T-cell formation in mice revealed that anti-CTLA-4 generates a more effective memory antitumor response than anti-PD-1. Memory T-cells arising after anti-CTLA-4 treatment exhibit greater expansion, cytokine production, and antitumor activity than those from anti-PD-1. Notably, anti-CTLA-4 preserves more TCF-1+ T-cells during priming, while anti-PD-1 leads to more TOX+ T-cells. Experiments using conditional TCF-1- or TOX-knockout mice highlight TCF-1 is essential for memory response generated by anti-CTLA-4, whereas TOX deletion alone in T cells has no effect on response to anti-PD-1. Deepening our understanding of how checkpoint inhibition affects memory response is crucial for advancing our understanding of the enduring impacts of these immunotherapies on the immune system.
Citation Format: Stephen Mok, Huey Liu, Nana-Ama A.S. Anang, James J. Mancuso, Didem Ağaç Çobanoğlu, James P. Allison. Anti-CTLA-4 generates memory T-cells with greater expansion and functionality than anti-PD-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1354.
Abstract 1364: Characterization of CHS-1000, an Fc-modified anti-ILT4 monoclonal antibody for reprogramming suppressive myeloid cells in solid tumors
Authors: Rajasekaran Narendiran , Wang Xiaoguang , Klakamp Scott , Ravindranathan Sruthi , Tatarewicz Suzanna , Du Julia , Nguyen Brian , Widmann Kate , Hawkins Nessa , Chin Daniel J. , LaVallee Theresa , Kapoor Varun 
Published: March 2024

Abstract
Tumor resident immunosuppressive myeloid cells play a significant role in inducing resistance to cancer immunotherapy and are associated with poor prognosis in several solid tumors. The leukocyte immunoglobulin-like receptor B2 (LILRB2), also known as ILT4, is primarily expressed on myeloid cells and is a negative regulator of myeloid cell activation. ILT4 and its primary ligands (HLA-G, HLA-A) are widely expressed in various solid tumors and are associated with disease progression, tumor metastasis and poor clinical outcome. Abrogating inhibitory signals mediated through ILT4 and its ligands is a promising strategy to reprogram suppressive myeloid cells and enhance efficacy of immune checkpoint therapies. Here we report IND-enabling preclinical characterization of CHS-1000, a novel recombinant humanized Fc-modified IgG1 antibody with attenuated Fc-gamma receptor (FcγR) binding, that specifically targets immunoglobulin-like transcript 4 (ILT4). CHS-1000 selectively binds to human ILT4 with high affinity and potently blocks ILT4 interactions with its primary ligands (HLA-A, HLA-G). Functionally, CHS-1000 promotes re-polarization of suppressive myeloid cells to a pro-inflammatory phenotype and enhances activation of dendritic cells and T cells. Combinations of CHS-1000 with PD-1 inhibitors or other immunotherapy agents hold particular promise for enhanced anti-tumor activity. These preclinical characterization data support clinical development of CHS-1000 in combination with toripalimab (a commercial stage anti-PD-1 antibody) as an immunotherapy treatment for patients with solid tumors.
Citation Format: Narendiran Rajasekaran, Xiaoguang Wang, Scott Klakamp, Sruthi Ravindranathan, Suzanna Tatarewicz, Julia Du, Brian Nguyen, Kate Widmann, Nessa Hawkins, Daniel J. Chin, Theresa LaVallee, Varun Kapoor. Characterization of CHS-1000, an Fc-modified anti-ILT4 monoclonal antibody for reprogramming suppressive myeloid cells in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1364.
Abstract 138: UCHL5 and PAX3-FOXO1 resolve replication stress in rhabdomyosarcoma
Authors: Sabnis Amit J. , Sahu Pushpendra K. , Pan Yue 
Published: March 2024

Abstract
PAX3-FOXO1 positive rhabdomyosarcoma (RMS) is an aggressive pediatric sarcoma with a terrible prognosis. The resultant fusion acts as a chimeric transcription factor, in part remodeling chromatin to inhibit terminal differentiation and maintain cancer cell proliferation. As this oncoprotein is not directly druggable, we have used genetic screens to identify dependencies downstream of PAX3-FOXO1 to improve our understanding of pathogenesis and develop new therapeutic targets. We performed pooled CRISPRi screening in an isogenic system of a patient-derived RMS cell line with or without knockdown of PAX3-FOXO1. Loss of the ubiquitin hydroxylase UCHL5 led to selective depletion of PAX3-FOXO1 positive Rh30 cells compared to PAX3-FOXO1 knockdown cells, suggesting that the fusion creates UCHL5 dependence. We validated this finding in competition growth assays in additional fusion positive (FP) and fusion negative (FN) RMS cell lines, and observed UCHL5 dependency only in the former. By contrast, UCHL5 was dispensable for cell growth and survival in FN RMS cell lines. These data were recapitulated in the large DepMap dataset, which also identified the top genetic co-dependencies of UCHL5 as INO80-complex (INO80c) members. We therefore investigated whether the fusion selective effects of UCHL5 were mediated by the INO80c, of which UCHL5 is an N-terminal member. We observed that knockdown of another N-terminal component of INO80c, NFRKB, phenocopies the fusion-selective effects of UCHL5 loss. Conversely, the catalytic ATPase INO80 was pan-essential, suggesting that only N-terminal subunits of INO80c regulate PAX3-FOXO1 specific functions. INO80c plays an essential role in mitigating DNA replication stress. Indeed, loss of UCHL5 led to DNA damage as measured by γH2AX and slowing of replication forks as measured by fiber assays in FP, but not FN RMS. Unexpectedly, acute degradation of PAX3-FOXO1 also slowed DNA replication fork speed, suggesting a genetic model in which UCHL5 and PAX3-FOXO1 cooperate to resolve replication stress in FP RMS. Finally, in vivo experiments using cell line xenografts confirms that loss of UCHL5 slows the growth of FP RMS, but not FN RMS. These findings suggest that loss of UCHL5 induces replication stress in a fusion-specific manner, and offers both an opportunity to study the mechanisms by which the PAX3-FOXO1 oncoprotein mitigates replication stress, and to develop UCHL5 inhibitors as precision therapies for FP RMS patients.
Citation Format: Amit J. Sabnis, Pushpendra K. Sahu, Yue Pan. UCHL5 and PAX3-FOXO1 resolve replication stress in rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 138.
Abstract 1414: HBM9014, a first-in-class fully human anti-LIFR antibody with excellent preclinical efficacy and safety profile
Authors: Zeng Jue , Zhang Dongxu , Liu Louis , Zhang Lingbing 
Published: March 2024

Abstract
Background: Leukemia inhibitory factor (LIF) and cardiotrophin like cytokine factor 1 (CLCF1) are multi-functional cytokines from IL-6 family. They are reported to be highly expressed in a variety of human cancers such as pancreatic carcinoma, cholangiocarcinoma, NSCLC, GBM, head and neck cancer etc. Their expression is associated with poor prognosis and survival. LIFR is the key component of LIF/CLCF1 receptors. Antibody targeting LIFR has the advantage to block both LIF and CLCF1 pathways thus inhibiting tumor growth more effectively than products to block single cytokines.
Methods: Fully human Anti-LIFR antibodies were generated from H2L2 Harbour Mice® transgenic platform. In vitro function of the antibodies was tested for their abilities to block LIF/CLCF1 induced downstream signaling pathway and tumor spheroid proliferation. In vivo efficacy was tested in multiple tumor models as monotherapy and in combination with cisplatin. DRF toxicokinetics was evaluated on NHP with a 4-week repeat-dose toxicity study.
Results: HBM9014, a fully human anti-LIFR antibody generated by H2L2 Harbour Mice®, specifically binds LIFR thus blocks the interaction between LIF/CLCF1 and their respective receptors, inhibits downstream STAT3 phosphorylation, and reduces exogenous and endogenous LIF induced tumor spheroid proliferation in vitro. Furthermore, HBM9014 shows potent anti-tumor activity in multiple tumor models in vivo. In a GLP NHP 4-week repeat-dose toxicity study, HBM9014 is well tolerated up to 150 mg/kg with no discernable drug-related toxicity.
Conclusions: HBM9014 specifically binds to the key component of LIF and CLCF1 receptor, LIFR, thus blocks both LIF and CLCF1 signaling pathways. HBM9014 shows significant cell proliferation inhibition alone or in combo with small molecule inhibitors in 3D culture of multiple cancer cell lines. It also shows significant in vivo antitumor efficacy as monotherapy, and enhanced efficacy in combination with Cisplatin in multiple mouse models. Importantly, despite the benefits of double blocking, HMB9014 has an excellent safety profile. Taken together, HMB9014 is a promising drug candidate for advanced cancer with favorable efficacy and safety profiles that warrant clinical validation.
Citation Format: Jue Zeng, Dongxu Zhang, Louis Liu, Lingbing Zhang. HBM9014, a first-in-class fully human anti-LIFR antibody with excellent preclinical efficacy and safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1414.
Abstract 1432: Development of transparent transgenic zebrafish model to study CNS microglia and NF-kB activity in glioblastoma
Authors: Rajpurohit Surendra K. , Nasanally Sai , Hotwani Simran , Gossman Taitum , Bhatt Keshu , Van Derhei Aiden , Pasi Rohan , Manhiani Devan-Anmol , Kimmerling Kirk , Lokeshwar Balakrishna L. 
Published: March 2024

Abstract
Microglia are resident macrophages of the central nervous system (CNS) and have crucial roles in normal brain homeostasis, function, and immune response. Microglia play key roles in the healthy brain, ranging from phagocytosis of dying neurons and CNS debris to modulating adaptability. The role of microglia has been well documented but their specific contributions to the development and progression of cancers, such as glioblastoma, have recently garnered wide attention. The zebrafish have proven novel tool for modeling innate immune responses. A macrophage-specific marker mpeg1 and its promoter are used in mpeg1-driven transgenes. mpeg1-driven transgenes mpeg1:mCherryFP are expressed in macrophage-lineage cells that do not express neutrophil-marking transgenes. These zebrafish transgenes contribute to the fields of inflammation, infection, and leukocyte biology. We have recently developed a novel transparent transgenic homozygous strain Tg(6xNF-kB:EGFP); Casper(roy−/−, nacre−/−) of zebrafish to the in-vivo study of NF-kB activity under normal and inflammation stage at the cellular, organ-specific and whole organism level. To perform an in-vivo study of microglial function, we are developing Casper;mpeg1:mCherryFP microglia specific strain and integrating with newly developed Tg(6xNF-kB:EGFP); Casper(roy−/−, nacre−/−) strain through crossbreeding of Casper and transgenic zebrafish. We have generated F1 generation of newly developed strains of Casper;mpeg1:mCherryFP and Tg(6xNF-kB:EGFP);Casper. The presence of fluorescence mCherry and GFP, in crossbred progeny was identified through the screening of larvae at 72 HPF stage. The expression of these fluorescent proteins determines the presence of the reporter genes. F1 generation confirmed heterozygous and allowed them to grow into adults to breed transparent transgenic strain to get F2 generation. This process will be continued to F2, F3, F4, and F5 generation until achieving homozygous progeny. This model allows for in-vivo examination of microglia functional morphology by using fluorescent and confocal microscopy. This novel transgenic model will be applied to identify novel anti-inflammatory drug inhibitors in NF-kB pathophysiology for glioblastoma and cardio-oncology experimental therapeutics.
Citation Format: Surendra K. Rajpurohit, Sai Nasanally, Simran Hotwani, Taitum Gossman, Keshu Bhatt, Aiden Van Derhei, Rohan Pasi, Devan-Anmol Manhiani, Kirk Kimmerling, Balakrishna L. Lokeshwar. Development of transparent transgenic zebrafish model to study CNS microglia and NF-kB activity in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1432.