bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A003: Identification of a potential chemoprevention agent for BRCA1- mutated cancers
Authors: Shanmugam Sujeeth , Hosch Eboni , Konar Dipasri , Ford James M. , Alli Elizabeth 
Published: December 2022

Abstract
BRCA1 mutation carriers are predisposed to developing aggressive breast, ovarian, and other cancers at a relatively early age. Unfortunately, these cancers lack an effective chemoprevention option. We have found that cells containing mutant BRCA1 harbor defective repair of oxidative DNA damage, an early trigger to tumorigenesis. Therefore, we sought to target this defect and discover a novel chemoprevention agent for these cancers. High-throughput screening of a chemical library identified a novel class of small-molecules that enhance repair of oxidative DNA damage, which we termed DNA repair-activating agents. One of these agents, benserazide, increased base-excision repair of oxidative DNA damage utilizing a cell-based DNA repair assay, decreased levels of 8-oxo-g (i.e. most common oxidized lesion in human genome) using flow cytometric analysis, and decreased levels of oxidative DNA damage as determined by alkaline comet assay modified for detection of oxidized DNA lesions. These results were observed in mutant but not wild-type BRCA1 breast cancer cells. Benserazide, but not tamoxifen (current FDA-approved breast cancer chemoprevention agent), also decreased in vitro tumorigenesis of mutant BRCA1 or BRCA1-depleted breast cancer cells according to the soft-agar colony formation assay, and delayed tumor formation in vivo using a xenograft mouse model. Lastly, benserazide led to elevated levels of 8-oxo-dG (a by-product of base-excision repair) in conditioned media of mutant BRCA1 breast cancer cells, and concurrently increased serum levels of 8oxodG and decreased tumor burden in mice. Taken together, benserazide is a DNA-repair activating agent that enhances repair of oxidative DNA damage and decreases tumorigenesis in vitro and in vivo, and thus may serve as a potential chemoprevention agent for BRCA1-mutated cancers.
Further, circulating levels of 8oxoG/8oxodG may function as a predictive biomarker for the efficacy of benserazide, which would prove useful in the clinical evaluation of benserazide for cancer chemoprevention.
Citation Format: Sujeeth Shanmugam, Eboni Hosch, Dipasri Konar, James M. Ford, Elizabeth Alli. Identification of a potential chemoprevention agent for BRCA1- mutated cancers [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A003.
Abstract A011: Effect of IL-23 knockdown on obesity driven CRC in high-fat diet fed Apcmin/+ mice
Authors: Madka Venkateshwar , Chiliveru Srikanth , Zhang Yuting , Stratton Nicole , Bao Anh , Kumar Nandini , Rao Chinthalapally V. 
Published: December 2022

Abstract
Colorectal cancer (CRC) is the 3rd common cancer in the United States with an estimated 151,030 new cases and 52,580 deaths in 2022. Several studies suggest that western-style diet-induced obesity contributes to CRC promotion via systemic inflammatory mediators. Recently, we have reported significant elevation of circulating IL-23 levels in obese human subjects (BMI&gt;30). Also, TCGA gene expression data indicated IL-23A over expression in colonic tumors (CT) that correlated with tumor stage, patient obesity, nodal metastasis, and poor survival rates. Importantly, we have shown that IL-23 knockdown in Apc min/+ mice led to significant suppression of the intestinal tumors strongly supporting our hypothesis that pro-inflammatory cytokine IL-23 could be a possible link between obesity and CRC. Here we explored the contribution of IL-23 in obesity induce CRC in vivo using high-fat diet (HFD) fed Apc min/+ mouse model. For this study, Apc min/+ and IL-23 KO (IL-23A p19-/- mice; MMMRC) were cross-bred to generate Apc min/+ mice with IL-23 normal (IL-23+/+) or KO (IL-23-/-) genotypes. Six-week old Apc min/+ mice (N≥15/gender) were grouped by IL-23 genotypes and fed HFD (60 Kcal) until termination. Mice were euthanized at 20 weeks age, intestines were harvested and evaluated for tumors incidence and multiplicity. In Apc min/+ mice, IL-23 deletion had significant suppressive effect on HFD driven CT and small intestinal tumors (SIT). IL-23-/-
Apc min/+ male mice had 50% less CT (0.81+0.25 vs 1.61±0.27; p&lt;0.05) while female mice had 40% less CT (0.40±0.16 vs 0.94±0.21; p=0.05) compared to the IL-23+/+ Apc min/+ control mice. Similarly, CT incidence was also suppressed by 36% and 48% in male and female IL-23-/- Apc min/+ mice respectively compared to control mice. SIT multiplicity was also inhibited by 48% in male (15.00±1.13 vs 28.54±1.11; p&lt;0.0001) and by 41% in female (14.83±1.35 vs 25.18±1.71; p&lt;0.0005) IL23-/- Apc min/+ compared to control mice. Tumor data was complemented by significant reduction in markers of proliferation, immune evasion, circulating proinflammatory cytokine and chemokines (IL-1, IL- 17, IL-23, IL-10, CCL-3, CCL-2, CCL-5, IFNγ, TNFα, etc.) in IL-23 KO compared to control mice. Our data clearly indicates that IL-23 is a promising target for CRC prevention in high-risk obese individuals and warrants further investigation. (Supported in part by P30CA225520 and Kerley-Cade Endowed Chair).
Citation Format: Venkateshwar Madka, Srikanth Chiliveru, Yuting Zhang, Nicole Stratton, Anh Bao, Nandini Kumar, Chinthalapally V. Rao. Effect of IL-23 knockdown on obesity driven CRC in high-fat diet fed Apcmin/+ mice [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A011.
Abstract A11: Tumor-induced immune disorder: the root cause of cancer cachexia and therapeutic target
Authors: Zhang Lingbing 
Published: December 2022

Abstract
It’s well known that tumor growth induces immune system dysfunction, and cancer immunology has been focused on studying anti-tumor immunity, however the impact of the immune dysfunction on health of the host has not been studied. In this study, we investigate the immune system change and its impact on the host under tumor development from tumor establishment to overall health deterioration and death. We identified significant and multifaceted abnormalities of the immune system which triggers cancer cachexia onset and development. Thus, we propose a new term tumor-induced immune disorder (TID) for these abnormalities. We defined the TID by two parameters: multiple inflammatory cytokines expression; loss of balance and normal behavior of immune cells. Furthermore, we took efforts to explore potential treatments to correct the TID. We have identified a novel immunomodulator, i.e., (R)-ketorolac which can suppress expression of multiple inflammatory cytokines, and consistently, it can fully remove symptoms of cancer cachexia. Thus, we established the causative relationship between TID and cachexia. Interestingly cachectic mice treated by (R)-ketorolac are not only cured of cachexia thus avoid imminent death but also tolerate and respond to full dose anti-tumor chemotherapies. These findings have important clinical implications given majority of late-stage cancer patients with cachexia cannot tolerate chemotherapies and other anti-tumor treatments, thus get stuck in the treatment dilemma. Thus, this study points out a new direction to develop cancer immunotherapies by targeting and correcting the TID, which can not only prevent imminent death by curing cancer cachexia, but also provide opportunities for patients to receive and respond to anti-tumor treatments.
Citation Format: Lingbing Zhang. Tumor-induced immune disorder: the root cause of cancer cachexia and therapeutic target [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A11.
Abstract A13: Siglec-7/9-sialic acid interactions inhibit T cell immune response in prostate cancer
Authors: Wen Ru M , Stark Jessica C. Stark C , García-Marqués Fernando , Zhao Hongjuan , Nolley Rosie , Bertozzi Carolyn R , Pitteri Sharon J , Brooks James D. 
Published: December 2022

Abstract
Immunotherapy has rapidly expanded in the care of patients with cancer with the discovery of immune checkpoints like PD-1 and CTLA-4. However, current immune checkpoint inhibitors are largely ineffective for prostate cancer. Recent studies suggest an alternative immune evasion pathway through the interactions between Sialic acid-binding immunoglobulin-type lectin proteins (Siglec) and their ligands, sialylated glycoprotein. Siglec-7/9-sialic acid interactions are reported to inhibit the immune cell response in several cancer types including leukemia, melanoma, and non-small cell lung cancer. Here, we demonstrated that Siglec-7/9 ligands were expressed in both prostate cancer tumor tissues and cell lines. We promoted T cell-mediated cytotoxicity of cancer cells by disrupting the interactions between Siglec-7/9 and their ligands. We discovered that FXYD5 and CD59 are potential Siglec-7 and Siglec-9 ligands, respectively, with CRISPRi screen. We then found that FXYD5 and CD59 knockout cells had reduced Siglec-7/9 binding capacity and enhanced T cells mediated killing effects on prostate cancer cells. These results provide a rationale for novel immune checkpoints and potential approaches for targeting Siglec-7/FXYD5 and Siglec-9/CD59 immune checkpoints for prostate cancer.
Citation Format: Ru M Wen, Jessica C. Stark C Stark, Fernando García-Marqués, Hongjuan Zhao, Rosie Nolley, Carolyn R Bertozzi, Sharon J Pitteri, James D. Brooks. Siglec-7/9-sialic acid interactions inhibit T cell immune response in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A13.
Abstract A43: Analysis of the effects of therapeutic vaccination with tumor vascular-primed dendritic cells in a mouse model of colon cancer
Authors: Wooster Amanda L , Anderson Trevor S , Piersall Savanna L , Lowe Devin B 
Published: December 2022

Abstract
Colorectal cancer remains the third leading cause of cancer-related death in the United States despite advances in targeted therapies such as monoclonal antibodies and tyrosine kinase inhibitors. Progression of vascularized tumors, including colorectal cancer, is reliant on a functioning blood system that provides cancer cells sufficient nutrients and oxygen. This process is ultimately driven by a concerted effort of pro-angiogenic factors, namely vascular endothelial growth factors (VEGFs) and their cognate receptors – the VEGF receptors (VEGFRs). However, tumor vascularization tends to be an unregulated process that results in the overexpression of angiogenic molecules that promote the development of abnormal and chaotic blood vessels, which ultimately impede the perfusion and efficacy of small molecule drugs or immune-based approaches that incorporate cytotoxic CD8+ T cells. FDA-approved targeted agents have been developed against major angiogenic components such as VEGF and VEGFRs, but, despite short-term clinical benefits, these drugs are generally cytostatic and quickly lead to resistance in most patients. To address such shortcomings, active immunotherapeutic strategies directed at auxiliary targets within the tumor vasculature represent a potentially improved direction toward prolonging cancer protection by instituting the long-term destruction of endothelial cell and pericyte networks that provide tumors critical support. We hypothesize that therapeutic vaccination using autologous alpha-type-1 polarized dendritic cells (DCs) pulsed with endothelial cell-and pericyte-derived peptides will induce a protective and safe cytotoxic T cell response in animals. This clinically-relevant DC approach should ultimately lead to colon cancer regressions in mice and allow our group to identify immunologic-based mechanisms that contribute to lasting immunity against the disease.
Citation Format: Amanda L Wooster, Trevor S Anderson, Savanna L Piersall, Devin B Lowe. Analysis of the effects of therapeutic vaccination with tumor vascular-primed dendritic cells in a mouse model of colon cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A43.
Abstract A44: Therapeutic blocking of VEGF binding to Neuropilin-2 diminishes PD-L1 expression to activate anti-tumor immunity in prostate cancer
Authors: Wang Mengdie , Wisniewski Christi A , Xiong Choua , Chhoy Peter , Goel Hira , Xu Zhiwen , Loda Massimo , Jiang Zhong , Brehm Michael , Mercurio Arthur 
Published: December 2022

Abstract
Prostate cancers (PC) are largely unresponsive to immune checkpoint inhibitors and there is strong evidence that PD-L1 expression itself must be inhibited to activate anti-tumor immunity. Here, we report that neuropilin-2 (NRP2), which functions as a VEGF receptor on tumor cells, is an attractive target to activate anti-tumor immunity in prostate cancer because we demonstrate that VEGF/NRP2 signaling sustains PD-L1 expression. NRP2 depletion increased T cell activation in vitro and immune-mediated tumor elimination in vivo using a humanized mouse model. Inhibition of the binding of VEGF to NRP2 using a mouse specific anti-NRP2 mAb in a syngeneic model of prostate cancer that is resistant to checkpoint inhibition resulted in significant necrosis and tumor regression compared to control IgG. This therapy also decreased tumor PD-L1 expression and increased immune cell infiltration. We also observed that the NRP2 and VEGF-A genes are amplified in metastatic castration resistant and neuroendocrine prostate cancer (NEPC) and that NRP2high PD-L1high population in metastatic tumors had a significantly lower AR and higher NEPC scores than other populations. Therapeutic inhibition of VEGF binding to human NRP2 with a high affinity humanized mAb, which is suitable for clinical use, in organoids derived from NEPC patients also diminished PD-L1 expression and caused a significant increase in immune-mediated tumor cell killing consistent with the animal studies. These findings provide justification for the initiation of clinical trials using this novel function-blocking NRP2 mAb in prostate cancer, especially for patients with aggressive primary and metastatic cancers, where blocking NRP2-VEGF signaling shows potential in mitigating the morbidity and mortality associated with these cancers.
Citation Format: Mengdie Wang, Christi A Wisniewski, Choua Xiong, Peter Chhoy, Hira Goel, Zhiwen Xu, Massimo Loda, Zhong Jiang, Michael Brehm, Arthur Mercurio. Therapeutic blocking of VEGF binding to Neuropilin-2 diminishes PD-L1 expression to activate anti-tumor immunity in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A44.
Abstract B16: Verteporfin synergizes antitumoral effect of anti-PD-1 in mice cholangiocarcinoma models
Authors: Lee Jihye , Bian Jing , Wang Xin , Cam Meggie , Xie Changqing 
Published: December 2022

Abstract
Cholangiocarcinoma (CCA) is a heterogenous cancer originated from the biliary epithelium in the biliary tree system. The incidence of CCA has gradually increased across nation/worldwide and overall prognosis is poor with only 10% of 5-year survival rate. Recently developed immune checkpoint inhibitor-based immunotherapy has less benefit on CCA patients. We investigated antitumoral effect of verteporfin in combination of anti-PD-1 in YAP/Akt and Notch/Akt hydrodynamic injected mouse model. Our result showed reduced liver weight in verteporfin treated mice group compared to vehicle treated mice group, both in anti-PD-1 and isotype control groups. Single cell RNA sequence showed there is reduced expression of stemness related cells from data observed in verteporfin treated group. B cell, CD8+ T cell, TAM M1 populations were increased in verteporfin treatment group and similar pattern was observed in anti-PD1 treated verteporfin group. In conclusion, verteporfin reduced tumorigenesis in CCA via control of cancer stemness in CCA animal models with anti-PD-1 immunotherapy.
Citation Format: Jihye Lee, Jing Bian, Xin Wang, Meggie Cam, Changqing Xie. Verteporfin synergizes antitumoral effect of anti-PD-1 in mice cholangiocarcinoma models [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B16.
Abstract B21: Elucidating the molecular mechanism of Myeloid Derived Suppressor Cell (MDSC) divergence in the tumor microenvironment (TME) of pancreatic cancer
Authors: Dahal Ankit , Hong Yeonsun , Kim Minsoo 
Published: December 2022

Abstract
Pancreatic cancer is one of the deadliest malignancies with an average five-year survival of mere 2-9%. Emerging evidence suggests that the presence of polymorphonuclear (PMN) myeloid derived suppressor cells (MDSCs) with neutrophil-like phenotypes and morphologies play a major role in adverse clinical outcomes due in part to their contribution in establishing immunosuppressive tumor microenvironment (TME). Despite recent advances in our understanding of MDSC phenotypes and characteristics in the TME, the underlying molecular mechanisms by which classical neutrophils differentiate into MDSC within the TME remails largely unknown. To investigate the microenvironmental cues that regulate PMN-MDSC differentiation at the tumor site, we established several in vitro co-culture systems using pancreatic cancer cells and 3D spheroid conditions. With live cell migration microscopy, we first showed that neutrophils actively swarmed into the pancreatic cancer spheroids and stayed active for an extended time period in the tumor. We further found that cancer cell culture supernatant significantly extended neutrophil survival and successfully differentiated neutrophils into MDSCs that exhibited decreased type 1 Interferon levels, increased arginase and ROS expression, and had the ability to suppress CD8 cytotoxicity. Additionally, when compared to other forms of neutrophil activators such as LPS and TNF, only tumor conditioned media enhanced neutrophil survival and MDSC differentiation. Our data suggest the presence of novel molecular processes that support MDSC differentiation at the tumor site. To identify the molecular regulators of MDSC formation, we have developed a CRISPR-Cas9 pooled library screen using the immortalized granulocyte-monocyte progenitor cell line, HoxB8. This study will further our understanding of MDSC differentiation and may help to develop therapeutics to limit MDSC development in the TME of pancreatic and other solid cancers.
Citation Format: Ankit Dahal, Yeonsun Hong, Minsoo Kim. Elucidating the molecular mechanism of Myeloid Derived Suppressor Cell (MDSC) divergence in the tumor microenvironment (TME) of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B21.
Abstract B24: Development of targeted T-cell cancer immunotherapies based on a novel enantiomeric cationic lipid that promotes antigen cross-presentation and upregulation of type I interferons
Authors: Gandhapudi Siva K , Sundarapandiyan Karuna , Ward Martin , Fatima Afsheen , Dorrani Mania , Banoub Mary , Dervan Joe , Wood Lauren , Conn Greg , Woodward Jerold G 
Published: December 2022

Abstract
The enantiomeric cationic lipid R-DOTAP nanoparticle platform (Versamune®) was reported (Gandhapudi et. al. 2019, J. Immunol.) to promote cross presentation of multi-epitope human papilloma virus (HPV) antigens and upregulation of Type I interferons, leading to induction of high levels of antigen-specific cytolytic polyfuctional CD8+ T-cells in vivo and complete regression of TC-1 tumors in preclinical models. In two ongoing Phase 2 human clinical trials (ASCO 2022), the early data in a group of the first 60 patients receiving PDS0101 (Versamune® plus HPV16 peptide mix) and who had previously failed standard of care suggests translation of the established mechanism of action into humans resulting in the induction of tumor-specific, clinically effective immune responses. In refractory and difficult-to-treat HPV-related cancers, improved patient survival and tumor shrinkage has been demonstrated. In this study we demonstrate expansion of the Versamune® platform to the treatment of non-viral associated cancers. We have developed Versamune® based drug formulations containing novel multi-epitope peptide sequences of the TARP (T-Cell receptor gamma chain Alternate Reading frame Protein) antigen expressed in 100% of adult and pediatric AML (acute myelogenous leukemia), over 90% of prostate cancers and over 50% of breast cancers. We have also developed Versamune® based drug formulations containing modified sequences of novel Mucin 1 oncoprotein (MUC1) agonist peptide antigens that are over expressed in multiple solid tumors. Using humanized HLA-A2 transgenic mice, we show that the Versamune® platform similarly promotes cross presentation of the non-viral antigens resulting in equally high levels of antigen-specific CD8+ T-cells as observed with HPV. These data demonstrate superior immunogenicity in breadth and potency of vaccine-induced immune responses, supporting progression of the targeted T-cell immunotherapies into human clinical trials.
Citation Format: Siva K Gandhapudi, Karuna Sundarapandiyan, Martin Ward, Afsheen Fatima, Mania Dorrani, Mary Banoub, Joe Dervan, Lauren Wood, Greg Conn, Jerold G Woodward. Development of targeted T-cell cancer immunotherapies based on a novel enantiomeric cationic lipid that promotes antigen cross-presentation and upregulation of type I interferons [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B24.